pathophysiology

I. Type 1 diabetes (b-cell destruction, usually leading to absolute insulin deficiency)

A. Immune medicated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin
deficiency to a predominantly secretory defect with insulin resistance)
III. Other specific types
A. Genetic defects of b-cell function
. !hromosome "#, $%&-'a (()*+)
". !hromosome ,, gluco-inase (()*+")
.. !hromosome ", $%&-a (()*+.)
'. !hromosome ., insulin promoter factor-(I/&-0 ()*+')
1. !hromosome ,, $%&-b (()*+1)
2. !hromosome ", %euro* (()*+2)
,. (itochondrial *%A
3. )thers
B. Genetic defects in insulin action
. 4ipodystrophic syndromes
". 5ype A insulin resistance
.. 4eprechaunism
'. 6abson-(endenhall syndrome
1. )thers
!. *iseases of the e7ocrine pancreas
. /ancreatitis
". 5rauma8pancreatectomy
.. %eoplasia
pathophysiology
'. !ystic fibrosis
1. $emochromatosis
2. &ibrocalculous pancreatopathy
*. 9ndocrinopathies
. !ushing:s syndrome
". Acromegaly
.. Glucagonoma
'. /heochromocytoma
1. )thers
9. *rug- or chemical-induced
. Glucocorticoids
". Atypical Antipsychotics
.. /entamidine
'. *ia;o7ide
1. a-Interferon
2. )thers
.&. Infections
. !ongenital rubella
G. <ncommon forms of immune-mediated diabetes
. =>tiff-man? syndrome
". Anti-insulin receptor antibodies
.. )thers
$. )ther genetic syndromes sometimes associated with diabetes
. *own:s syndrome
". 5urner:s syndrome
.. @olfram:s syndrome
'. 4aurence-(oon-Biedl syndrome
pathophysiology
1. /rader-@illi syndrome
2. )thers
IV. Gestational diabetes mellitus (GDM AA
V. Type ! Diabetes mellitus
"

AAs additional subtypes are discovered it is anticipated that they will be reclassified
within their own specific category.
AAIncludes the former categories of gestational impaired glucose tolerance and gestational
diabetes.
I. Type 1 (betaBcell destruction, usually leading to absolute insulin deficiency)
1
". "utoimmune Diabetes Mellitus
#ynonyms$ InsulinBdependent diabetes (I**(), 5ype diabetes, or CuvenileB onset
diabetes,
It results from autoimmune mediated destruction of the beta cells of the pancreas.
Variations
5he rate of destruction is Duite variable, being rapid in some individuals and slow in
others.
o The rapidly pro%ressi&e form$ commonly observed in children, but also may
occur in adults.
o The slo'ly pro%ressi&e formE generally occurs in adults and is sometimes
referred to as latent autoimmune diabetes in adults (4A*A).
pathophysiology
>ome patients, particularly children and adolescents, may present with -etoacidosis
as the first manifestation of the disease.
)thers have modest fasting hyperglycaemia that can rapidly change to severe
hyperglycaemia and8or -etoacidosis in the presence of infection or other stress.
>till others, particularly adults, may retain residual betaBcell function, sufficient to
prevent -etoacidosis, for many years. Individuals with this form of 5ype diabetes
often become dependent on insulin for survival eventually and are at ris- for
-etoacidosis. At this stage of the disease, thereis little or no insulin secretion as
manifested by low or undetectable levels of plasma !Bpeptide.
Mar(ers of immune destruction$
Islet cell autoantibodies, and8or autoantibodies to insulin, and Autoantibodies to
glutamic acid decarbo7ylase (GA*) are present in 31BF# G of individuals with 5ype
diabetes mellitus when fasting diabetic hyperglycaemia is initially detected. 5he
pea- incidence of this form of 5ype diabetes occurs in childhood and adolescence,
but the onset may occur at any age, ranging from childhood to the ninth decade of life.
5here is a genetic predisposition to autoimmune destruction of beta cells, and it is also
related to environmental factors that are still poorly defined. Although patients are
usually not obese when they present with this type of diabetes, the presence of obesity
is not incompatible with the diagnosis. 5hese patients may also have other
autoimmune disorders such as Graves: disease, $ashimoto:s thyroiditis, and
Addison:s disease.
). Idiopathic
pathophysiology
5here are some forms of 5ype diabetes which have no -nown aetiology. >ome of these
patients have permanent insulinopenia and are prone to -etoacidosis, but have no evidence of
autoimmunity. 5his form of diabetes is more common among individuals of African and
Asian origin. In another form found in Africans an absolute reDuirement for insulin
replacement therapy in affected patients may come and go, and patients periodically develop
-etoacidosis.
II. Type 2 (predominantly insulin resistance 'ith relati&e insulin deficiency or
predominantly an insulin secretory defect 'ith*'ithout insulin resistance
1
#ynonyms$ %onB insulinBdependent diabetes (%I**(), or adultBonset diabetes.
It is a term used for individuals who have relative (rather than absolute) insulin deficiency.
/eople with this type of diabetes freDuently are resistant to the action of insulin. At least
initially, and often throughout their lifetime, these individuals do not need insulin treatment to
survive.
&eaturesE
5his form of diabetes is freDuently undiagnosed for many years because the
hyperglycaemia is often not severe enough to provo-e noticeable symptoms of
diabetes.
%evertheless, such patients are at increased ris- of developing macrovascular and
micro vascular complications.
5here are probably several different mechanisms which result in this form of diabetes,
and it is li-ely that the number of people in this category will decrease in the future as
identification of specific pathogenic processes and genetic defects permits better
differentiation and a more definitive classification with movement into =)ther types?.
pathophysiology
Although the specific aetiologies of this form of diabetes are not -nown, by definition
autoimmune destruction of the pancreas does not occur.
5he maCority of patients with this form of diabetes are obese, and obesity itself causes
or aggravates insulin resistance. (any of those who are not obese by traditional
weight criteria may have an increased percentage of body fat distributed
predominantly in the abdominal region.
III. Other #pecific Types
1
". Genetic defects of betacell function
(any genetic defects have been identified in association with diabetes mellitus such as
(onogenic defects in betaBcell function, freDuently characteri;ed by onset of mild
hyperglycaemia at an early age (generally before age "1 years). 5hey are usually
inherited in an autosomal dominant pattern. /atients with these forms of diabetes,
formerly referred to as maturityB onset diabetes of the young (()*+), have impaired
insulin secretion with minimal or no defect in insulin action.
Abnormalities at three genetic loci on different chromosomes have now been
characteri;ed.
o 5he most common form is associated with mutations on chromosome " in a
hepatic nuclear transcription factor referred to as $%&H.
o A second form is associated with mutations in the gluco-inase gene on
chromosome ,p. Gluco-inase converts glucose to glucoseB2Bphosphate, the
metabolism of which in turn stimulates insulin secretion by the beta cell. 5hus,
gluco-inase serves as the =glucose sensor? for the beta cell. Because of defects
pathophysiology
in the gluco-inase gene, increased levels of glucose are necessary to elicit
normal levels of insulin secretion.
o A third form is associated with a mutation in the $%&'H gene on chromosome
"#D. $%&'H is a transcription factor which is involved in the regulation of the
e7pression of $%&H.
o A fourth variant has recently been ascribed to mutations in another
transcription factor gene, I/&B, which in its homo;ygous form leads to total
pancreatic agenesis.
>pecific genetic defects in other individuals who have a similar clinical presentation are
currently being defined.
/oint mutations in mitochondrial *%A have been found to be associated with
diabetes mellitus and deafness. 5he most common mutation occurs at position ."'. in
the t6%A leucine gene, leading to an A to G substitution. An identical lesion occurs in
the (94A> syndrome ((itochondrial myopathy, 9ncephalopathy, 4actic Acidosis,
and >tro-eBli-e syndrome)0 however, diabetes is not part of this syndrome, suggesting
for un-nown reasons different phenotypic e7pressions of this genetic lesion.
Genetic abnormalities that result in the inability to convert pro-insulin to insulin have
been identified in a few families. >uch traits are usually inherited in an autosomal
dominant pattern and the resultant carbohydrate intolerance is mild.
(utant insulin molecules with impaired receptor binding have been identified in a
few families. 5hese are also associated with autosomal inheritance and either normal
or only mildly impaired carbohydrate metabolism
). Genetic defects in insulin action
pathophysiology
5here are some unusual causes of diabetes which result from genetically determined
abnormalities of insulin action.
5he metabolic abnormalities associated with mutations of the insulin receptor may
range from hyperinsulinaemia and modest hyperglycaemia to symptomatic diabetes
.>ome individuals with these mutations has acanthosis nigricans.
@omen may have virili;ation and have enlarged, cystic ovaries. In the past, this
syndrome was termed 5ype A insulin resistance.
4eprechaunism and 6absonB(endenhall syndrome are two paediatric syndromes that
have mutations in the insulin receptor gene with subseDuent alterations in insulin
receptor function and e7treme insulin resistance .5he former has characteristic facial
features while the latter is associated with abnormalities of teeth and nails and pineal
gland hyperplasia.
+. Diseases of the e,ocrine pancreas
Any process that diffusely inCures the pancreas can cause diabetes.
AcDuired processes include pancreatitis, trauma, infection, pancreatic carcinoma, and
pancreatectomy.
@ith the e7ception of cancer, damage to the pancreas must be e7tensive for diabetes
to occur. $owever, adenocarcinomas that involve only a small portion of the pancreas
have been associated with diabetes. 5his implies a mechanism other than simple
reduction in betaBcell mass.
If e7tensive enough, cystic fibrosis and haemochromatosis will also damage beta cells
and impair insulin secretion.
pathophysiology
&ibrocalculous pancreatopathy may be accompanied by abdominal pain radiating to
the bac- and pancreatic calcification on IBray and ductal dilatation. /ancreatic
fibrosis and calcified stones in the e7ocrine ducts are found at autopsy.
D. -ndocrinopathies
>everal hormones (e.g. growth hormone, cortisol, glucagon, and epinephrine) antagoni;e
insulin action. *iseases associated with e7cess secretion of these hormones can cause
diabetes (e.g. Acromegaly, !ushing:s syndrome, Glucagonoma and /haeochromocytoma).
5hese forms of hyperglycaemia typically resolve when the hormone e7cess is
removed. >omatostatinoma, and aldosteronomaBinduced hypo-alaemia, can cause diabetes,
at least in part by inhibiting insulin secretion. $yperglycaemia generally resolves following
successful removal of the tumour.
-. Dru% or chemicalinduced diabetes
(any drugs can impair insulin secretion. 5hese drugs may not, by themselves cause diabetes
but they may precipitate diabetes in persons with insulin resistance .In such cases, the
classification is ambiguous, as the primacy of betaB cell dysfunction or insulin resistance is
un-nown.
!ertain to7ins such as Jacor (a rat poison) and pentamidine can permanently destroy
pancreatic beta cells.
5here are also many drugs and hormones which can impair insulin action. 97amples
include nicotinic acid and glucocorticoids.
5he following list shows the more commonly recogni;ed drug, hormone, or to7in induced
forms of diabetes and hyperglycaemia.
pathophysiology
Dru%. or +hemical.induced Diabetes
%icotinic acid
Glucocorticoids
5hyroid hormone
Alpha-adrenergic agonists
Beta-adrenergic agonists
5hia;ides
*ilantin
/entamidine
Jacor
Interferon-alpha therapy
)thers
/. Infections
!ertain viruses have been associated with betaBcell destruction. *iabetes occurs in some
patients with congenital rubella. In addition, !o7sac-ie B, cytomegalovirus and other viruses
(e.g. adenovirus and mumps) have been implicated in inducing the disease
G. 0ncommon but specific forms of immunemediated diabetes mellitus
*iabetes may be associated with several immunological diseases with a pathogenesis or
aetiology different from that which leads to the 5ype diabetes process.
pathophysiology
/ostprandial hyperglycaemia of a severity sufficient to fulfil the criteria for diabetes
has been reported in rare individuals who spontaneously develop insulin
autoantibodies. $owever, these individuals generally present with symptoms of
hypoglycaemia rather than hyperglycaemia.
5he =stiff man syndrome? is an autoimmune disorder of the central nervous system,
characteri;ed by stiffness of the a7ial muscles with painful spasms. Affected people
usually have high titres of the GA* autoantibodies and appro7imately one-half will
develop diabetes. /atients receiving interferon alpha have been reported to develop
diabetes associated with islet cell autoantibodies and, in certain instances, severe
insulin deficiency.
AntiBinsulin receptor antibodies can cause diabetes by binding to the insulin receptor,
thereby reducing the binding of insulin to target tissue. $owever, these antibodies also
can act as an insulin agonist after binding to the receptor and can thereby cause
hypoglycaemia. AntiBinsulin receptor antibodies are occasionally found in patients
with systemic lupus erythematosus and other autoimmune diseases. As in other states
of e7treme insulin resistance, patients with antiBinsulin receptor antibodies often have
acanthosis nigricans. In the past, this syndrome was termed 5ype B insulin resistance.
1. Other %enetic syndromes sometimes associated 'ith diabetes
(any genetic syndromes are accompanied by an increased incidence of diabetes mellitus.
5hese include the chromosomal abnormalities of *own:s syndrome, Klinefelter:s syndrome
and 5urner:s syndrome.
@olfram:s syndrome is an autosomal recessive disorder characteri;ed by insulinB
deficient diabetes and the absence of beta cells at autopsy. Additional manifestations
pathophysiology
include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. 5hese
and other similar disorders are listed in the following 5able.
Other Genetic #yndromes #ometimes "ssociated 'ith Diabetes
*ownLs syndrome
&riedreichLs ata7ia
$untingtonLs chorea
KlinefelterLs syndrome
4awrence-(oon-Biedel syndrome
(yotonic dystrophy
/orphyria
/rader-@illi syndrome
5urnerLs syndrome
@olframLs syndrome
)thers
IV.Gestational 1yper%lycaemia and Diabetes
1
DefinitionE Gestational diabetes is carbohydrate intolerance resulting in hyperglycaemia of
variable severity with onset or first recognition during pregnancy.
*ifference between =diabetes mellitus and pregnancy? and Gestational $yperglycaemia
It does not e7clude the possibility that the glucose intolerance may antedate
pregnancy but has been previously unrecogni;ed. 5he definition applies irrespective
of whether or not insulin is used for treatment or the condition persists after
pregnancy.
@omen who become pregnant and who are -nown to have diabetes mellitus which
antedates pregnancy do not have gestational diabetes but have =diabetes mellitus and
pregnancy? and should be treated accordingly before, during, and after the pregnancy.
pathophysiology
In the early part of pregnancy (e.g. first trimester and first half of second trimester)
fasting and postprandial glucose concentrations are normally lower than in normal,
nonB pregnant women. 9levated fasting or postprandial plasma glucose levels at this
time in pregnancy may well reflect the presence of diabetes which has antedated
pregnancy, but criteria for designating abnormally high glucose concentrations at this
time have not yet been established. 5he occurrence of higher than usual plasma
glucose levels at this time in pregnancy mandates careful management and may be an
indication for carrying out an )G55 .%evertheless, normal glucose tolerance in the
early part of pregnancy does not itself establish that gestational diabetes may not
develop later.
