DIABETES MELLITUS

Handout for 4th Medical Lecture

Definition

Diabetes Mellitus is a chronic disorder of carbohydrate, fat and protein metabolism. It is

characterised by absolute or relative lack of insulin and by abnormalities of structure and function of
blood vessels. Approximately 3% of the world population (100 million people) suffer from diabetes
making it a very common disease.

Insulin is produced by the endocrine pancreas. The islets of Langerhans in the pancreas which
constitute approximately 2% of the total weight of the pancreas, elaborate several hormones. The
main hormones produced are insulin, somatostatin, glucagon and pancreatic polypeptide. The four
main hormones are produced by four different cell types. Beta cells (68% of the islet cell population)
produce insulin. Alpha cells secrete glucagon (20% of the population). Glucagon causes
hyperglycemia by its glycogenolytic activity in the liver. Delta cells contain somatostatin which
suppresses insulin and glucagon release. PP cells contain pancreatic polypeptide, which has a number
of gastro-intestinal effects including stimulation of intestinal enzymes.

Insulin is a major anabolic hormone. It is necessary for

1. Transmembrane transport of glucose and aminoacids.
2. Glycogen formation in the liver and skeletal muscle.
3. Glucose conversion to triglycerides.
4. Nucleic acid synthesis
5. Protein synthesis

The main metabolic function of insulin is to increase the rate of glucose transport into certain cells
of the body (striated muscle cells, fibroblasts and fat cells). Insulin also initiates DNA synthesis in
certain cells and stimulates their growth and differentiation. Insulin first binds to the insulin receptor
on the target cell, which is a tyrosine kinase receptor. Receptor bound insulin will then trigger
intercellular responses. One of these important early responses involves translocation of glucose
transport proteins or units (GLUTS) from the Golgi apparatus to the plasma membrane thereby
facilitating cellular uptake of glucose. There are several different forms of GLUTS. Some glucose
transport proteins are insulin- independent such as those present in liver hepatocytes and beta cells of
the pancreas, and in these cells the glucose transport units facilitate rapid equilibration of glucose
between the extra cellular and intercellular compartments.

There are two main types of diabetes mellitus, Type 1 and Type 2.
Type 1 diabetes mellitus was previously referred to as insulin dependent diabetes mellitus and Type 2
was previously referred to as non-insulin dependent diabetes mellitus.
There are two main causes of hyperglycemia. The first is due to insulin antagonism or receptor
downregulation or dysfunction and this situation pertains in both Type 2 diabetes mellitus and in
situations with excess somatotrophin, excess cortisol, excess glucagon or catecholamines all of which
are antagonistic to insulin and have the effect of raising blood sugar.
The second main cause of hyperglycemia is due to reduction of the functional islet cell mass. The
latter pertains in Type 1 diabetes mellitus but also in conditions such as haemochromatosis and in
surgical removal of the pancreas, chronic pancreatitis and treatment with aloxan.

Normally insulin promotes transmembrane transport of glucose and aminoacids and maintains
normoglycemia. It promotes glycogen formation in the liver and muscle and conversion of glucose
to triglycerides in fat. It also promotes protein synthesis from aminoacids.
In diabetes however there is failure of transmembrane transport of glucose given rise to
hyperglycemia. Glycogen is not formed and the existing stocks of glycogen in liver and muscle are
broken down by the unopposed action of glucagon. Fat is also broken down leading to increased free

1
fatty acids which are then oxidised in the liver to acetone, beta-oh-butyric acid and acetoacetic acid.
Hyperglycemia and insulin deficiency also promotes breakdown of existing protein to produce amino
acids, which are converted to glucose in the liver, which further increases the existing hyperglycemia.

Type 1 or juvenile insulin dependent diabetes mellitus is characterised by the presence of HLA-DR3
or HLA-DR4 alleles or both. These alleles are present in about 95% of white patients. The
monozygous twin concordance however is only 40-50% so factors other than genetic susceptibly is
obviously involved.

Type 2 or adult non-insulin dependent diabetes mellitus shows no HLA relationship but does however
demonstrate strong genetic influence indicated by monozygous twin concordance of 50-90%.
However, among identical twins the cumulative concordance risk (i.e. both twins affected) from birth
to age 35 is 70% in Type 1 diabetes.

