The burden of diabetes

What is diabetes?
World Health Organization
s definition of diabetes

A metabolic disorder of multiple aetiology
characterised by chronic hyperglycaemia with
disturbances of carbohydrate, fat and protein
metabolism resulting from defects in insulin
secretion, insulin action, or both.

International Diabetes Federation (IDF; 2007)

Estimated prevalence of 246 million

IDF (2003):

...the fourth or fifth leading cause of death in most

developed countries...

...there is substantial evidence that it is epidemic in
many developing and newly industrialised
nations...

is certain to be one of the most challenging health
problems in the 21st century

The importance of glucose

Blood glucose levels are maintained within a
narrow range (57 mmol/L = 90-126 mg/dL)
High enough to satisfy the energy needs of cells
The nervous system is particularly dependent on
glucose for energy

Low enough to minimise the toxic effects of

glucose

ADA Summary of recommendations for

adults with diabetes mellitus
Glycemic control

2003* ________

A1C

7.0%

Preprandial plasma glucose

90130 mg/dl (5.07.0 mmol/l)

Postprandial plasma glucose

180 mg/dl (10.0 mmol/l)

Increases in blood glucose levels

Glucose enters the blood when:
Food is digested and absorbed: this is the main
source of glucose
The storage product glycogen is broken down to
glucose (glycogenolysis)
Glucose is synthesised from sources such as
glycerol and amino acids in the liver
(gluconeogenesis)

Decreases in blood glucose levels

Glucose is removed from the blood to be:
Broken down within cells to release energy
Converted to glycogen for storage (glycogenesis)

Key measures & diagnostic criteria

Key measures of blood glucose

Postprandial glucose levels glucose levels after meals

Fasting glucose glucose levels after an overnight fast
A diagnosis of diabetes (ADA recommendations) is made if ;

Postprandial glucose levels glucose levels after

meals
Fasting glucose glucose levels after an overnight
fast

Fasting Plasma Glucose (FPG) level 126mg/dl

2 h postprandial plasma glucose (2hPPG) level 200mg/dl on
at least 2 different occasions
Test

Normal values
mg/dl

Borderline
IFG/IGT

Diabetes
(mg/dl)

FPG

80-100

100-125

126

2h Post load Glucose

Up to 140

140-200

200

Diagnosis: diabetes and impaired

glucose metabolism
Venous plasma glucose
mmol/L

mg/dL

Random value:
diabetes

11.1

200

Fasting value:
impaired fasting glycaemia

5.6

100

diabetes

7.0*

126*

2-h value (OGTT):

impaired glucose tolerance
diabetes

7.8
11.1

Hormonal control of blood glucose:

glucagon and adrenaline

Glucose
synthesis

Glycogen
breakdown

140
200

Overnight of fasting followed by 75g of glucose in water and testing after 1 and 2 h
if more than 200mg/dl then diabetes
Adapted from A Desktop Guide to Type 2 Diabetes Mellitus, European Diabetes Policy Group 19981999

Glucagon increases blood

glucose levels by:

Glycogen
breakdown

Glycogen
breakdown
Lipid (fat)
breakdown

Liver

increasing glycogenolysis
in the liver and skeletal
muscles
increasing
gluconeogenesis in the
liver

Adrenaline increases
blood glucose levels by
stimulating glycogenolysis
and lipid breakdown
(lipolysis)

Hormonal control of blood glucose:

insulin
Glycogen
breakdown
Glucose
synthesis

Glucose
uptake

Glucose
uptake

Liver

The only hormone to

lower blood glucose
levels
Suppresses endogenous
glucose production in the
liver

inhibits glycogenolysis
inhibits gluconeogenesis

Stimulates peripheral
glucose uptake in skeletal
muscle and adipose tissue

Other effects of insulin

Increases the storage of lipids that cells could use
instead of glucose
e.g. reduced lipolysis in adipose tissue

Increases the storage of protein

e.g. increased amino acid transport

Insulin synthesis and storage

Hormones that counteract insulin action
Glucagen
Adrenaline/Noradrenaline
Steroid hormones
Cortisol
Growth hormone
In case of hypoglycaemia, these hormones are secreted
to maintain glucose homeostasis or normal blood
glucose levels. (defense mechanism of body)

Synthesised by
pancreatic beta-cells
Series of biochemical
reactions converts
the precursor
molecule,
preproinsulin, into
insulin
Insulin is stored as
hexamers in
secretory granules
before release