Individuals at high ris- for gestational diabetes include older women, those with previous
history of glucose intolerance, those with a history of large for gestational age babies, women
from certain highBris- ethnic groups, and any pregnant woman who has elevated fasting, or
casual, blood glucose levels. It may be appropriate to screen pregnant women belonging to
highBris- populations during the first trimester of pregnancy in order to detect previously
undiagnosed diabetes mellitus. &ormal systematic testing for gestational diabetes is usually
done between "' and "3 wee-s of gestation
V."l2heimer3s Disease Is Type ! Diabetes
2
5he term =type . diabetes? accurately reflects the fact that A* represents a form of
diabetes that selectively involves the brain and has molecular and biochemical features that
overlap with both type diabetes mellitus and 5"*(
Al;heimer:s disease (A*) has characteristic histopathological, molecular, and
biochemical abnormalities, including cell loss0 abundant neurofibrillary tangles0 dystrophic
pathophysiology
neurites0 amyloid precursor protein, amyloid-M (A//-AM) deposits0 increased activation of
prodeath genes and signaling pathways0 impaired energy metabolism0 mitochondrial
dysfunction0 chronic o7idative stress0 and *%A damage. Gaining a better understanding of
A* pathogenesis will reDuire a framewor- that mechanistically interlin-s all these
phenomena.
5he pathophysiology of *( revolves around impairment of insulin secretion, insulin
resistance, or both, resulting in reduced utili;ation of glucose, hyperglycemia, and
impairment of fatty acid metabolism. >ymptoms and complications of *( are due to
hyperglycemia as well as lac- of adeDuate insulin action.
Glucose (etabolismE
!arbohydrates, bro-en down mainly into glucose, are an important source of energy in
humans. !onsideration of glucose and insulin metabolic pathways is crucial to understanding
the pathophysiology of *( (&igure ).
.

Glucose is derived from three sourcesE intestinal absorption following digestion of dietary
carbohydrates0 glycogenolysis, the brea-down of glycogen, which is the polymeri;ed storage
form of glucose0 and gluconeogenesis, the formation of glucose from precursors including
lactate (and pyruvate), amino acids (especially alanine and glutamine), and to a lesser e7tent,
glycerol.
'
)nly the liver and -idneys are capable of releasing glucose into circulation by
glycogenolysis and gluconeogenesis. All tissues can utili;e glucose as a substrate for energy
production, but only the brain is wholly dependent upon glucose as its main energy source.
5hus mechanisms to maintain a steady-state supply of glucose to the central nervous system
are integral to metabolic control. Both insulin-dependent and non- insulin independent
pathways can determine whole body clearance of glucose.
'
Glucose is transported into the
cells by specific transporters, activated by phosphorylation to glucose-2- phosphate by the
&igure . Action of Insulin N Glucagon under &eeding N &asting !onditions
&eeding, satiety, and the neurohumoral response to feeding are integrated by the brain, especially the
hypothalamus. 5his consists of the vagal system, incretin hormone secretion, and gut motility hormones, among
other mechanisms.
<pon feeding, the neurohormonal response, as well as direct glucose stimulation of the pancreas, results in
activation of pathways that will lead to efficient insulin secretion as well as a decrease in glucagon secretion
from the Islets of 4angerhans in the pancreas into the portal tract. 5his results in increased liver upta-e of
glucose, inhibition of hepatic gluconeogenesis, increased fatty acid synthesis, and J4*4 secretion and increased
glycogen storage. Although the maCority of insulin is cleared by the liver, it also reaches the central circulation
where in the fat, it increases glucose upta-e and triglyceride storage, and inhibits free fatty acid release. In
muscle, insulin increases glucose upta-e and glycogen storage0 in the -idney it inhibits gluconeogenesis.
<nder fasting conditions, the neurohumoral response is switched to maintenance of glucose levels, resulting in
decreased insulin and increased glucagon secretion, with the resultant opposite effects on the above-described
target organs. In the liver, gluconeogenesis, glycogenolysis, and fatty acid brea-down is stimulated. In adipose
tissues, fat is mobili;ed with increased lipolysis and free-acid release. In muscle, decreased glucose upta-e and
increase fatty acid catabolism ta-e place. All of these actions are tightly regulated and coordinated to account for
all physiological processes, ranging from short-term energy e7penditure (such as e7ercise) to both short- and
long term fasting. In addition, many other hormones (e.g., cortisol, growth hormones, catecholamines) are
tissue-specific en;ymes he7o-inase or gluco-inase, allowing it to enter metabolic pathways
such as the glycolysis, glycogen synthesis, he7osamine biosynthesis (alternative pathway to
glycolysis), or pentose phosphate pathways.
'
5hese pathways are subCect to regulation by
insulin, as well as glucagon. It is important to note that entry of glucose into different tissues
is regulated by e7pression of different glucose transporters0 in muscle and fat, glucose entry
is allowed only via an insulin-dependent translocation of the glucose transporter (G4<5)-',
to the cell surface, whereas in the brain, G4<5- is constitutively active and not dependent
upon insulin action. Insulin regulates glucose upta-e, inhibits glycogen brea-down and
gluconeogenesis, whereas glucagon has the opposite effects.3 $ence, absolute deficiency of
insulin (as in 5ype *(), or relative (as in 5ype " *(), is associated with decreased
clearance of blood glucose from the body and leads to hyperglycemia.
.
6ole of Insulin in the Body
Insulin is secreted by b-cells of Islets of 4angerhans, an endocrine organ, present in the
pancreas. 5he pancreatic islet comprises a group of cells, termed O-, P-, and Q-cells,
surrounded by e7ocrine pancreas. 5hese islets synthesi;e and release a number of hormones,
the classic ones being insulin and amylin from the P -cell, glucagon from the O cell,
somatostatin from the Q -cell, as well as a number of other bioactive polypeptides. Insulin is
synthesi;ed as a pro-hormone, transported to granules where it is processed by a pro-protein
convertase, resulting in mature insulin, !-peptide (by product of proinsulin processing), and
amylin. 5hese are stored in these mature granules until released upon stimulation of the b-
cell. Insulin production usually e7ceeds the need, so the unreleased granules are stored or
destroyed in the lysosomal compartment of the b-cell. Glucose is the primary stimulant of
insulin secretion, and o7idative metabolism of glucose is reDuired for glucose to stimulate
granule e7ocytosis. A number of other secretagogues, including hormones, gut peptides, and
amino acids also have the ability to provo-e insulin secretion.
Insulin:s primary physiologic function in the body can be described as anabolic, resulting in
storage of fuels from ingested carbohydrate and fat and regulating catabolism of stored fuel.
Its main target tissues are liver s-eletal muscle, and adipose tissue and its action on these
tissues (or lac- thereof) is responsible for the systemic effects of insulin. If insulin is the
=+in,? a group of hormones such as glucagon, cortisol, and growth hormone comprise the
=+ang? to counteract and -eep the metabolism in balance for energy needs. <nder feeding
conditions, with entry of nutrients, insulin increases and glucagon decreases, resulting in
storage of the incoming nutrients. <nder fasting conditions, insulin decreases, glucagon
increases, resulting in increased lipolysis from fat to allow fatty acids to be transported to the
liver and other tissues, and increased gluconeogenesis from the liver (and -idney) to maintain
blood glucose, and some glycogenolysis. <nder prolonged starvation, fatty acids are
metaboli;ed to -etone bodies to supply the central nervous system with fuel, in addition to
the glucose.
Insulin e7erts its action by binding to a cell-surface receptor, the insulin receptor (I6), which
has an e7tracellular and intracellular domain. Intracellular domain possesses tyrosine-specific
protein -inase activity, which activated by insulin binding, phosphorylates several intra-
cellular proteins, specifically insulin receptor substrates (I6>) -, -", -., and -' (&igure ").
5hese phosphorylated I6>s lead to activation of multiple downstream signaling pathways and
ultimately to activation of metabolic pathways, including increased upta-e of glucose by
muscle and fat, activation of glycogen synthesis, and suppression of gluconeogenesis by liver
and lipolysis by fat. In addition to carbohydrate metabolism, insulin has several other actions.
Its principle effect on adipose tissue is to suppress lipolysis, increase upta-e of fatty acids,
and synthesi;e triglycerides, thus -eeping circulating free fatty acid levels in chec-.
Insulin >ignaling /athways
1
9levated free fatty acids inhibit glucose utili;ation by peripheral tissues and also increase
hepatic gluconeogenesis. *isordered metabolism of fatty acids has been proposed as having a
maCor effect on pathophysiology in diabetes. Insulin:s effect on adipose tissue appears to be
as important as its effects on carbohydrate metabolism. 5he development of *( thus
involves not only pancreatic b-islet cell dysfunction8 destruction, but also involves action of
insulin in the periphery. Although attention is usually focused on insulin, it is important to
Insulin signaling occurs via many pathways and leads to the various actions of insulin. 5hese signaling
pathways interact with many other pathways that are not depicted (e.g., cortisol, epinephrine, glucagon) and
the concept of critical nodes has been evo-ed to e7plain some -ey interactions. !ritical nodes form an
important part of the signaling networ- that functions downstream of the insulin receptor (I6Rblac-
arrows) and the insulin growth factor- receptor (IG&6Rblue arrows). >ignaling pathways that are
activated by cyto-ines such as tumor necrosis factor-O (5%&-O), interleu-in-2 (I4-2), and leptin interfere
with insulin signaling through crosstal- (orange and red arrows). 5hree important nodes in the insulin
pathway are the I6, the I6 substrates (I6> -'Rlight blue bo7), the phosphatidylinositol .--inase (/I.K)
with its several regulatory and catalytic subunits (light green bo7), and the three AK58protein -inase B
(/KB) isoforms (pin- bo7). *ownstream or intermediate effectors as well as modulators of these critical
nodes includeE
S A-t substrate of 2# -*a (A>2#)
S atypical protein -inase ! (a/K!)
S !as-Br-( (murine)
S !bl-associated protein (!A/)
S !otropic retroviral transforming seDuence homo logue (!bl)
S !ell-division cycle '" (!*!'")
S c-Tun-%-terminal -inase (T%K)
S 97tracellular signal-regulated -inase and " (96K and 96K")
S &or-head bo7 ) (&)I))
S Glycogen synthase -inase . (G>K.)
S Tanus -inase (TAK)
S mammalian target of rapamycin (m5)6)
S pF# ribosomal protein >2 -inase (pF#6>K)
S /hosphatase and tensin homologue (/59%)
S /hosphoinositide-dependent -inase and " (/*K and ")
S /rotein tyrosine phosphatase-B (/5/B)
S 6ac
S 6as
S 6as homologue gene family, member U (A6$U0 also called 5!#)
S >ignal transducer and activator of transcription (>5A5)
S >rc-homology-"-containing protein (>hc)
S >uppressor of cyto-ine signaling (>)!>)
ac-nowledge the role counter-regulatory hormones (the =+ang?) play to fully understand the
pathophysiology of *(.
The Oral Glucose Tolerance Test
4
5he oral glucose tolerance test ()G55) is principally used for diagnosis when blood glucose
levels are eDuivocal, during pregnancy, or in epidemiological studies.
5he )G55 should be administered in the morning after at least three days of unrestricted diet
(greater than 1# g of carbohydrate daily) and usual physical activity. 6ecent evidence
suggests that a reasonable (.#B1#g) carbohydrate containing meal should be consumed on the
evening before the test. 5he test should be preceded by an overnight fast of 3B' hours,
during which water may be drun-. >mo-ing is not permitted during the test. 5he presence of
factors that influence interpretation of the results of the test must be recorded (e.g.
medications, inactivity, infection, etc.).
5rocedure
After collection of the fasting blood sample, the subCect should drin- ,1 g of
anhydrous glucose or 3".1 g of glucose monohydrate (or partial hydrolysates of starch
of the eDuivalent carbohydrate content) in "1#B.## ml of water over the course of 1
minutes.
&or children, the test load should be .,1 g of glucose per -g body weight up to a total
of ,1 g of glucose.
5iming of the test is from the beginning of the drin-. Blood samples must be collected
" hours after the test load.
<nless the glucose concentration can be determined immediately, the blood sample
should be collected in a tube containing sodium fluoride (2 mg per ml whole blood)
and immediately centrifuged to separate the plasma0 the plasma should be fro;en until
the glucose concentration can be estimated.
Methods for measurin% substances in blood and urine
4
(easurement of glucose in blood
6eductiometric methods (the >omogyiB%elson, the ferricyanide and neocuprine autoanalyser
methods) are still in use for blood glucose measurement.
5he oBtoluidine method also remains in use but en;ymeBbased methods are widely available,
for both laboratory and nearBpatient use.
$ighly accurate and rapid (B" min) devices are now available based on immobili;ed glucose
o7idase electrodes.
$e7o-inase and glucose dehydrogenase methods are used for reference.
@hole blood samples preserved with fluoride show an initial rapid fall in glucose of up to #
G at room temperature, but subseDuent decline is slow0 centrifugation prevents the initial fall.
@hole blood glucose values are 1 G lower than corresponding plasma values in patients
with a normal haematocrit reading, and arterial values are about , G higher than
corresponding venous values.
5he use of reagentBstrip glucose o7idase methods has made bedside estimation of blood
glucose very popular. $owever, the cost of the reagentBstrips remains high.
>ome methods still reDuire punctilious techniDue, accurate timing, and storage of strips in
airtight containers. 6easonably Duantitative results can be obtained even with visual colourB
matching techniDues. 9lectrochemical and reflectance meters can give coefficients of
variation of well under 1G. 6eagentBstrip methods have been validated under tropical
conditions, but are sensitive to e7treme climatic conditions.
*iabetes may be strongly suspected from the results of reagentBstrip glucose estimation, but
the diagnosis cannot be confidently e7cluded by the use of this method. !onfirmation of
diagnosis reDuires estimation by laboratory methods.
/atients can easily collect small blood samples themselves (either in specially prepared
plastic or glass capillary tubes or on filterBpaper), and selfBmonitoring using glucose
reagentBstrips with direct colourBmatching or meters is now widely practised. /atients should
be properly trained in the appropriate techniDues to avoid inaccurate or misleading results.
Glycemic profile$ 5he insulinBtreated patient is commonly reDuested to build up a
=glycaemic profile? by selfBmeasurement of blood glucose at specific times of the day (and
night). A =,Bpoint profile? is useful, with samples ta-en before and F# min after brea-fast,
before and F# min after lunch, before and F# min after an evening meal, and Cust before going
to bed. )ccasionally patients may arrange to wa-e at #.## h to collect and measure a
nocturnal sample. 5he complete profile rarely needs to be collected within a single "'Bhour
period, and it may be compiled from samples collected at different times over several days.
2

(easurement of glucose in urine
2
InsulinBtreated patients who do not have access to facilities for selfBmeasurement of blood
glucose should test urine samples passed after rising, before main meals, and before going to
bed.
%onBinsulinBdependent patients do not need to monitor their urine so freDuently. <rine tests
are of somewhat limited value, however, because of the great variation in urine glucose
concentration for given levels of blood glucose. 5he correlation between blood and urine
glucose may be improved a little by collecting shortBterm fractions (1B.# min) of the urine
output. Benedict:s Duantitative solution or selfBboiling, caustic soda8copper sulphate tablets
may be used or the more convenient, but costly, semiBDuantitative en;ymeBbased testB strips.
6etone bodies in urine and blood
2
5he appearance of persistent -etonuria associated with hyperglycaemia or high levels of
glycosuria in the diabetic patient points to an unacceptably severe level of metabolic
disturbance and indicates an urgent need for corrective action. 5he patient should be advised
to test for -etone bodies (acetone and acetoBacetic acid) when tests for glucose are repeatedly
positive, or when there issubstantial disturbance of health, particularly with infections.
6othera:s sodium nitroprusside test may be used or, alternatively, reagentBstrips that are
sensitive to -etones. In emergency situations such as diabetic -etoacidosis, a greatly raised
concentration of plasma -etones can be detected with a reagentBstrip and roughly Duantified
by serial in " dilution of plasma with water.