With regard to the pathogenesis of Type 1 diabetes mellitus the current hypothesis is as follows:
There is evidence for organ-specific autoimmunity with antibodies to islet cells in most acute cases.
Antibodies to islet cells are mainly directed against glutamic acid decarboxidase (GAD) and other
cytoplasmic proteins but it is possible that this may be a secondary phenomenon. GAD
autoantibodies can be detected long before the onset of clinical symptoms. Associated familial
autoimmunity has also been described and lymphocytic insulitis is observed in the islets of patients in
early diabetes and also in animal models of autoimmune diabetes. The infiltrate consists of CD8
positive T lymphocytes with variable numbers of CD4 T cells and macrophages.
In summary there is overwhelming evidence implicating autoimmunity and immune mediated injury
as causes of beta cell loss in Type 1 diabetes. There is also epidemiological evidence for viral damage
to islets in many patients. High titres of coxackie antibodies have been detected in acute cases
particularly in the first year. A seasonal variation in incidence of Type 1 diabetes has been noted, the
onset being higher in autumn and winter than spring and summer. Several scenarios have been
postulated for the role of viruses. One is that viruses cause mild beta cell injury which is followed
than by an autoimmune reaction against previously sequestered antigens in virally altered beta
cells in persons with HLA linked susceptibility. Many viruses are beta cell trophic but direct viral
injury alone is rarely severe enough to cause diabetes mellitus. However, during viral insulitis
cytokines such as gamma interferon are secreted locally by T cells and cause beta cells to express
class 2 MHC molecules (HLA). These antigenically altered cells provide a target for cytotoxic CD8
positive T cells.

The pathogenesis of Type 2 diabetes mellitus remains an enigma. There is no evidence that
autoimmune mechanisms are involved. Lifestyle clearly plays a role but genetic susceptibility is even
more important than in Type 1 diabetes. The disease is not linked to any HLA genes. Age and obesity
are significant factors in genetically susceptible individuals. The two main metabolic defects that
characterise Type 2 diabetes are
1. A derangement of beta cell secretion of insulin
2. A decreased response of peripheral tissues in responding to insulin.

The beta cell defect will lead to deranged insulin secretion (initially hyperinsulinemia, later insulin
secretion appears normal with loss of the pulsatile pattern of secretion, later a mild to moderate insulin
deficiency). Both the deranged insulin secretion and the inadequate glucose utilisation (due to
inadequate glucose utilisation) lead to hyperglycemia, beta cell exhaustion and Type 2 diabetes.
Receptor downregulation may be due to a relative decrease in the number of insulin receptors and or
to defective post-receptor signalling. Beta cell hypofunction may be due to exhaustion due to
persistent hyperglycemia caused by the above or a reduction of beta cell mass due to autoimmune
destruction or toxic/viral agents. Obesity is an extremely important environmental influence in Type
2 diabetes and approximately 80% of Type 2 diabetics are obese with abdominal obesity having a
greater impact. Intra-abdominal fat catabolism delivers free fatty acids to the liver yet is relatively
resistant to the modulating effect of insulin (neither of which is true for subcutaneous fat).

2
Islet Pathology in Diabetes

The pancreas in long standing Type 1 diabetes shows absence of beta cells in the islets. In Type 2
diabetes the islets may appear normal or may show replacement by amyloid due to deposition of
amylin, a protein that is co-secreted with insulin by the beta cells.

Pathogenesis of the Complications for Diabetes

The morbidity associated with long standing diabetes of either type results from a number of serious
complications namely microangiopathy, retinopathy, nephropathy and neuropathy. Evidence suggests
that the complications are a consequence of the metabolic derangements, mainly hyperglycemia.

Nonenzymatic Glycosylation

This is a process where by glucose chemically attaches to the amino group of proteins without the aid
of enzymes. Initially, glucose forms chemically reversible glycosylation products with protein but
later irreversible cross-linkage of basement membrane collagen Type 4 develops, resulting in
advanced glycosylation end-products (AGE) which accumulate over the life time of the vessel wall.
AGE formation on protein such as collagen causes cross links between polypeptides of the collagen
molecule with trapping of plasma or interstitial protein resulting in a thickened and leaky basement
membrane.
AGE cross linked proteins are resistant to proteolytic digestion and impair the interaction of collagen
with other matrix components (laminin, proteoglycans) all of which result in structural and functional
defects in the basement membrane. These mechanisms are thought to be the main mechanisms
involved in diabetic retinopathy and nephropathy.
Not all cells require insulin for glucose importation, intracellular hyperglycemia in neural and
vascular cells results in high intracellular glucose which is converted to sorbitol and fructose. The
presence of these sugars in the cell leads to increased intracellular osmolarity and influx of water and
eventually to osmotic cell injury. Schwann cells and pericytes are damaged resulting in diabetic
neuropathy and microaneurysm formation. In the lens osmotically embided water causes swelling
and opacity (cataract formation). Sorbitol accumulation is known to impair ion pumps and thereby
promote injury of Schwann cells and pericytes of the retinal capillaries. Experimental inhibition of
aldoreductases may ameliorate the development of cataracts and neuropathy.