Daily insulin secretion

Insulin is released
when the secretory
granules fuse with
the cell membrane
(exocytosis)
Hexamers dissociate
into monomers
Monomers are
transported in the
blood

70

Short-lived, rapidly
generated meal-related
insulin peaks (prandial)

60
Insulin (U/mL)

Insulin secretion

50

Sustained
insulin profile
(basal)

40
30
20
10
0
6:00

10:00

14:00

18:00

22:00

2:00

Time of day
Breakfast

Lunch

Polonsky et al. J Clin Invest 1988;81:4428

Dinner

6:00

 Phase 1: rapid insulin

release to suppress
endogenous glucose
production in the liver
Phase 2: continued release
as glucose from the meal
is absorbed

360

360

Plasma insulin
pmol/L

Each prandial peak has two

phases

Postprandial glucose levels

Endogenous
glucose
appearance

Type 2 diabetes
Healthy individuals

120

60

60 120 180 240 300

12
8
4

60

60 120 180 240 300

20
mmol/L

Plasma glucose

High insulin levels facilitate peripheral glucose uptake (skeletal

muscle and adipose tissue)
These actions minimise rises in blood glucose associated with
meals

240

240

0
mol/kg/min

Biphasic prandial insulin response

The prandial insulin

response minimises
the rise in blood
glucose after a meal

15
10
5

60 0 60 120 180 240 300

Time since glucose ingestion (min)

Adapted from: Mitrakou et al. Diabetes 1990;39:138190

Diabetes types

Type 1 vs. type 2 diabetes

Type 1 diabetes

Characteristics

Total insulin deficiency due to the destruction of

pancreatic beta-cells

Type 2 diabetes
Characterised by insulin resistance and insulin deficiency
Degrees of resistance and deficiency vary but insulin
deficiency is key to developing diabetes

Genetic defects of beta-cell function and insulin action

e.g. maturity onset diabetes of the young

Gestational diabetes
Glucose intolerance first detected in pregnancy that often
resolves after the birth of the baby

Age of onset
Peak age
Body weight

Type 1

Type 2

Usually < 35 years

Usually > 35 years

1014 years

6070 years

Usually thin

80% obese
(excluding Asian origin)
50% obese
(when of Asian origin)

Symptoms

Acute onset
of symptoms

Gradual onset, very often

diagnosed without symptoms

Heredity
Treatment

No
Insulin is
mandatory

Yes
Diet and tablets
Insulin required at a certain stage

Type 1 diabetes

Epidemiology of type 1 diabetes

Idiopathic type 1 diabetes

Approximately 10% of all diabetes cases (=25 million)

Cause unknown

Autoimmune destruction of beta cells

Thought to be triggered by an environmental agent
(e.g. virus) in genetically predisposed individuals
Approximately 90% of type 1 diabetes cases
Onset tends to be fast and aggressive in children and
adolescents
Slower onset in adulthood is often named late-onset
autoimmune diabetes of adults

Incidence peaks in the early teenage years for boys and

girls
Geographically:
incidence increases considerably from the Equator to the
Poles
incidence is highest in Finland and lowest in Japan

Incidence has been increasing over the past 20 years

Type 2 diabetes

Effects of type 1 diabetes on glucose

metabolism

Approximately 90% of all diabetes cases

(=221 million)

In the absence of insulin:

A disorder related to lifestyle, particularly obesity

and physical inactivity

The liver continues to produce glucose

The uptake of glucose by peripheral tissues is
diminished

Associated with older age but increasing in children

due to increasing obesity and decreasing physical
activity

Blood glucose levels increase (hyperglycaemia)

Incidence:

Excess glucose is excreted by the kidneys in urine

increasing worldwide
varies among ethnic groups

Increased urination (polyuria) and excessive thirst

(polydipsia)

Risk factors for type 2 diabetes

Risk factors include:

Age
Ethnic group
Genetic factors
Obesity

Physical inactivity
High calorie intake
Hypertension
Dyslipidaemia
Previous diagnosis of
gestational diabetes

Diabetic
complications

Classification of diabetic complications

Acute diabetic complications:
diabetic ketoacidosis (DKA)

Diabetic ketoacidosis (DKA)

Caused by severe insulin deficiency
Hallmark of type 1 diabetes insulin deficiency

hyperosmolar non-ketotic coma (HONK)