Values for dia%nosis of diabetes mellitus and other cate%ories of hyper%lycaemia (71O.
1888
1
Glucose concentration, mmol lB (mg dlB)
@hole blood /lasmaA
Jenous !apillary Jenous
Diabetes Mellitus$
&asting V 2. (V #) V 2. (V #) V ,.# (V "2)
or
"-h post glucose load
or both V #.# (V 3#) V . (V "##) V . (V "##)
Impaired Glucose
Tolerance (IGT$
&asting (if measured)
"nd
"-h post glucose load
W 2. (W #)
V 2., (V "#)
and
W # (W 3#)
W 2. (W #)
V ,.3 (V '#) and
W . (W "##)
W ,.# (W"2)
V ,.3 (V '#) and
W . (W "##)
Impaired /astin%
Glycaemia (I/G$
&asting
and (if measured)
"-h post glucose load
V 1.2 (V ##)and
W 2. (W #)
W 2., (W "#)
V 1.2 (V ##)and
W 2. (W #)
W,.3 (W '#)
V 2. (V #)and
W ,.# (W"2)
W ,.3 (W '#)
&or epidemiological or population screening purposes, the fasting or "-h value after ,1 g oral
glucose may be used alone. &or clinical purposes, the diagnosis of diabetes should always be
confirmed by repeating the test on another day unless there is uneDuivocal hyperglycaemia
with acute metabolic decompensation or obvious symptoms.
+9IT-9I" /O9 T-#TI:G /O9 DI")-T-# I: "#;M5TOM"TI+ "D0<T
I:DIVID0"<# . T")<- 1("merican Diabetes "ssociation.2=1!
>
*IAB959>
5+/9
6I>K &A!5)6> and &69U<9%!+ )& >!699%I%G
5ype 5ype prevention studies suggest that measurement of islet
autoantibodies identifies individuals at ris- for developing type
diabetes. >uch testing may be appropriate in highRris- individuals, such
as those with prior transient hyperglycemia or those who have relatives
with type diabetes, in the conte7t of clinical research studies
5ype " . 5esting should be considered for all adults who are overweight (B(I V
"1) and have additional
ris- factorsE
$istory of cardiovascular disease
habitual physical inactivity
first degree relative with diabetes
delivered baby X F lbs, G*(
polycystic ovary syndrome
$5% V '#8F# or on meds
$*4 .1 mg8dl or triglyceride "1# mg8dl
Al c V 1.,G, IG5 or l9G
)ther clinical conditions associated with insulin resistance
(obesity, A%)
$igh ris- ethnic population (African American, 4atino, %ative
American, Asian American, /acific Islanders)
".In the absence of the above ris-, start testing for diabetes at age '1
.. If results normal, repeat test at . year intervals or more freDuently
depending on ris-
59>5> 5) *IAG%)>9 *IAB959> R 5AB49 "
stage &or all the below tests, in the absence of uneDuivocal hyperglycemia,
results should be confirmed by repeat testing.
Al !
%G>/
certifiedN
standardi;ed
&asting /lasma
Glucose (&/G)
Y%o inta-e 3 8hrs
6andom /lasma
Glucose
)ral Glucose
5olerance
5est ()G55) ,1-
g
assay
*iabetes Al ! V .1G &/G V "2
mg8dl
6andom plasma
glucose V "##
mg8dI
/lus symptoms
6andom Z any
time of *ay
w8out regard to
time since last
meal, symptoms
include usual
polyuria,
polydipsia, and
une7plained
weight loss.
5woRhour
plasma
glucose ("h/G)
V "## mg8dl
Increased
ris- of
diabetes
A! 1.,- 2-'G Impaired
&asting BG
(I&G) Z
&/G ##-"1
mg8dl
Impaired
Glucose
5olerance (I!5)
Z "h/G
'# -FF mg8dl
%ormal A! W 1.,G &/G W ##
mg8dl
"h/G W '#
mg8dl
Gestational diabetes (G*()
*IAG%)>I> !6I596IA 59>5 *IAG%)>I> !6I596IA
At the first prenatal visit,
screen
for undiagnosed type " in
>tandard *iagnostic 5esting
and !riteria as
>tandard *iagnostic 5esting
and !riteria as listed in
those
w8 ris- factors as listed in
5able
listed in *iagnosing
*iabetes R5able "
*iagnosing *iabetes R5able
"
>creen for G*( at "'R"3
wee-s of gestation for all
pregnant women not -nown to
have diabetes.
>creen women with G*( for
diabetes 2R" w-s.
postpartum
/erform a ,1g )G55, with
plasma glucose
measurement fasting and at
and " h.
5he )G55 should be
performed in morning after
an overnight fast of at least
3 h.
5he diagnosis of G*( is
made when A%+ of
following BG values are
e7ceededE
&asting V F" mg8dl
h V 3# mg8dl
" h V 1. mg8dl
American *iabetes Association !linical /ractice 6ecommendations. >tandards of medical
care for patients with *(. Tanuary "#. vol. .1 >upplement >R>2.
*iagnostic sensitivity and specificity of autoimmune mar-ers in patients with newly
diagnosed type diabetes mellitus
3
>ensitivity >pecificity
Glutamic acid decarbo7ylase
(GA*21)
,#BF#G FFG
Insulin (IAA) '#B,#G FFG
5yrosine phosphatase (IA-") 1#B,#G FFG
[inc transporter 3 ([n53) 1#-,#G FFG
Mana%ement of Diabetes Mellitus
+linical Trials in Diabetes
&indings of the *iabetes !omplications and !ontrol 5rial (*!!5) and of the <nited
Kingdom /rospective *iabetes >tudy (<K/*>), have confirmed the beneficial effects of
improved glycemic control in both type and type " diabetes, respectively. In addition, with
increased understanding of the pathophysiology of both type and type " diabetes, large
prospective studiesR*iabetes /revention 5rial (*/5-) and the *iabetes /revention
/rogram (*//)Rhave been performed in attempts to prevent onset of these disorders
". +linical Trials in Type 1 Diabetes
*iabetes /revention 5rial-(*/5-)
5his multicenter study sponsored by the %ational Institutes of $ealth (%I$) was designed to
determine whether the development of type diabetes mellitus could be prevented or delayed
by immune intervention therapy. *aily low-dose insulin inCections were administered for up
to 3 years in first-degree relatives of type diabetic patients who were selected as being at
high ris- for development of type diabetes because of detectable islet cell antibodies and
reduced early-insulin release. <nfortunately, this immune intervention failed to affect the
onset of type diabetes compared with a randomi;ed untreated group. A related study using
whose early insulin release remains intact also failed to show an effect on the onset of type
diabetes. After an average of '.. years of observation, type diabetes developed in about
.1G of persons in both the oral insulin and the placebo groups.
F
5he *iabetes !ontrol and !omplications 5rial
5his long-term therapeutic study involving '' patients with type diabetes mellitus
reported that =near? normali;ation of blood glucose resulted in a delay in the onset and a
maCor slowing of the progression of established microvascular and neuropathic complications
of diabetes during a follow-up period of up to # years. (ultiple insulin inCections (22G) or
insulin pumps (.'G) were used in the intensively treated group, who were trained to modify
their therapy in response to freDuent glucose monitoring. 5he conventionally treated groups
used no more than two insulin inCections, and clinical well-being was the goal with no
attempt to modify management based on $bAc determinations or the glucose results.
In half of the patients, a mean hemoglobin Ac of ,."G (normalE W 2G) and a mean blood
glucose of 11 mg8d4 (3.2 mmol84) were achieved using intensive therapy, while in the
conventionally treated group $bAc averaged 3.FG with an average blood glucose of ""1
mg8d4 (".1 mmol84). )ver the study period, which averaged , years, there was an
appro7imately 2#G reduction in ris- between the two groups in regard to diabetic
retinopathy, nephropathy, and neuropathy. 5he intensively treated group also had a
nonsignificant reduction in the ris- of macrovascular disease of 'G (F1G !I, B# to 23).
Intensively treated patients had a threefold greater ris- of serious hypoglycemia as well as a
greater tendency toward weight gain. $owever, there were no deaths definitely attributable to
hypoglycemia in any persons in the *!!5 study, and no evidence of posthypoglycemic
cognitive damage was detected.
>ubCects participating in the *!!5 study were subseDuently enrolled in a follow-up
observational study, the 9pidemiology of *iabetes Interventions and !omplications (9*I!)
study. 9ven though the between-group differences in mean $bAc narrowed over ' years, the
group assigned to intensive therapy had a lower ris- of retinopathy at ' years,
microalbuminuria at , to 3 years, and impaired glomerular filtration rate (W 2# m48min8.,.
m") at "" years of continued study follow-up. (oreover, by the end of the -year follow-up
period, the intensive therapy group had significantly reduced their ris- of any cardiovascular
disease events by '"G (F1G !I, FG to ".G0 / Z #.#"). 5hus, it seems that the benefits of
good glucose control persist even if control deteriorates at a later date.
5he general consensus of the A*A is that intensive insulin therapy associated with
comprehensive self-management training should become standard therapy in patients with
type diabetes mellitus after the age of puberty. 97ceptions include those with advanced
chronic -idney disease and the elderly, since in these groups the detrimental ris-s of
hypoglycemia outweigh the benefits of tight glycemic control.
#
Immune intervention trials in new-onset type diabetes
At the time of diagnosis of type diabetes, patients still have significant B cell function. 5his
e7plains why soon after diagnosis patients go into a partial clinical remission (=honeymoon?)
reDuiring little or no insulin. 5his clinical remission is short-lived, however, and eventually
patients lose all B cell function and have more labile glucose control. Attempts have been
made to prolong this partial clinical remission using medications such as cyclosporine,
a;athioprine, prednisone, and antithymocyte globulin. 5hese medications have had limited
efficacy, and there are concerns about to7icity and the need for continuous treatment.
%ewer agents that may induce immune tolerance and appear to have few side effects have
been used in patients with new-onset type diabetes mellitus. 5he !*. comple7 is the maCor
signal transducing element of the 5 cell receptor and the anti-!*. antibodies are believed to
modulate the autoimmune response by selectively inhibiting the pathogenic 5 cells or by
inducing regulatory 5 cells. /hase I8II and II8III clinical trials using the humani;ed
monoclonal antibodies against !*., h)K5.\ (Ala-Ala) (tepli;umab) and !hAgly!*.
(oteli7i;umab) delayed but did not completely arrest the decline in insulin production in
patients with newly diagnosed type diabetes. >tudies are ongoing to identify which
individuals may benefit from this therapy. A study using anti-!*. antibody prior to clinical
onset of diabetes is also under consideration. 5hese and other approaches that selectively
modulate the autoimmune 5 cell response hold promise that type diabetes may eventually
be preventable without prolonged immunosuppression.

B. !linical 5rials in 5ype " *iabetes

. 5he *iabetes /revention /rogram
5his study was aimed at discovering whether treatment with either diet and e7ercise or
metformin could prevent the onset of type " diabetes in people with impaired glucose
tolerance0 .".' overweight men and women aged "1B31 years with impaired glucose
tolerance participated in the study. Intervention with a low-fat diet and 1# minutes of
moderate e7ercise (eDuivalent to a bris- wal-) per wee- reduced the ris- of progression to
type " diabetes by ,G compared with a matched control group. /articipants ta-ing 31# mg
of metformin twice a day reduced their ris- of developing type " diabetes by .G, but this
intervention was relatively ineffective in those who were either less obese or in the older age
group.
@ith the demonstration that intervention can be successful in preventing progression to
diabetes in these subCects, a recommendation has been made to change the terminology from
the less comprehensible =impaired glucose tolerance? to =prediabetes.? 5he latter is a term
that the public can better understand and thus respond to by implementing healthier diet and
e7ercise habits.
"
". Kumamoto studyE
5he Kumamoto study involved a relatively small number of patients with type " diabetes (n Z
#) who were nonobese and only slightly insulinresistant, reDuiring W .# units of insulin per
day for intensive therapy. )ver a 2-year period, it was shown that intensive insulin therapy,
achieving a mean $bAc of ,.G, significantly reduced microvascular end points compared
with conventional insulin therapy achieving a mean $bAc of F.'G. !ardiovascular events
were neither worsened nor improved by intensive therapy, and weight changes were li-ewise
not influenced by either form of treatment.
.
.. 5he <nited Kingdom /rospective *iabetes >tudy
5his multicenter study was designed to establish, in type " diabetic patients, whether the ris-
of macrovascular or microvascular complications could be reduced by intensive blood
glucose control with oral hypoglycemic agents or insulin and whether any particular therapy
was of advantage. A total of .32, patients aged "1B21 years with newly diagnosed diabetes
were recruited between F,, and FF, and studied over # years. 5he median age at baseline
was 1' years0 ''G were overweight (X "#G over ideal weight)0 and baseline $bAc was
F.G. 5herapies were randomi;ed to include a control group on diet alone and separate
groups intensively treated with either insulin or sulfonylurea (chlorpropamide, glyburide, or
glipi;ide). (etformin was included as a randomi;ation option in a subgroup of .'"
overweight or obese patients, and much later in the study an additional subgroup of both
normal-weight and overweight patients who were responding unsatisfactorily to sulfonylurea
therapy were randomi;ed to either continue on their sulfonylurea therapy alone or to have
metformin combined with it. In F3,, an additional modification was made to evaluate
whether tight control of blood pressure with stepwise antihypertensive therapy would prevent
macrovascular and microvascular complications in ,13 hypertensive patients among this
<K/*> population compared with .F# of them whose blood pressure was treated less
intensively. 5he tight control group was randomly assigned to treatment with either an
angiotensin- converting en;yme (A!9) inhibitor (captopril) or a P-bloc-er (atenolol). Both
medications were stepped up to ma7imum dosages of ## mg8d and then, if blood pressure
remained higher than the target level of W 1#831 mm $g, more medications were added in
the following stepwise seDuenceE a diuretic, slow-release nifedipine, methyldopa, and
pra;osinRuntil the target level of tight control was achieved. In the control group,
hypertension was conventionally treated to achieve target levels W 3#8#1 mm $g, but these
patients were not prescribed either A!9 inhibitors or P-bloc-ers.
Intensive treatment with either sulfonylureas, metformin, combinations of those two, or
insulin achieved mean $bAc levels of ,G. 5his level of glycemic control decreased the ris-
of microvascular complications (retinopathy and nephropathy) in comparison with
conventional therapy (mostly diet alone), which achieved mean levels of $bAc of ,.FG.
@eight gain occurred in intensively treated patients e7cept when metformin was used as
monotherapy. %o cardiovascular benefit and no adverse cardiovascular outcomes were noted
regardless of the therapeutic agent. $ypoglycemic reactions occurred in the intensive
treatment groups, but only one death from hypoglycemia was documented during ",,###
patient-years of intensive therapy.
@hen therapeutic subgroups were analy;ed, some une7pected and parado7ical results were
noted. Among the obese patients, intensive treatment with insulin or sulfonylureas did not
reduce microvascular complications compared with diet therapy alone. 5his was in contrast to
the significant benefit of intensive therapy with these medications in the total group.
&urthermore, intensive therapy with metformin was more beneficial in the overweight or
obese persons than diet alone with regard to fewer myocardial infarctions, stro-es, and
diabetes-related deaths, but there was no significant reduction by metformin of diabetic
microvascular complications as compared with the diet group. (oreover, in the subgroup of
obese and nonobese patients in whom metformin was added to sulfonylurea failures, rather
than showing a benefit, there was a F2G increase in diabetes-related deaths compared with
the matched cohort of patients with unsatisfactory glycemic control on sulfonylureas who
remained on their sulfonylurea therapy. !hlorpropamide also came out poorly on subgroup
analysis in that those receiving it as intensive therapy did less well regarding progression to
retinopathy than those conventionally treated with diet.