Advanced Glycosylation End Products

AGE’S cause accelerated atheroma by damage to basement membrane of vessels (i.e. larger vessels)
allowing low density lipoprotein (LDL) to accumulate in the intima. AGES derived from
glycosylated plasma proteins also bind to receptors and lymphocytes and macrophages and block
effective cell-cell signalling. This is probably the cause of relative immune incompetence and the
increased susceptibility to infection in diabetes.

Conditions which effect diabetes atypically (i.e. more severely) or more frequently than normal
include atheroma, infection, cataract, gallstones and foetal death or defect. The latter is probably a
result of varying maternal glucose levels during gestation. Neonatal hypoglycaemia may be due to
increased foetal beta cell mass induced by persistently high maternal glucose levels.

Diabetic renal disease includes the following: nodular and or diffuse glomerulosclerosis, arteriolar
nephrosclerosis, pyelonephritis and renal papillary necrosis. The glomerular capillary basement
membranes are thickened throughout their entire length. This change can be detected by electron
microscopy within a few years of the onset of diabetes, sometimes without any associated change in
renal function. Diffuse glomerulosclerosis consists of a diffuse increase in mesangial matrix along
with mesangial cell proliferation and is always associated with basement membrane thickening. This
is found in patients with disease of more than ten years duration. When this becomes marked patients
will manifest the nephrotic syndrome, which is characterised by proteinuria, hypoalbuminemia and

3
oedema. Nodular glomerulosclerosis describes a lesion made distinct by ball like deposits of matrix
within the mesangial core of the lobule. These nodules tend to develop in the periphery of the
glomerulus and push the capillary loops even more to the periphery. This change has been called the
Kimmelstiel-Wilson lesion. These lesions contain trapped mesangial cells. Later tubule ischaemia
and interstitial fibrosis occur. Nodular glomerulosclerosis occurs in 10 to 35% of diabetics and is a
major cause of morbidity and mortality. It is specific for diabetes. Renal atherosclerosis and
arteriolosclerosis also constitute part of the systemic involvement of blood vessels in diabetes. Both
acute pyelonephritis and chronic pyelonephritis occur in non diabetics as well as in diabetes but are
much more common in diabetes then in the general population. Once affected, diabetics tend to have
more severe involvement. One special pattern of acute pyelonephritis is renal papillary necrosis
(bilateral in 70% of cases), that is characterised by a sluggish blood flow in the vasa rectae which is
poorly oxygenated. Swelling in infection or urine outflow obstruction then easily compromises this.
Ischaemia of the papilla leads to sloughing and clinically this presents as rigors, loin swelling,
oliguria and uraemia. This process may also occur in analgesic abuse.

Diabetic ocular complications include retinopathy, cataract formation or glaucoma.

The central and peripheral nervous system are not spared by diabetes and the most frequent pattern of
involvement is a peripheral symmetric neuropathy of the lower extremities that effects both motor and
sensory function but particularly the latter.

It is difficult to sketch with brevity the diverse clinical presentations of diabetes mellitus. In Type 1
diabetes mellitus leading to diabetic coma, hyperglycemia causes glycosuria leading to polyuria
with loss of electrolytes, dehydration and subsequent polydipsia. Insulin is an anabolic hormone so
fat and protein metabolism are also effected. Loss of calories from glycosuria will lead to hunger and
polyphagia, weight loss and mobilisation of fat and protein. By -products of mobilisation of fat and
protein will lead to a negative nitgrogen balance, acidosis and a combination of these factors may
result in coma (Ketoacidotic coma) and death. This complication occurs almost exclusively in Type 1
diabetes which is stimulated by severe insulin deficiency coupled with a relative or absolute increase
in glucagon.

Type 2 diabetes may also present with polyuria and polydypsia but the patients are usually older and
frequently obese. Frequently the diagnosis is made after routine blood or urine testing in
asymptomatic persons. Patients with Type 2 diabetes also have metabolic derangements but are easier
to control and less severe. In the decompensated state these patients develop hyperosmolar non-
ketotic coma which is a syndrome engendered by severe dehydration resulting from sustained
hyperglycaemic diuresis in patients who do not drink enough water to compensate for urinary losses.
Typically the patient is an elderly diabetic who is disabled by a stroke or an infection and unable to
maintain adequate water intake.

In both forms of long standing diabetes atherosclerotic events such as myocardial infarction,
cerebrovascular accidents, gangrene of the leg and renal insufficiency are the most threatening and
most frequent complications. Diabetes continues to be one of the top ten killers in the United States.
Currently strict glycemic controls offers the only hope for preventing the deadly complications
of diabetes.

B.Loftus AMNCH