'
5ight control of blood pressure (median value ''83" mm $g vs 1'83, mm $g)
substantially reduced the ris- of microvascular disease and stro-e but not myocardial
infarction. In fact, reducing blood pressure by this amount had substantially greater impact on
microvascular outcomes than that achieved by lowering $bAc from ,.FG to ,G. An
epidemiologic analysis of the <K/*> data did show that every # mm $g decrease in
updated mean systolic blood pressure was associated with G reduction in ris- for
myocardial infarction. (ore than half of the patients needed two or more medications for
adeDuate therapy of their hypertension, and there was no demonstrable advantage of A!9
inhibitor therapy over therapy with P-bloc-ers with regard to diabetes end points. <se of a
calcium channel bloc-er added to both treatment groups appeared to be safe over the long
term in this diabetic population despite some controversy in the literature about its safety in
diabetics.
'
4i-e the *!!5 trialists, the <K/*> researchers performed post-trial monitoring to
determine whether there were long-term benefits of having been in the intensively treated
glucose and blood pressure arms of the study. 5he between-group differences in $bAc were
lost within the first year of follow-up, but the reduced ris- ("'G, / Z #.##) of development
or progression of microvascular complications in the intensively treated group persisted for
# years. 5he intensively treated group also had significantly reduced ris- of myocardial
infarction (1G, / Z #.#) and death from any cause (.G, / Z #.##,) during the follow-up
period. 5he subgroup of overweight or obese subCects who were initially randomi;ed to
metformin therapy showed sustained reduction in ris- of myocardial infarction and death
from any cause in the follow-up period. 5he between group blood pressure differences
disappeared within " years of the end of the trial. <nli-e the sustained benefits seen with
glucose control, there were no sustained benefits from having been in the more tightly
controlled blood pressure group. Both blood pressure groups were at similar ris- for
microvascular events and diabetes-related end points during the follow-up period.
3
5hus, the follow-up of the <K/*> type " diabetes cohort showed that, as in type diabetes,
the benefits of good glucose control persist even if control deteriorates at a later date. Blood
pressure benefits, however, last only as long as the blood pressure is well controlled.
'. 5he >teno-" study
5he >teno-" study was designed in FF# to validate the efficacy of targeting multiple
concomitant ris- factors for both microvascular and macrovascular disorders in type "
diabetes. A prospective, randomi;ed, open, blinded end point design was used where 2#
patients with type " diabetes and microalbuminuria were assigned to conventional therapy
with their general practitioner or to intensive care at the >teno *iabetes !enter. 5he
intensively treated group had step-wise introduction of lifestyle and pharmacologic
interventions aimed at -eeping glycated hemoglobin W 2.1G, blood pressure W .#83# mm
$g0 total cholesterol W ,1 mg8d4 ('.1 mmol84), and triglycerides W 1# mg8d4 (.,
mmol84). All the intensively treated group received A!9 inhibitors and if intolerant, an
angiotensin II-receptor bloc-er. 5he lifestyle component of intensive intervention included
reduction in dietary fat inta-e to W .#G of total calories0 smo-ing cessation program0 light to
moderate e7ercise0 daily vitamin-mineral supplement of vitamin !, 9, and chromium
picolinate. Initially, aspirin was only given as secondary prevention to patients with a history
of ischemic cardiovascular disease0 later, all patients received aspirin. After a mean follow-up
of ,.3 years, cardiovascular events (eg, myocardial infarction, angioplasties, coronary bypass
grafts, stro-es, amputations, vascular surgical interventions) developed in ''G of patients in
the conventional arm and only in "'G in the intensive multifactorial armRabout a 1#G
reduction. 6ates of nephropathy, retinopathy, and autonomic neuropathy were also lower in
the multifactorial intervention arm by 2"G and 2.G, respectively.
1
1. A!!)6* (Action to !ontrol !ardiovascular 6is- in *iabetes) trial
sponsored by the %ational $eart, 4ung and Kidney Institute is being conducted to study
effects of tight glycemic control, blood pressure treatment, and lipid control on
cardiovascular outcomes in individuals with type " diabetes. In &ebruary "##3, the A!!)6*
investigators halted the intensive glycemic control arm (hemoglobin Ac goal less than 2G)
because of increased ris- of death in this arm. Although details of this study are not
published, at the time of this writing it appears that this group consisted of individuals who
had type " diabetes for an average of # years with at least two ris- factors for heart disease
other than diabetes or a previous history of heart disease. Among #,"1 participants, the
rates of death in intensive and conventional group were "1, and "#., respectively, over '
years of treatment. 5he incidence of deaths in this study ( deaths8### patients per year in
conventional treatment group versus ' deaths8### patients per year in intensive treatment
group over ' years) is lower than death rates found in similar population in other studies. At
this point, the cause for increased death is not clear and is under investigation.
2
Genome.7ide "ssociation #tudies
5he susceptibility to develop diabetes is determined by a combination of genetic and
environmental factors. Given the polygenic etiology of type " diabetes, the genes responsible
for the disease are not yet identified. $owever, with the completion of the $uman Genome
/roCect in "##. and the International $ap(ap /roCect in "##1, researchers are now able to
Duic-ly analy;e the whole genome for single-nucleotide polymorphisms (>%/s) in large
populations. Genomic areas with variations in >%/s between populations with and without
diabetes are then studied in greater details. 5he most comprehensive genome-wide
association study for type " diabetes was reported in April "##, by three groups wor-ing in
close collaboration B <>B&innish team, <>B >wiss team, and a British group. 5hese studies
identified four new genetic variants and confirmed e7istence of another si7.
,,3
#teps in the Mana%ement of the Diabetic 5atient
?
". Dia%nostic -,amination
!haracteri;e the type of diabetesE
Any features of the clinical picture that suggest end-organ insensitivity to insulin,
such as visceral obesity, must be identified. 5he family history should document not
only the incidence of diabetes in other members of the family but also the age at
onset, whether it was associated with obesity, and whether insulin was reDuired. An
attempt should be made to characteri;e the diabetes as type or type ", based on the
clinical features present and on whether or not -etonuria accompanies the glycosuria.
&or the occasional patient, measurement of I!A, GA*21, IAA, and I!A 1"
antibodies can help distinguish between type and type " diabetes. (any patients
with newly diagnosed type diabetes still have significant endogenous insulin
production, and ! peptide levels do not reliably distinguish between type and type "
diabetes. )ther factors that increase cardiac ris-, such as smo-ing history, presence of
hypertension or hyperlipidemia, or oral contraceptive pill use, should be recorded.
4aboratory diagnosis should document fasting plasma glucose levels above "2
mg8d4 (, mmol84) or postprandial values consistently above "## mg8d4 (.
mmol84) and whether -etonuria accompanies the glycosuria. A glycohemoglobin
measurement is useful for assessing the effectiveness of future therapy. >ome
fle7ibility of clinical Cudgment is appropriate when diagnosing diabetes mellitus in the
elderly patient with borderline hyperglycemia.
Baseline values include fasting plasma triglycerides, total cholesterol and $*4-
cholesterol, electrocardiography, -idney function studies, peripheral pulses, and
neurologic, podiatric, and ophthalmologic e7aminations to help guide future
assessments.
). 5atient -ducation (#elf.Mana%ement Trainin%
>ince diabetes is a lifelong disorder, education of the patient and the family is
probably the most important obligation of the clinician who provides initial care. 5he
best persons to manage a disease that is affected so mar-edly by daily fluctuations in
environmental stress, e7ercise, diet, and infections are the patients themselves and
their families. 5he =teaching curriculum? should include e7planations by the
physician or nurse of the nature of diabetes and its potential acute and chronic ha;ards
and how they can be recogni;ed early and prevented or treated. >elf-monitoring of
blood glucose should be emphasi;ed, especially in insulin-reDuiring diabetic patients,
and instructions must be given on proper testing and recording of data.
/atients ta-ing insulin should have an understanding of the actions of basal and bolus
insulin. 5hey should be taught to determine whether the basal dose is appropriate and
how to adCust the rapidly acting insulin dose for the carbohydrate content of a meal.
/atients and their families and friends should be taught to recogni;e signs and
symptoms of hypoglycemia and how to treat low glucose reactions. >trenuous
e7ercise can precipitate hypoglycemia, and patients must therefore be taught to reduce
their insulin dosage in anticipation of strenuous activity or to ta-e supplemental
carbohydrate. InCection of insulin into a site farthest away from the muscles most
involved in the e7ercise may help ameliorate e7ercise-induced hypoglycemia, since
insulin inCected in the pro7imity of e7ercising muscle may be more rapidly mobili;ed.
97ercise training also increases the effectiveness of insulin and insulin doses should
be adCusted accordingly. Infections can cause insulin resistance, and patients should
be instructed on how to manage the hyperglycemia with supplemental rapidly acting
insulin.
5he targets for blood glucose control should be elevated appropriately in elderly
patients since they have the greatest ris- if subCected to hypoglycemia and the least
long-term benefit from more rigid glycemic control. Advice on personal hygiene,
including detailed instructions on foot and dental care, should be provided. All
infections (especially pyogenic ones) provo-e the release of high levels of insulin
antagonists, such as catecholamines or glucagon, and thus bring about a mar-ed
increase in insulin reDuirements. /atients who are ta-ing oral agents may
decompensate and temporarily reDuire insulin.
/atients should be told about community agencies, such as *iabetes Association
chapters, that can serve as a continuing source of instruction. &inally, vigorous efforts
should be made to persuade new diabetics who smo-e to give up the habit, since large
vessel peripheral vascular disease and debilitating retinopathy are less common in
non-smo-ing diabetic patients.
+. Therapy
5reatment must be individuali;ed on the basis of the type of diabetes and specific
needs of each patient. $owever, certain general principles of management can be
outlined for hyperglycemic states of different types.
5ype diabetes
5raditional once- or twice-daily insulin regimens are usually ineffective in type
patients without residual endogenous insulin. In these patients, information and
counselling should be provided about the advantages of ta-ing multiple inCections of
insulin in conCunction with self -blood glucose monitoring. If near-normali;ation of
blood glucose is attempted, at least four measurements of capillary blood glucose and
three or four insulin inCections are necessary.
A combination of rapidly acting insulin analogs and long-acting insulin analogs
allows for more physiologic insulin replacement. 5he rapidly acting insulin analogs
have been advocated as a safer and much more convenient alternative to regular
human insulin for pre-prandial use. In a study comparing regular insulin with insulin
lispro, daily insulin doses and $bAc levels were similar, but insulin lispro improved
postprandial control, reduced hypoglycemic episodes, and improved patient
convenience compared with regular insulin. $owever, because of their relatively short
duration (no more than .B' hours), the rapidly acting insulin analogs need to be
combined with longer-acting insulins to provide basal coverage and avoid
hyperglycemia prior to the ne7t meal. In addition to carbohydrate content of the meal,
the effect of simultaneous fat ingestion must also be considered a factor in
determining the rapidly acting insulin analog dosage reDuired to control the glycemic
increment during and Cust after the meal. @ith low-carbohydrate content and high-fat
inta-e, there is an increased ris- of hypoglycemia from insulin lispro within " hours
after the meal. 5able below illustrates a regimen with a rapidly acting insulin analog
and insulin detemir or insulin glargine that might be appropriate for a ,#--g person
with type diabetes eating meals providing standard carbohydrate inta-e and
moderate to low fat content. Insulin glargine is usually given once in the evening to
provide "'-hour coverage. 5his insulin cannot be mi7ed with any of the other insulins
and must be given as a separate inCection. 5here are occasional patients in whom
insulin glargine does not seem to last for "' hours, and in such cases it needs to be
given twice a day. As shown, insulin detemir may also need to be given twice a day to
get adeDuate "'-hour basal coverage. Alternatively, small doses of %/$ ( .B' units)
can be given with each meal to provide daytime basal coverage with a larger dose at
night. <nli-e the long-acting insulin analogs, %/$ can be mi7ed in the same syringe
as the insulin lispro, insulin aspart, and insulin glulisine.
!ommon preparations used in type diabetes mellitus
F
Insulin )nset of action /ea- action 9ffective duration
Insulin lispro 1-1 min .#-F# min '-2 h
Insulin Aspart 1-1 min .#-F# min '-2 h
6egular .#-2# min "-. h 3-# h
%/$ "-' h '-l# h "-3 h
4ente "-' h '-l" h "-"# h
<ltralente 2R# h '-2 h 3-"' h
Insulin Glargine "-' h %one (pea-less) "#-"' h
/re-Brea-fast /re- 4unch /re- *inner At Bedtime
6apidly acting
insulin analog
1 units ' units 2 units
Insulin detemir 2B, units 3BF units
)6
6apidly acting
insulin analog 1 units ' units 2 units
----
Insulin glargine --- 1B2 units
Assumes that patient is consuming appro7imately ,1 g carbohydrate at brea-fast, 2#
g at lunch and F# g at dinner.
"5he dose of rapidly acting insulin can be raised by or " units if e7tra carbohydrate
(1B.# g) is ingested or if pre-meal blood glucose is X ,# mg8d4 (F.' mmol84).
.Insulin glargine or insulin detemir must be given as a separate inCection.
2. Type 2 diabetes
5herapeutic recommendations are based on the relative contributions of beta cell
insufficiency and insulin insensitivity in individual patients. 5he possibility that the
individual patient has a specific etiologic cause for their diabetes should always be
considered, especially when the patient does not have a family history of type " diabetes or
does not have any evidence of central obesity or insulin resistance. >uch patients should be
evaluated for other types of diabetes such as 4A*A or ()*+.
/atients with 4A*A should be prescribed insulin when the disease is diagnosed and treated
li-e patients with type diabetes. It is also important to note that many patients with type "
diabetes mellitus have a progressive loss of beta cell function and will reDuire additional
therapeutic interventions with time.
A. @eight reduction
B. Glucose lowering agents
Available drugs for type " diabetes and their dosages
3
*rug *aily 5ablet >i;e *ose *uration of
Action
>ulfonylureas
5olbutamide "1# and 1## mg #.1B" g in two or three divided
doses
2B" hours
5ola;amide ##, "1#, and 1## mg #.B g as single dose or in two
divided doses
<p to "'
hours
Acetohe7amide "1# and 1## mg #."1B.1 g as single dose or in
two divided doses
3B"' hours
!hlorpropamide ## and "1# mg #.B#.1 g as single dose "'B," hours
Glyburide ."1, ".1, and 1 mg ."1B"# mg as single dose or in
two divided doses
<p to "'
hours
Glipi;ide 1 and # mg ".1B'# mg as a single dose or in
two divided doses .# minutes
before meals
2B" hours
Glicla;ide 3# mg '#B3# mg as
single dose0
2#B."# mg as divided dose " hours
Glimepiride , ", and ' mg B' mg once a day is usual dose0
3 mg once a day is ma7imal
dose
<p to "'
hours
(eglitinide analogs
6epaglinide #.1, , and " mg #.1 to ' mg three times a day
before meals
. hours
(itiglinide 1 and # mg 1 or # mg three times a
day before
meals " hours
d-/henylalanine derivative
%ateglinide 2# and "# mg 2# or "# mg three times a day
before meals
.1 hours
Biguanides
(etformin 1##, 31#, and ###
mg B".1 g0
tablet with meals two or three
times daily
,B" hours
97tended-
release
metformin
1## and ,1# mg 1##B"### mg once a day <p to "'
hours
5hia;olidinediones
6osiglita;one ", ', and 3 mg 'B3 mg daily (can be divided) <p to "'
hours
/ioglita;one 1, .#, and '1 mg 1B'1 mg daily <p to "'
hours
Glucosidase inhibitors
Acarbose 1# and ## mg "1B## mg three times a day
Cust before meals
' hours
(iglitol "1, 1#, and ## mg s "1B## mg three times a day
Cust before meals
' hour
Joglibose #." and #.. mg #."B#.. mg three times a day
Cust before meals
' hours
G4/- receptor agonists
97enatide ." m4 and ".' m4
prefilled pens
containing 1 mcg and
# mcg (subcutaneous
inCection)
1 mcg subcutaneously twice a
day within hour of brea-fast
and dinner. Increase to # mcg
subcutaneously twice a day after
about a month. *o not use if
calculated creatinine clearance is
W .# m48min.
2 hours
97enatide, long-
acting release
" mg (powder) >uspend in provided diluent and
inCect subcutaneously
wee-
4iraglutide /re-filled, multi-dose
pen that delivers doses
of #.2 mg, ." mg, or
.3 mg
#.2 mg subcutaneously once a
day (starting dose). Increase to
." mg after a wee- if no
adverse reactions. *ose can be
further increased to .3 mg, if
necessary
"' hours
*//-' inhibitors
>itagliptin "1, 1#, and ## mg ## mg once daily is usual dose0
dose is 1# mg once daily if
calculated creatinine clearance is
.# to 1# m48min and "1 mg
once daily if clearance is W .#
m48min.
"' hours
>a7agliptin ".1 and 1 mg ".1 mg <se ".1 mg dose if calculated "' hours
or 1 mg once daily. creatinine clearance is ] 1#
m48min or if also ta-ing drugs
that are strong !+/.A'81
inhibitors such as -etocona;ole.
Jildagliptin 1# mg 1# mg once or twice daily.
!ontraindicated in patients with
calculated creatinine clearance ]
2# m48min or A>58A45 three
times upper limit of normal
"' hours
4inagliptin 1 mg 1 mg daily "' hours
)thers
/ramlintide 1 m4 vial containing
#.2 mg8m40 also
available as prefilled
pens. >ymlin pen 2#
or >ymlin pen "#
(subcutaneous
inCection)
&or insulin-treated type "
patients, start at 2# mcg dose
three times a day (# units on
<## insulin syringe). Increase
to "# mcg three times a day ("#
units on <## insulin syringe) if
no nausea for .B, days. Give
immediately before meal.
&or type patients, start at 1
mcg three times a day (".1 units
on <## insulin syringe) and
increase by increments of 1
" hours
mcg to a ma7imum of 2# mcg
three times a day, as tolerated.
5o avoid hypoglycemia, lower
insulin dose by 1#G on initiation
of therapy.
D. "cceptable <e&els of Glycemic +ontrol
?
A reasonable aim of therapy is to approach normal glycemic e7cursions without provo-ing
severe or freDuent hypoglycemia. @hat has been considered =acceptable? control includes
blood glucose levels of F#B.# mg8d4 (1B,." mmol84) before meals and after an overnight
fast, and levels no higher than 3# mg8d4 (# mmol84) hour after meals and 1# mg8d4
(3.. mmol84) " hours after meals. $bAc levels W ,G are a reasonable goal for nonpregnant
adults. 4ess stringent $bAc goals may be appropriate in children, those with a history of
severe hypoglycemia, limited life e7pectancy, and advanced microvascular and
macrovascular disease. In the elderly frail patient, an $bAc target of appro7imately 3G may
be reasonable although formal evidence is lac-ing. It should be emphasi;ed that the value of
blood pressure control was as great as or greater than glycemic control in type " patients as
regards microvascular as well as macrovascular complications.
". "cute complications of diabetes mellitus
. *iabetic -etoacidosisE
*iabetic -etoacidosis is the most common life threatening hyperglycemic emergency
in patients with diabetes and it is the leading cause of death in children with type
diabetes .*iabetic -etoacidosis may result from increased insulin reDuirements in type
patients during periods of physiological stress, such as infection, trauma, myocardial
infarction, or surgery, and when psychological stress or poor compliance are present.
@hile diabetic -etoacidosis is much less common in type " diabetes, it may develop
under conditions of severe stress.
*iabetic -etoacidosis is a metabolic abnormality characteri;ed by hyperglycemia and
metabolic acidosis as a result of hyper-etonemia with neurological manifestations. It
is usually preceded by polyuria, polydipsia, fatigue, nausea, vomiting, and finally
depression of sensorium and coma. /atients present with one or more of the
followingE hyperventilation (Kussmaul breathing), signs of dehydration, fruity breath
odor of acetone, hypotension, tachycardia, and hypothermia.
5he treatment of diabetic -etoacidosis is performed on an inpatient basis, with very
close monitoring of the patient. (anagement includes continuous intravenous
infusion of regular (shortacting) insulin, which helps to correct the acidosis by
reducing hyperglycemia, diminishing the flu7 of fatty acids to the liver, and
decreasing -etone production. &luid replacement should be initiated as soon as
possible to improve circulatory volume and tissue perfusion. 5he fluid deficit is
usually 9lectrolyte replacement for potassium and phosphate is also reDuired. It is
important to -eep in mind the identification and treatment of the underlying
precipitating condition that triggered the diabetic -etoacidotic event.
5he prevention of -etoacidosis is paramount in the education of the diabetic patient
and includes early recognition of symptoms and signs, as well as measurement of
urinary -etones when there is persistent hyperglycemia or in the event of infection.
/atients also need to -now the importance of compliance with diabetes management
regimens for the prevention of diabetic -etoacidosis. Because diabetic -etoacidosis
usually develops over several days or longer, it is less li-ely to occur acutely in the
dental office, when compared to hypoglycemic emergencies.
". $yperglycemic hyperosmolar state
$yperglycemic hyperosmolar state is the second most common life-threatening form
of decompensated diabetes mellitus. 5he greatest ris- is for elderly people,
particularly those bedridden or dependent on others for their daily care. Infection is a
common precipitating event, as is poor compliance with insulin therapy. Although
there are many possible causes, the final common pathway is usually decreased access
to water. Jarious drugs that alter carbohydrate metabolism, such as corticosteroids,
pentamidine, sympathomimetic agents, b-adrenergic bloc-ers, and e7cessive use of
diuretics in the elderly may also precipitate the development of hyperglycemic
hyperosmolar state. /resence of renal insufficiency and congestive heart failure
worsen the prognosis.
$yperglycemic hyperosmolar state is a metabolic abnormality characteri;ed by severe
hyperglycemia in the absence of significant -etosis, with hyperosmolarity and
dehydration secondary to insulin deficiency, and massive glycosuria leading to
e7cessive water loss. $yperglycemic hyperosmolar state
>ymptoms may occur more insidiously, with wea-ness, polyuria, polydipsia, and
weight loss persisting for several days before hospital admission. In hyperglycemic
hyperosmolar state, mental confusion, lethargy, and coma are more freDuent because
the maCority of patients, by definition, are hyperosmolar. )n physical e7amination,
profound dehydration in a lethargic or comatose patient is the hallmar-. >ome patients
present with focal neurological signs (hemiparesis or hemianopsia) and sei;ures.
5reatment of hyperglycemic hyperosmolar state consists of vigorous hydration,
electrolyte replacement, and small amounts of insulin. (ortality rate is around 1G in
hyperglycemic hyperosmolar state, and the ris- is increased substantially with aging
and the presence of a concomitant life-threatening illness. (ost deaths occur in the
first " days of hospitali;ation0 thereafter, a significant decrease in morbidity and
mortality is seen
.. $ypoglycemia
$ypoglycemia is a common problem in diabetic patients and in the seriously ill
patient because of the combination of medical conditions and the use of multiple
medications, particularly insulin.
$ypoglycemia is much more li-ely to be encountered in the dental office than are
complications such as diabetic -etoacidosis and hyperglycemic $yperosmolar >tate.
Although the purpose of medical treatment in diabetes is to achieve a level of
glycemic control that may prevent or delay the microvascular complications of the
disease, the ris- of hypoglycemia often precludes true glycemic control in patients
with type diabetes and many with type ".
(any hypoglycemic episodes are never brought to medical attention because they are
treated at home. $owever, severe hypoglycemia is a life-threatening event, and must
be managed immediately. $ospitali;ation is reDuired in a minority of patients, usually
secondary to neurological manifestations such as sei;ures, lethargy, coma, or focal
neurological signs.
$ypoglycemia is the result of absolute or relative therapeutic insulin e7cess and
compromised glucose counter-regulation. %ormally, as glucose levels fall insulin
production decreases. In addition, glucagon is secreted from the pancreas, resulting in
glycogenolysis and release of stored glucose from the liver. 9pinephrine is also
released from the adrenal medulla, causing further rise in blood glucose levels.
9pinephrine release is responsible for many of the signs and symptoms often
associated with hypoglycemia, such as sha-iness, diaphoresis, and tachycardia
>igns and symptoms of hypoglycemia
. !onfusion
". >ha-iness, tremors
.. Agitation
'. An7iety
1. *iaphoresis
2. *i;;iness
,. 5achycardia
3. &eeling of =impending doom?
F. >ei;ures
#. 4oss of consciousness
In some diabetic patients, especially those whose glucose levels are tightly controlled,
the patient:s physiological response to decreasing blood glucose levels becomes
diminished over time. 5his phenomenon is -nown as hypoglycemia unawareness.
Insulin levels do not decrease, epinephrine is not released, and glucagon levels do not
increase, as they normally would be in response to falling glucose levels. 5hus, a
severe hypoglycemic event may occur with little or no warning. In studies e7amining
the potential benefits of intensive diabetes management, the incidence of severe
hypoglycemia was increased
6is- factors for hypoglycemia in patients with diabetes
>-ipping or delaying meals
InCection of too much insulin
97ercise
Increasing e7ercise level without adCusting insulin or sulfonylurea dose
Alcohol consumption
Inability to recogni;e symptoms of hypoglycemia
An7iety8stress
/atient may confuse signs of hypoglycemia with an7iety
*enial of warning signs8symptoms
/ast history of hypoglycemia
$ypoglycemia unawareness
Good long-term glycemic control
5reatment of hypoglycemia
If patient is conscious and able to ta-e food by mouth, give 1B"# g oral
carbohydrateE
'B2 o; ('#B"## ml) fruit Cuice or soda, or
.B' teaspoons table sugar, or
hard candy or ca-e frosting eDuivalent to 1B"# g sugar
If patient is unable to ta-e food by mouth, and intravenous line is in place, giveE
.#B'# ml 1#G de7trose in water (*1#), or
mg glucagon
If patient is unable to ta-e food by mouth and intravenous line is not in place, giveE
mg glucagon subcutaneously or intramuscularly
6is- assessment for hypoglycemia. Uuestions to be as-ed by dentist to patient and8or
patient:s physician
o $ave you ever had a severe hypoglycemic reaction before^
o $ave you ever become unconscious or had sei;ures^
o $ow often do you have hypoglycemic reactions^
o $ow well controlled is your diabetes^
o @hat were your last two hemoglobin Ac values^
o @hat diabetic medication(s) do you ta-e^
o *id you ta-e them today^
o @hen did you ta-e them^ Is that the same time as usual^
o $ow much of each medication did you ta-e^ Is this the same amount you
normally ta-e^
o @hat did you eat today before you came to the dental office^
o @hat time did you eat^ Is that when you normally eat^
o *id you eat the same amount you normally eat for that meal^
o *id you s-ip a meal^
o *o you have hypoglycemia unawareness^
B. !hronic complications
+hronic complications of diabetes mellitus
6etinopathy !ataract, Impaired vision, Blindness
%ephropathy 6enal failure
%europathy
/eripheral neuropathy
S >ensory loss, /ain, (otor wea-ness
Autonomic neuropathy
S Gastrointestinal problems (gastroparesis0 altered
bowel habit), /ostural hypotension
(acrovascular disease
!oronary circulation
(yocardial ischaemia8infarction
!erebral circulation
5ransient ischaemic attac- >tro-e
/eripheral circulation
!laudication
Ischaemia
Altered wound healing
*iabetes causes changes in the periodontal tissues, oral mucosa, salivary gland function, and
oral neural function and increases the ris- for caries
"#
Although dental care providers have traditionally played a primary role in the e7amination
and diagnosis of the specific disorders of these tissues, other health care providers who are
responsible for diagnosing and managing patients with diabetes and pregnant patients can also easily
screen for these oral abnormalities. !hanges in oral soft tissues, in addition to periodontal tissues, can
be helpful in the diagnosis of diabetes in undiagnosed patients and may serve as aids in monitoring
the care of patients with -nown diabetes
21
5hese oral manifestations, their mechanisms, and their interrelationships are shown in &igure
&igureE)ral manifestations of diabetes and their mechanisms and interrelationships
>alivary Gland !hanges
"#
5he oral manifestations of diabetes in the salivary glands include sialoadenosis or
non-inflammatory, non-neoplastic enlargement of the parotid salivary glands, decreased
salivary flow rates and changes in salivary composition. Bilateral enlargement of the parotid
salivary glands has been reported to occur in #B'3G of diabetic patients and may be more
common in patients with poorly controlled diabetes.
""
5he enlargements are caused by gradual accumulation of fat in the glands,
hypertrophy of the acini or secreting units, and, eventually, impaired glandular secretion.
5hese structural changes may be the result of alteration in autonomic neuroregulation of the
glands and atrophy of the myoepithelial cells that facilitate secretion. 9nlarged parotid glands
are also observed in individuals with a history of alcoholism, malnutrition, eating disorders,
or medication side effects, and these conditions should be included in a differential
diagnosis.
"#
$owever, the pathophysiology of these conditions is different. Ierostomia, or the
sensation of dry mouth, is reported to occur in '#B3#G of diabetic patients and is related to
decreased salivary flow rates, particularly in unstimulated whole saliva (the combination of
secretions from all the salivary glands in the mouth). &low rates have been reported to be
significantly lower in patients with poorly controlled diabetes compared to patients whose
diabetes is controlled or nondiabetic patients.
".
5he mechanism by which salivary flow is affected in diabetic patients is thought to be
the result of autonomic nerve dysfunction or microvascular changes that diminish the ability
of the salivary glands to respond to neural or hormonal stimulation. )ther causes may include
dehydration or side effects of concomitant drug therapy commonly used in diabetic patients
(e.g., antihypertensives, diuretics, and antidepressants). 4ow salivary flow rates are
significant because saliva provides a protective coating for the oral mucosa that contains
antimicrobial proteins and immunoglobulins, buffers acidic foods and liDuids, and contains
calcium, which is important for mineral e7change at the tooth surface. 4ac- of adeDuate
saliva leads to an increased ris- of oral yeast infections, increased caries rate, and difficulty
with maintaining oral hygiene, as well as a decrease in Duality of life because of discomfort
from eating, swallowing, and tal-ing.
"#
Jalidated signs and symptoms of an abnormally low salivary flow rate have been
described in the literature.
"'
5hese signs and symptoms can facilitate the detection of
impaired salivary function by health care professionals and support referral to a dental health
care provider to manage or provide preventive or intervention care for these conditions.
(ucosal *isordersE
*isorders of the oral mucosa commonly occurring in diabetic patients include atrophy of the
mucosa, candidiasis (thrush), and lichen planus or lichenoid mucositis. 5hese disorders are
related to chronic salivary hypofunction and to the generali;ed immune dysfunction seen in
diabetic patients.
"#
5ongue AbnormalitiesE
After periodontal tissues, the oral site most freDuently affected in diabetes is the mucosa of
the tongue. %ormally, the dorsal surface of the tongue has an even distribution of the filiform
and fungiform papilla, giving a te7tured appearance that is light pin- in color.
5he ventral and lateral surfaces of the normal tongue are smooth, free of papilla, and
dar-er pin- in color, occasionally with prominent veins. In a fissured tongue, the smooth
te7ture of the dorsum is interrupted with one or more fissures that are predominantly aligned
along the length of the tongue.
5his fissuring may be the result of a chronic low salivary flow rate, which alters the
environment in the oral cavity such that slow-healing soft tissues are more easily traumati;ed
than in non-diabetic patients. A recent study of '#1 diabetic individuals showed that 1.'G of
patients with type diabetes had fissuring of the tongue dorsum compared with #.'G of
control subCects without diabetes (/ W #.###). In another study of '2 type " diabetic
patients, the rate of fissured tongue was ,.3G compared to ..2G in the age- and se7-
matched control subCects (/ W #.##). !omplete or patchy atrophy of the tongue papilla,
resulting in the appearance of a =bald? tongue, is also more common in diabetic patients..
Generali;ed atrophy of the papilla of the tongue has been attributed to nutritional
deficiencies, particularly if it is very red in appearance. &ocal areas of atrophy may indicate
an infection with candida organisms.
"1
A uniDue condition in which an atrophic =bald? spot is located at the midline,
posterior surface of the tongue, anterior to the J-shaped circumvallate papillae, is called
median rhomboid glossitis. It is commonly smooth and flat, but may be depressed or have a
lobular to papillary surface. It is a recogni;ed manifestation of chronic candidiasis.In a study
of ,2 diabetic patients, atrophy of the tongue was found in .FG of the patients, with almost
all appearing as central papillary atrophy.
"2
In another study, median rhomboid glossitis was significantly more prevalent in
diabetic patients than in non-diabetic patients and was associated with elevated levels of
!andida pseudo hyphae in oral smears and diabetic complications of nephropathy and
retinopathy. Another condition of the tongue that is more common in diabetic than in non-
diabetic patients is geographic tongue, or benign migratory glossitis. 5his condition features
focal atrophy of the papilla of the tongue in an irregular =geographic? pattern with
characteristic prominent white or yellowish raised borders that =migrate? over time. 5his
condition is not caused by a candida infection but is characteri;ed as inflammation and may
also be associated with similar symptoms of pain, itching, and burning of the mucosa.
"1
)ral !andidiasisE
5he combination of a low flow rate and immune dysfunction greatly increases the ris-
of oral candidiasis, which is supported by the finding of significantly higher rates of candida
carriage in patients with diabetes compared to control subCects. 5his may also be the result of
increased salivary glucose levels, which promote overgrowth of !andida, as well as
decreased antifungal immunoglobulins in saliva caused by diabetes.
"#
!andidiasis may also affect the palatal, buccal, or labial mucosa. *enture stomatitis is
a diffuse redness of the mucosa occurring under upper dentures in edentulous patients,
particularly when patients complain that their dentures do not fit well. 5he most common
symptom is a burning sensation, although patients may also be asymptomatic. 5his is
considered to be a form of candidiasis with the organism actually infecting the porous denture
acrylic and causing contact hypersensitivity inflammation of the adCacent mucosa.
"#
In a study of # edentulous individuals with type " diabetes compared to 1# control
subCects, 1,..G of the diabetic patients versus .#G of control subCects had denture
stomatitis.
"#
In another study of '#1 subCects with type diabetes compared to "23 non-diabetic
patients, elevated A! was shown to be significantly associated with the presence of denture
stomatitis or the presence of !andida pseudohyphae in oral swabs.
"#
Angular cheilitis is redness or fissures at the corners of the mouth involving the
Cunction of the mucosa and s-in and may also represent a form of candidiasis. 5his condition
occurs significantly more freDuently in diabetic than in non-diabetic patients. )ther causes of
angular cheilitis that should be included in a differential diagnosis include vitamin
deficiencies, anemia, staphylococcal infections, and decrease in face height caused by mouth
over closure from loss of teeth.
",
)ral 4ichen /lanus and 4ichenoid *rug 6eactions
@hite areas of the mucosa that do not wipe off may be a sign of a condition -nown as
lichen planus, a chronic sub epithelial inflammatory disorder that results in a characteristic
lacey or patch-li-e white pattern over reddened mucosa .
"#
Although its e7act etiology is not
-nown, the presence of this mucosal disease has been freDuently associated with diabetes.
$owever, similar mucosal changes called lichenoid drug reactions occur as an adverse side
effect to medications that diabetic patients are commonly prescribed. 5hese include anti
hyperglycemic and anti-hypertensive medications.
"3
)ral !ancer
4esions of the dorsal surface of the tongue are unli-ely to be cancerous but should be
referred to the dental team for diagnosis and treatment. $owever, the occurrence of a lesion
of the lateral or ventral tongue, whether it is white or red or a non-healing ulceration is
always of concern and should be referred immediately to rule out sDuamous carcinoma.
"F
5his
recommendation also applies to lesions occurring in other areas of high cancer ris- such as
the floor of the mouth and tonsillar areas. /atients with diabetes are at higher ris- for oral
cancer occurrence than patients without diabetes, particularly if there is a history of chronic
smo-ing and e7cessive alcohol inta-e.
"#
A study was done to evaluate possible correlation between diabetes and oral
premalignancies and tumors and the results showed that Benign tumors were found in '.1G
and precancerous lesions in 3G of diabetic patients. In the control group these values were
significantly lower, at 2.' and .."G, respectively (/ X #.#). 5he proportion of oral cavity
lesions was higher among diabetic patients compared with that of the control patients. In the
oral cancer patient group, diabetes was present in '.2G and an elevated blood glucose level
in F.,G. 5hese values are significantly higher than those for the tumor-free control group (/
W #.#). 5he gingival and labial tumor location was significantly more freDuent among
diabetic cancer patients than in the nondiabetic group (/ W #.#). 5he combination of diabetes
and smo-ing means a higher ris- for oral precancerous lesions and malignancies and the
authors concluded that *iabetes may be a ris- factor for oral premalignancies and tumors.
.#
9ffects of >mo-ing.
5here is substantial evidence that the presence of a smo-ing habit in diabetic patients
significantly increases not only the ris- of oral cancer, but also the ris- periodontal disease
and mucosal disorders of any type. 5hese factors support freDuent thorough oral
e7aminations and regular oral care, as well as smo-ing cessation programs in the
management of oral mucosal and periodontal disease in patients with diabetes who smo-e.
.
Burning >ensation of the )ral (ucosa
A burning sensation of the oral soft tissues is a freDuent complaint in diabetic patients,
ma-ing diabetes the systemic condition most freDuently associated with this symptom. A
neuropathic basis is supported by observations that the burning sensations in diabetic patients
are freDuently accompanied by changes in taste (dysgeusia) or other sensory distortions
"#
and
also patients with peripheral diabetic neuropathy are more li-ely to have burning sensations
in oral tissues than those without peripheral neuropathy
."
.5herefore, Duestions about
sensations of burning in the soft tissues of the oral soft cavity will be helpful to determine the
possible presence of candidiasis, lichen planus, oral dryness, or neuropathy, all of which may
assist in evaluation of irregular glycemic control.
!linical )ral $ealth !hec-list for *iabetes
"#
A chec-list to facilitate oral e7amination by non-dental providers and promote
communication between medical and dental providers


*enture stomatitis Benign migratory glossitis
(edian rhomboid glossitis. &issured tongue.

Acute pseudomembranous candidiasis. 4ichen planus.
(*iabetes and )ral $ealth Anh-5hi %guyen Agnes 5am Karen @ong)
6ay and )rban in F1# observed that the basic structural changes in the diabetic
periodontium are the degeneration of tissues and the presence of calcified bodies in and
around small blood vessels of the gingiva.
>ilva TA et al. reported atrophy and pleomorphism of the gingival epithelium, with decreased
cellular organelles and increased intercellular spaces, and a thic-ened -eratin layer with the
reduction of height of dermal papilla.
..
According to these authors, increased mitotic activity in epithelial basal layer can contribute
to the compromise of epithelial cells differentiation, leading to a thic-ening of the -eratin
layer and flattening of dermal papillae. &urthermore, they observed a reduction in collagen
solubility and the distortion of reticular fibers.
$illman G et al. in FF3, noticed that under pathologic conditions such as gingival
inflammation, stratum corneum is thic-er (hyper-eratosis), with freDuent fissures and flap lift
off. *ue to inflammation, cells with nuclear fragments appear (para-eratosis) because the
time during which cells migrated to the surface was too short to permit the total
transformation of cells content into -eratin.
.'
)ther researchers observed that epithelial cells are involved in synthesis and secretion of
thrombo7ane B" that appear during the inflammatory process in gingival tissue.
.1
>ome authors postulated that periodontal poc-et formation seems to be initiated by
degenerative changes that ta-e place into the second interior layer of the epithelium, from the
most apical part of Cunctional epithelium, which is in contact with subgingival dental plaDue.
!onsecutively an intraepithelial split occurs, followed by degeneration and desDuamation of
cells lining the split. 5he destruction of epithelial barrier and simultaneous penetration of
bacterial or to7ic products are supposed to be maCor factors involved in apparition of stable
periodontal lesions.
.2
>ome studies were focused on various aspects of immune response in subCects with diabetes,
including collagen metabolism, and have suggested new host modulatory approaches to
address the altered host immune reactions.
.,
>everal collagen abnormalities have been identified, including a large reduction in collagen
synthesis and solubility in gingiva, s-in and bone, and an even more profound increase in the
urinary e7cretion of hydro7yproline, an amino acid mar-er of collagen and its brea-down
fragments. 5hese findings suggest that the disease increases the degradation of newly
synthesi;ed collagen in various connective tissues throughout the body.
.3
Altered collagen metabolism may predispose patients with diabetes not only to periodontal
disease but also to other abnormalities of connective tissues, such as impaired wound healing.
9levations of collagenase activity in gingival crevicular fluid
.3
and decreases in gingival
collagen synthesis
.3
in patients with diabetes have been observed.
/olymorphonuclear leu-ocyte (/(%) functions, such as chemota7is and phagocytosis, are
decreased in patients with diabetes and periodontal disease. >ome studies have observed a
decrease in /(% chemota7is in patients with poorly controlled diabetes, and the severity of
this /(% defect was correlated to the degree of glycemic control.
.F
5here was also reported
an altered monocytic response in diabetic subCects. 9levated levels of chemical mediators of
inflammation -nown as prostanoids (prostaglandin 9", or /G9") have been detected in the
blood of patients with type diabetes.
'#,'

It is -nown that gingival vascular bed gives a clear picture of the general state of the patients.
>ome authors found statistically significant abnormalities in a study of gingival tissue from
diabetes mellitus. /articularly stri-ing were the /A>-positive diastase resistant thic-ening of
the vessel walls and the swelling and proliferation of endothelial cells, which in many cases
produced luminal obliteration. $istological studies have demonstrated that gingival blood
vessels in subCects with long-term diabetes mellitus have more atherosclerosis compared to
those of non-diabetic controls.
.3
In some studies thic-ening of basement membrane of blood vessels in diabetic subCects was
observed in a light microscopic study
'"
. In diabetics, the periodontium is probably affected by
increased collagenase action, functional abnormalities of neutrophil degranulation as a source
of gingival crevicular fluid collagenase or other metabolic abnormalities in periodontal
ligament fibroblast. Jascular changes in properly controlled long-term diabetes shows
microangiopathy.
'.

*iabetes is often associated with increased gingival inflammation in response to bacterial
plaDue. 5his response may be related to the level of glycemic control, with subCects with
well-controlled diabetes having a similar degree of gingivitis as non-diabetic individuals and
poorly controlled diabetic subCects having significantly increased inflammation. Increased
gingival inflammation may be seen in diabetic subCects even though plaDue levels are similar
to non-diabetic controls.
5ype I diabetes and gingivitis
Bemic- et al. (F,1) described a more severe gingivitis in I**( children than in age-
matched control patients, despite similar oral hygiene status. 5his result suggests that such
children are less resistant to gingival inflammation than non I**( patients.
!ianciola et al. (F3") e7amined "2. diabetic children and young adults with insulin-
dependent diabetes mellitus and "#3 non diabetic controls. 5hey observed that, gingivitis
appeared between the age of and . and periodontitis at age . and older. hyperglycaemia
and poor metabolic control of diabetes increased gingival bleeding.
(5he onset of diabetes and poor metabolic control increases gingival bleeding in children and
adolescents with insulin-dependent diabetes mellitus T !lin /eriodontot FF2, ".E #2#-
#2,)
/eriodontitis
5he influence of diabetes on the periodontium has been thoroughly studied. It is difficult to
ma-e definitive conclusions from many of these studies owing to the heterogeneity of study
designs, differences in the populations studied, changes in the classification of periodontal
diseases and diabetes over the years, changes in the methods for diagnosing diabetes and
evaluating glycemic control, inadeDuacy of study controls, and differences in periodontal
parameters or outcome variables measured. >ome research with relatively small numbers of
subCects suggests that diabetes has little influence on the prevalence and severity of
periodontal diseases. $owever, modern epidemiologic methods used in large populations
have clearly established that diabetes is a ris- factor for periodontal disease.
5he meta-analysis conducted by Khader et al. ("##2) included eight comparative cross-
sectional studies, three prospective cohort studies and baseline data of two clinical trials that
compared oral hygiene, gingival and periodontal status between diabetics and nondiabetics.
5his meta-analysis demonstrated that diabetics had poor oral hygiene as measured by the
average of plaDue inde7 (/4I), higher severity of the gingival disease as measured by the
average of gingival inde7 (GI) and B/) score, and higher severity of periodontal disease as
measured by the average of /*, clinical attachment loss and pro7imal bone loss inde7. )n
the other hand, this meta-analysis showed that both diabetics and nondiabetics had similar
e7tent of oral hygiene, gingival and periodontal disease.
A cross-sectional study was designed to evaluate the periodontal status of 31 "-3 year-old
&rench adolescents with insulin-dependent diabetes (I**() and .3 healthy controls in the
same age group.
(Guideline on )ral health for people with diabetes) In their "##3 review, 5aylor and
Borgna--e e7amined , cross-sectional studies reported since "###, and considered that
these reinforced the impression gained from a previous analysis of '3 observational studies
reported between F2# and "### that diabetes adversely affects periodontal health'.
$owever, they made no formal assessment of the Duality of the reports. A meta-analysis of ".
cross-sectional or cohort studies reported between F,# and "##. found greater severity but
the same e7tent of periodontal disease in people with diabetes compared with those without
diabetes
>everal of these studies failed to distinguish between type diabetes and type " diabetes, and
other sources of heterogeneity included age, and duration of diabetes. /eriodontal destruction
can start very early in life, as demonstrated in a recent case-control study of children and
adolescents (age 2-3 years). @hen compared with a non-diabetic control group of 2# with
comparable caries e7perience, the case group of 3" children with type diabetes had
significantly higher plaDue and gingival inflammation levels and significantly more teeth
with evidence of attachment loss. A study in which 3 individuals (age 1-.2 years) refrained
from oral hygiene measures for " days allowing Ye7perimental gingivitis: to develop in
response to accumulation of plaDue, found that the group with type diabetes (with good to
moderate metabolic control) developed an earlier and significantly higher inflammatory
response to a comparable bacterial challenge than did the age- and gender-matched control
group without diabetes. 6esumption of oral hygiene measures restored gingival health in both
groups.
9ffects of 5ype of *iabetes
A number of reports on the relationship between diabetes and periodontal disease have
included children and adolescents (!ianciola et al. F3"0 Gusberti et al. F3.0 >astrowiCoto et
al. FF#0 de /ommereau et al. FF"0 KarCalainen and Knuuttila FF2). 5he consensus has
been that in patients with childhood onset diabetes, periodontitis seems to ensue around
puberty and to progress with age (4alla et al. "##,a). It was suggested that periodontal
destruction can start very early in life in diabetes, becomes more prominent as children
become adolescents (4alla et al. "##2a, b), and is related to the level of metabolic control
(4alla et al. "##,b).
5he relationship between type " diabetes and periodontal disease is complicated by the fact
that diabetes onset generally occurs after the age of '# years, coinciding with the time point
when periodontal disease becomes more prevalent (>alvi et al. "##3). 5he relationship
between *( and oral health status was determined in /ima Indians from the Gila 6iver
Indian !ommunity in Ari;ona. 5his tribe of %ative Americans has the world:s highest
reported incidence and prevalence of noninsulindependent (type ") *(. It was reposted that
subCects with type " diabetes have an increased ris- of destructive periodontitis with an odds
ratio of ".3 (F1G !IE .FB '..) when attachment loss is used to measure the disease. 5he
odds ratio for diabetic subCects was ..'. (F1G !IE "."3B1.2) where bone loss was used to
measure periodontal destruction (9mrich et al. FF). &urther evidence of type " diabetes as a
ris- factor for more severe periodontal disease has been reported (5sai et al. "##"0 >andberg
et al. "###0 !ampus et al. "##10 Tansson et al. "##20 >alvi et al. "##3).
5aylor et al. (FF3a) performed a "-year period longitudinal study of the oral health of
residents of the Gila 6iver Indian !ommunity. !hange in bone score category was computed
as the change in worst bone score reading after " years. 5he cumulative odds ratio for type "
diabetes at each threshold of AB4 of the ordered response was '.
/eriodontal diseases and glycaemic control
As >alvi et al. ("##3) reported, while some studies found no relationship between the level of
glycaemic control and periodontal status ($ove and >tallard F,#0 Barnett et al. F3'0
Bac-ley et al. F330 $ayden and Buc-ley F3F0 >astrowiCoto et al. F3F, FF#0 /inson et al.
FF1), other studies indicated that the degree of glycaemic control may influence the severity
of periodontal disease (Gisl_n et al. F3#0 9rvasti et al. F310 <nal et al. FF.0 &iratli et al.
FF'0 Bridges et al. FF20 5aylor et al. FF2, FF3a, b0 5sai et al. "##"0 !ampus et al. "##1).
9vidence comes from several longitudinal studies that revealed that poorly controlled
diabetes was associated with periodontitis .5aylor et al. (FF3) analy;ed data from a "-year
longitudinal study of the oral health of residents of the Gila 6iver Indian !ommunity. /oorly
controlled type " diabetes was positively associated with greater ris- for a change in bone
score (compared to subCects without type " *() when the covariates were included in the
modelE odds ratio Z.' (F1G !IE ".1B1...). &or subCects with better glycemic control, the
odds ratio was "." (F1G !IE #.,B2.1), when contrasted to those without type " diabetes
5sai et al. ("##") investigated the association between glycemic control of type " *( and
severe periodontal disease in ',.'. persons ages '1BF# years from the %ational $ealth and
%utrition 97amination >tudy III. It was revealed that individuals with poorly controlled
diabetes (glycosylated hemoglobin XFG) had a significantly higher prevalence of severe
periodontitis than those without diabetes ()6 Z ".F#0 F1G !IE .'#B2.#.), after controlling
for age, education, smo-ing status and calculus. &or the better-controlled diabetes
(glycosylated hemoglobin ]FG), there was only a slight tendency for a higher prevalence of
severe periodontitis ()6 Z .120 F1G !IE #.F#B".23) compared with a non-diabetic status
In a case-controlled study of adult *( patients with gingivitis and mild periodontitis, and
patients with *( and severe periodontitis, it was reported that subCects with severe
periodontitis had significantly greater prevalence of cardiovascular and renal complications in
to years, inspite of the fact that haemoglobin Ac ($bAc) values were similar - i.e the
same glycemic control. It seems that classic complications of *( stand in close relationship
with periodontitis, and it is reasonable to spea- of periodontitis as Hthe si7th complication of
*(H
A meta-analysis was performed to assess the effectiveness of >6/ in improving glycemic and
metabolic control in patients with chronic periodontitis and *( ". After the study selection
process, five randomi;ed clinical trials were included .5he results indicated that >6/ can
effectively improve the glycemic control of patients with *(" by reducing the serum levels
of $bac and &/G. %o evidence of effectiveness was found in the improvement of metabolic
control .$owever, because the roles of important prognostic factors remain to be analy;ed
and further high-Duality studies are needed,( 9ffectiveness of /eriodontal 5reatment to
Improve (etabolic !ontrol in /atients @ith !hronic /eriodontitis and 5ype " *iabetesE A
(eta-Analysis of 6andomi;ed !linical 5rials. *)IE #.F#"8Cop."#"."#.,,)
Mechanisms of interaction bet'een diabetes mellitus and periodontium
!hanges in subgingival environment Altered microbiota
!hange in gingival crevicular fluid
!omposition
Altered tissue homeostasis and wound healing *ecreased collagen production
Increased matri7 metalloproteinase
activity
Accumulation of advanced glycation end
products
*ecreased tissue turnover
!hanges in host immunoinflammatory
response
*ecreased polymorphonuclear leu-ocyte
chemota7is, adherence, phagocytosis
9levated pro-inflammatory cyto-ine
response from monocytes8macrophages
Increased tissue o7idant stress
Kuo etal has proposed hypothetical mechanisms through which diabetes may influence the
periodontium
Influence of AG9s and 6AG9 on diabetic periodontium. 5his figure summari;es our
hypotheses regarding the potential role of enhanced AG9 interaction with cellular 6AG9 in
the pathogenesis of diabetes-associated periodontal disease. (/sE macrophages. I4-2E
interleu-in-2. 5%&-aE tumor necrosis factor a. ((/sE matri7 metalloproteinases.
( /eriodontology "###, Jol. "., "###, 1#B2")
5o delineate possible causal lin-s between periodontal disease and medical inflammatory
diseases, research may e7amine whether the following criteria can be fulfilledE
. /revalence and incidence of the medical disease in Duestion should be significantly higher
in periodontitis patients than in periodontally healthy individuals (retrospective data)
". )nset of the medical disease should follow the onset of periodontitis (prospective data)
.. 6emoval or reduction of periodontitis should decrease the incidence of the medical disease
(effect of treatment)
'. (icro-organism(s) (if recoverable8identifi able) of the medical infection should be the
same as (species, biotype, serotype, genotype) the oral microorganism(s) of the patient
(specific etiologic agent)
1. Appropriate e7perimental animals with periodontitis or with inoculated microorganisms
should develop more medical diseases than periodontally healthy animals. $uman
populations with periodontitis in controlled studies should develop the medical disease more
freDuently than periodontally healthy populations (e7perimental reproduction8 study of
medical disease)
2. 5he postulated association between periodontal disease and medical disease should be
biologically feasible (pathogenic mechanism) (>lots FF3)
In analy;ing the literature, we find the following information about each of the Bradford $ill
criteria about the association between diabetes mellitus and periodontal disease.
a) Association. >trength of association and temporal relationshipE
/eriodontitis as a ris- factor for diabetesE
5o determine the prevalence of diabetes in subCects with and without periodontitis must focus
on the data from the %$A%9> (%ational healthand %utrition 97amination >urvey) III.
Analysis indicates thatE ) of ,"F. patients with periodontitis, ".1G had diabetes, ") of
",,3 subCects without periodontitis, only 2..G had diabetes. 5he prevalence of diabetes in
patients with periodontitis is statistically higher (almost " times) than the patients without
periodontitis. &urthermore, of the F"3 subCects with diabetes, ,..G had periodontitis in non-
diabetics, FG had periodontitis. 5hus, there is epidemiological evidence that periodontal
disease is more prevalent among diabetics.
*iabetes as a ris- factor for periodontitisE
5he relationship between diabetes and periodontitis has been e7tensively studied, has been
shown that the presence of diabetes increases the prevalence, incidence and severity of
periodontitis. Analy;ing the prevalence of subCects with attachment loss V 1 mm, there was an
increase in the prevalence of periodontitis with increasing age up to groups of '1 to 1', with
higher values in diabetic subCects. 5hus, in the lower age groups (1-"' years) diabetic
subCects suffer '.3 times more than non-diabetic periodontitis, while in those of "1-.' years,
the difference is ".. times . 6egarding the severity of destruction estimated average insertion
loss is again higher in diabetic subCects between 1 and 11 years, with duplicate values shown
against non-diabetic subCects in the age group between 1 and "' years.
b) Association. *ose-responseE
5here is sufficient evidence to affirm the e7istence of a dose-response relationship between
periodontitis and diabetes, so that a worsening of glycemic control is an increase in the
adverse effects of diabetes on periodontal disease, and vice versa . In general, it is considered
that there is a good diabetes when $bAc (glycosylated hemoglobin which is a test that
allows us to see the evoluaci`n of blood glucose control over the past three months) are less
than ,G moderate control when $bAc values are between , and 3G, and poor when $bAc
over 3G .
9ffect of glycemic control on periodontitisE
>cientific evidence confirms that poorer glycemic control contributes to a worse periodontal
status. >ystematic review of 5aylor "## concluded that of the five studies evaluating the
association between glycemic control and periodontitis in subCects with type " *(, four
found that poor glycemic control is a factor associated with poorer periodontal status.
9ffect of periodontitis on glycemic controlE
5he best evidence in relation to this field comes from treatment studies and observational
studies. 5he combined results allow us to confirm the e7istence of the effect of periodontitis
on glycemic control of diabetic patients. A longitudinal study of reference in this field is that
of 5aylor et al, FF2, on the /ima Indian population. *uring the years F3"-F3F the subCects
scans performed at intervals of two years. 5he results indicate that subCects with severe
periodontitis are about 2 times more li-ely to have worse glycemic control ($bAc) at follow
up. @hen considering the effect of age, there is observed as a decreased effect on glycemic
control periodontitis as it affects age. >o that for the age group "1 years to baseline, the )6 of
..1,, compared to #., for the group of 1#.
A cohort study conducted by (orita et al. "#" had shown that /eriodontal disease (poc-ets
X2mm) leads to increased incidence of type " diabetes ($bAcX2.1G) in 1 years
6etrospective !ohort done by >aito et al."##' had shown that /roportion with *( increased
significantly with mean //*, 9ach additional mm mean //* corresponded to #..G $bAc
increase (pZ#.##,) , severity of disease (e7pressed as either //* or !A4) was significantly
associated with development of manifest diabetes
Ide et al. "# conducted a 6etrospective !ohort study in which they concluded that
(oderateNsevere periodontitis was significantly associated with *( ris-, there is an
increased tendency for increased ris-, but not significant, &emales with moderate
periodontitis have significantly higher ris- for *(
c) Biological plausibilityE )ver the years have proposed multiple mechanisms that attempt to
e7plain the association between diabetes and periodontitis. 5hey could be divided into three
groupsE those that focus on a direct effect of diabetes on periodontitis, which focus the
opposite relationship, ie, the direct effect of periodontitis on diabetes, and finally, the
proponents of e7istence of a pathological pathway common to both diseases, which would
determine the e7istence of a host susceptible to them.
d) 97perimental modelsE (any studies in e7perimental animals made in this field. @ith their
demonstrated the effect of diabetes on the inflammatory response to /. gingivalis in the
connective tissue of a mouse model of type " diabetes " and type . 97perimental studies in
animal models allow you to chec- what had been previously demonstrated in epidemiological
studies in humans, thus providing more evidence and greater strength to the bidirectional
relationship between diabetes and periodontitis.
e) !ausation. Intervention studiesE A meta-analysis was conducted as periodontal treatment
shows a decrease of #..3G $bAc, with no statistically significant differences with respect to
the control group. >eparating the studies based on the type of diabetes, it was observed that in
the case of type " diabetes periodontal treatment effect was greatest, a reduction of #.1,G in
$bAc (although not statistically significant). As for the type of treatment, mechanical
therapy alone has declined by #.'G compared to antibiotic treatment in type " diabetes,
which gives a slightly greater reduction (#.,G). . in new studies that have been conducted,
these reductions were even greater ("-#G reduction)
-ffect of periodontal disease on %estational diabetes
A !ase-!ontrol study done by Iiong et al."##F on 1F pregnant women (1. G*( and #2
non-G*() with a mean Age of "F.F(a1.2) yrs and ",.(a1.F) yrs respectively. 5hey have
concluded that /* was consistently associated with increased ris- of G*(, regardless of /*
definition. 5here was a dose-response relationship of increased G*( ris- with increasing
severity of periodontal disease, assessed by //* or !A4
A !ase-!ontrol study done by *asanaya-e et al. "##3E 9levated ris- for G*( in women
with high vaginal levels of 5annerella forsythia,5. forsythia in cervi7 N dental plaDue not
statistically significant , $aving /* not statistically significant
@hat is the mechanism by which hyperglycemia affects the periodontium or how
periodontitis may modulate the metabolic control^
If we analy;e the relationship diabetes - diabetes periodontitis since we must consider that a
maCor pathophysiological conseDuences of hyperglycemia by !ommission e7cessive
chemical interaction of glucose with proteins, binding occurs between the first and the latter
without any need for intervention en;yme, a process -nown as glycosylation, solely depends
on the glucose concentration and the contact time of this monosaccharide with proteins. 5his
process leads to the formation of so-called glycosylation end products.
5he advanced glycation end products (AG9s) accumulate in the presence of prolonged
hyperglycemia and its formation alters the function of many components of the e7tracellular
matri7 by modifying the matri7 interactions -matri7 and matri7-cells. 5hese disturbances
have an adverse effect on the target tissues, especially the stability of the collagen and
vascular integrity. (onocytes, macrophages and endothelial cells have high affinity receptors
for these AG9s AG9s. 4auni`n macrophage receptor will lead to an increased secretion of
I4-l, 5%&-O and insulin growth factor-li-e, while the binding of AG9s to endothelial cell
receptor will lead to changes in coagulation involving focal thrombosis and vasoconstriction.
It is -nown that these AG9s mediated events have great importance in the pathogenesis of
diabetic complications such as retinopathy, neuropathy, nephropathy and atherosclerosis, but
they may also be involved in the pathogenesis of periodontitis increasing tissue destruction
this level .
4i-ewise, affects glycemic control resist cia host against infection. investigations to h shown
an reduction in chemota7is, phage citosis neutrophil and death in diabetic intracellular cos
poorly controlled. &ebruary
5hus if hyperglycemia occurs consider glycosylation end products (AG9s) which lead to the
condition of the macrophages thus promoting the release of 5%&, I4-, and other mediators
involved with periodontal disease, as also affects the function of the neutrophils, it is easy to
assume that both conseDuences affect the pathogenesis of the disease.
If we analyse the relationship starting from periodontal disease is important to remember that
)ffenbacher made a thorough review of the pathogenesis of periodontitis and the role of
bacteria and mediators inflammation responsible for tissue destruction where periodontal
bacteria to submit a number of virulence factors that are either secreted or part of the
structure of the organism (lipopolysaccharide, fatty acids s short chain to7ins ... ) interacts
with the hostLs immune mechanisms triggering the release of inflammatory mediators
catabolic matter mainly b I4-l, I4-2, /G9" and 5%&-a cause destruction of connective tissue
and bone resorption.
Infections, such as periodontal disease. alter the metabolic state of the host-endocrinological
difficult to control their blood sugar levels.
Bacterial infections produce tissue resistance to insulin to stimulate the secretion of
cyto-ines, mainly 5%&-a and I4-l that decrease >ame action on tissues
5he insulin receptor tyrosine -inase, the e7pression of second messengers and protein -inase
action and, individually or together, mediate some of the effects of insulin, such as the
translocation and activation of transport proteins Kanety glucosa." 5he study suggests that
5%&-a is primarily responsible for inducing tissue resistance to insulin by suppressing the
phosphorylation of the insulin receptor to I6>-l (insulin receptor substrate- l).
5herefore, to decrease the action of insulin has a greater presence of hyperglycemia why
there is a Hvicious cycleH in the relationship diabetes - periodontal disease and vice versa.
%etwor- of potential mechanisms involved in the pathogenesis of periodontitis in diabetes.
5he hyperglycaemic state that characteri;es diabetes has several deleterious effects. It drives
the formation of irreversible advanced glycation end-products (AG9s) and the e7pression of
their chief signalling receptor 6AG9. 5his interaction, in turn, leads to immune cell
dysfunction, alters phenotype and function of other -ey cells in the periodontium, and
contributes to cyto-ine imbalance with increased generation of certain pro-inflammatory
cyto-ines. $yperglycaemia also contributes to enhanced levels of reactive o7ygen species
(6)>) and a state of o7idative stress, both directly and indirectly through the AG986AG9
a7is, promoting Duantitative and Dualitative shifts in cyto-ine profiles. &inally,
hyperglycaemia modulates the 6A%K48)/G ratio, again directly and indirectly via the
AG986AG9 a7is, tipping the balance towards enhanced inflammation and destruction. All
the above, complemented by the effects of ecological shifts in the subgingival biofilm and the
circulating adipo-ines generated due to diabetes-associated adiposity and dyslipidaemia,
drive this vicious cycle of cellular dysfunction and inflammation. 5he end result is a loss of
eDuilibrium where enhanced periodontal tissue destruction and impaired repair ensue, leading
to accelerated and severe periodontitis. Importantly, as shown, several of the associations
between the different elements in the figure are bidirectional0 for e7ample, the pro-
inflammatory state further feeds the generation of AG9s, 6)>, and adipo-ines, increases the
6A%K48)/G ratio and helps pathogenic subgingival bacteria thrive. It is also important to
note that a) the amount and Duality of evidence supporting the various pathways in this figure
varies, and b) although the goal is to depict the maCor mechanisms and networ-s described in
the literature, other pathways and lin-s among the various elements shown do e7ist, but
cannot easily be demonstrated in a single schematic. &inally, the processes outlined are
potentially modified by several other factors, such as genetics, age, smo-ing, stress, all of
which may contribute significantly to inter-individual variations in disease e7perience.
c "#. 9uropean &ederation of /eriodontology and American Academy of /eriodontology
>ummaryE In summary, more research is needed to reinforce e7tant information on the
importance of the limited number of factors studied to date and provide data on additional,
potentially relevant mediators. 5he rubric for such research should shift from cross-sectional
clinical studies to longitudinal studies of disease progression and treatment effects, integrated
with in vitro analyses of cellular responses and holistic studies using animal models. 5he
conclusions of this review suggest that more detailed studies of 5%&-a, I4- b, I4-2, 6A%K4
and )/G are all warranted, integrated with studies of pro-inflammatory pathways activated
by AG986AG9 and possibly o7idative stress particularly in the conte7t of bone and tissue
turnover and repair. *elineating the role ofthe cellular elements of inflammation, for
e7ample, monocytes8macrophage, neutrophils and 5-cells is more challenging but eDually
important. 5he appropriate design of future studies is critical for a more definitive
understanding of the comple7 processes involved.
T !lin /eriodontol "#.0 '# (>uppl. ')E >.B>.' doiE #.8Ccpe."#1F
>chematic representation of the proposed two-way relationship between diabetes and
periodontitis. 97acerbated and dysregulated inflammatory responses are at the heart of the
proposed two-way interaction between diabetes and periodontitis (purple bo7), and the
hyperglycaemic state results in various proinflammatory effects that impact on multiple body
systems, including the periodontal tissues. Adipo-ines produced by adipose tissue include
proinflammatory mediators such as 5%&-O, I4-2 and leptin. 5he hyperglycaemic state results
in deposition of AG9s in the periodontal tissues (as well as elsewhere in the body), and
binding of the receptor for AG9 (6AG9) results in local cyto-ine release and altered
inflammatory responses. %eutrophil function is also altered in the diabetic state, resulting in
enhancement of the respiratory burst and delayed apoptosis (leading to increased periodontal
tissue destruction). 4ocal production of cyto-ines in the periodontal tissues may, in turn,
affect glycaemic control through systemic e7posure and an impact on insulin signalling
(dotted arrow). All of these factors combine to contribute to dysregulated inflammatory
responses that develop in the periodontal tissues in response to the chronic challenge by
bacteria in the subgingival biofilm, and which are further e7acerbated by smo-ing
Gene 97pression *ynamics during *iabetic /eriodontitis
/rolonged inflammation in diabetes has a broad effect in up regulating the e7pression of host
response genes and apoptotic genes in the periodontium. 5his is consistent with findings that
diabetes leads to dysregulation of cyto-ine networ-sE 5here is an up-regulation of pro-
inflammatory and pro-apoptotic pathways in vivo in diabetic fracture-healing (Kayal et al.,
"##). 5he results presented here indicate that diabetes-enhanced inflammation both up- and
down-regulates genes involved in cellular activity and cell signaling, while it predominantly
up-regulates genes involved in the host response, apoptosis, and coagulation8homeostasis
complement and down-regulates m6%A levels of neuron, retina, and energy8metabolism-
associated genes.( T *ent 6es F(")E2#-21, "#")
/eriodontal diseases and complications of diabetes
5horstensson et al., FF20 T !lin /eriodontol..F case-control pairs, type and type " diabetes
c,ases (severe periodontal disease) had greater ris- for /roteinuria , !ardiovascular
complicationsE stro-e, 5IA, angina, myocardial infarction, and intermittent claudication.
>aremi et al., "##10 *iabetes !are. /rospective cohort study of nZ2"3, type " diabetes
>evere periodontal diseaseE .."7 greater ris- for cardiorenal mortality (ischemic heart disease
and nephropathy) , !ontrolled for established ris- factorsEage, se7, duration, B(I,
hypertension, blood glucose, cholesterol, 9!G abnormalities, macroalbuminuria, and
smo-ing , *iabetes and /rogression of /eriodontal *estruction
>hultis et al., "##,0 *iabetes !are.
/rospective cohort study of nZ1"F, type " diabetes, >evere periodontal disease associated
with incidence of macroalbuminuria and 9>6* adCusted for age and se7
conclusions
!onsistent, world-wide evidence that diabetes adversely affects periodontal health
9vidence that chronic periodontitis may potentiate insulin resistance
9vidence that treating periodontal infection canE
4ead to improved glycemic control
/ossibly prevent, delay, or reduce severity of complications
/ossibly prevent the development of diabetes itself
. !onsultation @$). *efinition, diagnosis and classification of diabetes mellitus and its
complications. Geneva Switz World Health Organ FFF0.EB1F.
". >u;anne (, @ands T6. Al;heimer:s disease is type . diabetesRevidence reviewed. J
Diabetes Sci Technol "##30"E#B..
.. Genco 6T, @illiams. Periodontal disease and overall health: a clinicians guide.
+ardley, /a.E /rofessional Audience !ommunications0 "##.
'. (elmed >, /olons-y K>, 4arsen /6, et al. Williams Tetboo! o" #ndocrinolog$: #%ert
&onsult. 9lsevier $ealth >ciences0 "#.
1. 5aniguchi !(, 9manuelli B, Kahn !6. !ritical nodes in signalling pathwaysE insights
into insulin action. 'at (ev )ol &ell *iol "##20,E31BF2.
2. !olledge %6, @al-er B6, 6alston >, et al. Davidsons %rinci%les and %ractice o"
medicine+ 9dinburgh0 %ew +or-E !hurchill 4ivingstone89lsevier0 "##.
,. American *iabetes Association. >tandards of (edical !are in *iabetes--"#.. Diabetes
&are "#"0.2E>B>22.
3. (c/hee >T, /apada-is (A, 6abow (@. ,-./ current medical diagnosis 0 treatment.
%ew +or-0 4ondonE (cGraw-$ill (edical 0 (cGraw-$ill ddistributore0 "#".
F. *iabetes /revention 5rial--5ype *iabetes >tudy Group. 9ffects of insulin in relatives
of patients with type diabetes mellitus. ' #ngl J )ed "##"0.'2E231BF.
#. Intensive *iabetes 5reatment and !ardiovascular *isease in /atients with 5ype
*iabetes. ' #ngl J )ed "##10.1.E"2'.B1..
. Bluestone TA, $erold K, 9isenbarth G. Genetics, pathogenesis and clinical interventions
in type diabetes. 'ature "##0'2'E"F.B.##.
". /revention of 5ype " *iabetes @ith 5roglita;one in the *iabetes /revention /rogram.
Diabetes "##101'E1#B2.
.. >hichiri (, Kishi-awa $, )h-ubo +, et al. 4ong-term results of the Kumamoto >tudy
on optimal diabetes control in type " diabetic patients. Diabetes &are "###0". >uppl
"EB"B"F.
'. 5ight blood pressure control and ris- of macrovascular and microvascular complications
in type " diabetesE <K/*> .3. *)J FF30.,E,#.B..
1. Gfde /, 4und-Andersen $, /arving $-$, et al. 9ffect of a (ultifactorial Intervention on
(ortality in 5ype " *iabetes. ' #ngl J )ed "##30.13E13#BF.
2. A!!)6* !linical 5rial /ublishes 6esults. "##30 Available fromE
httpE88www.nhlbi.nih.gov8news8press-releases8"##38accord-clinical-trial-publishes-
results.html
,. >a7ena 6, Joight B&, 4yssen-o J, et al. Genome-@ide Association Analysis Identifies
4oci for 5ype " *iabetes and 5riglyceride 4evels. Science "##,0.2E..B2.
3. >cott 4T, (ohl-e K4, Bonnycastle 44, et al. A Genome-@ide Association >tudy of
5ype " *iabetes in &inns *etects (ultiple >usceptibility Jariants. Science
"##,0.2E.'B1.
F. *e@itt *9, $irsch IB. )utpatient insulin therapy in type and type " diabetes mellitusE
scientific review. J1)1 J 1m )ed 1ssoc "##.0"3FE""1'B2'.
"#. Gandara BK, (orton 5$. %on-/eriodontal )ral (anifestations of *iabetesE A
&ramewor- for (edical !are /roviders. Diabetes S%ectr "#0"'EFFB"#1.
". (ealey B4. 5he Interactions Between /hysicians and *entists in (anaging the !are of
/atients @ith *iabetes (ellitus. J 1m Dent 1ssoc "##30.FE'>B,>.
"". 4alla 6J, *:ambrosio TA. *ental management considerations for the patient with
diabetes mellitus. J 1m Dent 1ssoc "##0."E'"1B.".
".. >reebny 4(, +u A, Green A, et al. Ierostomia in *iabetes (ellitus. Diabetes &are
FF"01EF##B'.
"'. %ava;esh (, !hristensen !, Brightman J. !linical !riteria for the *iagnosis of
>alivary Gland $ypofunction. J Dent (es FF"0,E.2.BF.
"1. Bastos A de >, 4eite A6/, >pin-%eto 6, et al. *iabetes mellitus and oral mucosa
alterationsE prevalence and ris- factors. Diabetes (es &lin Pract "#0F"E##B1.
"2. &arman AG. Atrophic lesions of the tongueE A prevalence study among ,1 diabetic
patients. J Oral Pathol F,201E"11B2'.
",. Bic-le K, 6oar- 56, $su >. Autoimmune bullous dermatosesE a review. 1m 2am
Ph$sician "##"021E32B,#.
"3. 6omero (A, >eoane T, Jarela-!entelles /, et al. /revalence of diabetes mellitus
amongst oral lichen planus patients. !linical and pathological characteristics. )ed Oral
3rgano O" Soc #s% )ed Oral 1cad 4beroam Patol )ed *ucal "##"0,E"BF.
"F. 6eamy BJ, *erby 6, Bunt !@. !ommon tongue conditions in primary care. 1m 2am
Ph$sician "##03E2",B.'.
.#. <Cpgl (, (atos ), Bhbo- G, et al. *iabetes and )ral 5umors in $ungary
9pidemiological correlations. Diabetes &are "##'0",E,,#B'.
.. (oore /A, @eyant 6T, (ongellu;;o (B, et al. 5ype *iabetes (ellitus and )ral
$ealthE Assessment of /eriodontal *isease. J Periodontol FFF0,#E'#FB,.
.". (oore /A, Guggenheimer T, )rchard 5. Burning mouth syndrome and peripheral
neuropathy in patients with type diabetes mellitus. J Diabetes &om%lications
"##,0"E.F,B'#".
... >ilva TA&, 4orencini (, 6eis T66, et al. 5he influence of type I diabetes mellitus in
periodontal disease induced changes of the gingival epithelium and connective tissue.
Tissue &ell "##30'#E"3.BF".
.'. $illmann G, *ogan >, Geurtsen @. $istopathological Investigation of Gingival 5issue
&rom /atients @ith 6apidly /rogressive /eriodontitisA. J Periodontol FF302FEF1B"#3.
.1. Bons->icard !, !hoDuet A, 9scola 6. 4ocali;ation and Duantification of 5IB" in
human healthy and inflammatory gingival mucosa. J Periodontal (es FF30..E",B.".
.2. 5a-ata 5, *onath K. 5he mechanism of poc-et formation. A light microscopic study on
undecalcified human material. J Periodontol F3301FE"1B".
.,. Golub 4(, 4ee $(, 4ehrer G, et al. (inocycline reduces gingival collagenolytic
activity during diabetes. /reliminary observations and a proposed new mechanism of
action. J Periodontal (es F3.03E12B"2.
.3. (onea A, (e;ei 5, (onea (. 5he influence of diabetes mellitus on periodontal tissuesE
a histological study. (om J )or%hol #mbr$ol "#"01.E'FB1.
.F. (anouchehr-/our (, >pagnuolo /T, 6odman $(, et al. Impaired %eutrophil
!hemota7is in *iabetic /atients with >evere /eriodontitis. J Dent (es F302#E,"FB.#.
'#. !hase $/, @illiams 64, *upont T. Increased prostaglandin synthesis in childhood
diabetes mellitus. J Pediatr F,F0F'E31BF.
'. Bagdade T*, >tewart (, @alters 9. Impaired Granulocyte AdherenceE A 6eversible
*efect in $ost *efense in /atients with /oorly !ontrolled. Diabetes F,30",E2,,B3.
'". $ove KA, >tallard 69. *iabetes and the /eriodontal /atient. J Periodontol
F,#0'E,.B3.
'.. Kronman T$, !ohen ((, !ote *, et al. $istologic and $istochemical >tudy of $uman
*iabetic Gingiva. J Dent (es F,#0'FE,,B,,.