~25% of cases are newly-diagnosed type 1 diabetes

patients

hypoglycaemia due to treatment

Hyperglycaemia, ketosis and acidosis

Long-term diabetic complications:

macrovascular complications

coronary heart disease, stroke, peripheral

vascular disease

microvascular complications
retinopathy, nephropathy, neuropathy
Watkins et al. In: Diabetes and its Management 2003

Diabetic ketoacidosis: symptoms and treatment

Hyperosmolar non-ketotic coma (HONK)

Main clinical features of DKA:

Hyperglycaemic emergency of type 2 diabetes

Usually in older people

Dehydration
Hyperventilation
Drowsiness/confusion
Vomiting
Hypothermia
Low potasium

Key biochemical markers:

Leucocytosis (elevated number of white cells)

Elevated serum amylase

Treatment priority: initial rehydration and insulin replacement

Normally, the kidneys make up for high glucose levels in the

blood by allowing the extra glucose to leave the body in the
urine.

HONK, water is scarce, the kidneys conserve fluid, and glucose

levels become higher. This results in greater need for fluid also
result in Dehydration

Patients dehydrated, elderly and frail

Treatment: careful rehydration and insulin

Prevalence of diabetic complications

Risk of complications increases as

HbA1c increases

Death: 2 times higher

Stroke: 2 to 4 times higher
Blindness among adults aged 2074 years
Kidney failure: 44% of new cases
Non-traumatic lower-limb amputations: >60%

Incidence per
1000 patient-years

Diabetes increases risk of:

Myocardial infarction

Updated mean HbA1c (%)

Americal Diabetes Association. In: National Diabetes Fact Sheet 2005

Stratton et al. BMJ 2000;321:40512

Macrovascular complications of diabetes

Macroangiopathy: definition and related conditions

Stroke

Damage to the macrovascular

blood vessels by atheroma
formation

Cardiovascular/heart disease

Associated with:

Peripheral vascular disease

Cholesterol deposits

Atherosclerotic plaque

International Diabetes Federation. Diabetes Atlas 2006;1112

Watkins et al. In: Diabetes and its Management 2003

coronary heart disease,

angina, myocardial infarction
and heart failure
cardiomyopathy
stroke
peripheral vascular disease

stenosis

stenosis

Angina, myocardial
infarction (MI), heart failure
May be confused with
hypoglycaemia because of a
lack of pain
Immediate and long-term
mortality increased in
diabetes

Patients with type 2 diabetes at increased risk of

cardiovascular disease (CVD)
Incidence of myocardial
infarction over 7 years

Patients (%)

Coronary heart disease (CHD)

Risk of cardiovascular disease

is greater in patients with
diabetes than in those without
Having diabetes results in a
similar risk of heart attack as a
prior heart attack

With diabetes n=1059

Without diabetes n=1373

Diagram shows stenosis (narrowing) of the coronary arteries

Haffner et al. N Engl J Med 1998;339:22934

80

Diabetic

60
40

20

10
Non-diabetic
0
0

(a)

5
6
4
Serum cholesterol
(mmol/L)

Number of deaths per 10,000 patient-years

Ten-year CHD mortality (per 1000)

Prevention of macrovascular complications

140
120

Non-diabetic
subjects
Subjects with
type 2 diabetes

100
80
60
40
20
0

(b)

0
1
2
3
Number of risk factors

Adapted from Stamler et al. Diabetes Care 1993;16:43444

Reduce risk factors for

cardiovascular disease:

stop smoking
treat hypertension
treat hyperlipidaemia
improve glycaemic
control
reduce weight in the
obese
take regular exercise

Microvascular complications of diabetes

Retinopathy and blindness

Nephropathy
Neuropathy

Diabetic foot disease

International Diabetes Federation. Diabetes Atlas 2006;1112

 Damage to small blood vessels and capillaries

retinopathy
nephropathy
neuropathy

Severity is related to the duration and degree of

hyperglycaemia

Risk of retinopathy
progression

Rate per 100 patient years

Microangiopathy: definition and related

conditions

Rate per 100 patient years

DCCT: microvascular complications increase as

HbA1c increases

16
12
8
4
0
0

9 10 11 12

Risk of developing
microalbuminuria
16
12
8
4
0
0

HbA1c (%)
DCCT. N Engl J Med 1993;329:97786

9 10 11 12

Microangiopathy: definition and classification

Damage to the
microvascular
circulation
Retinopathy (eyes)
Nephropathy
(kidneys)
Neuropathy
(autonomic and
peripheral nerves)

Nephropathy- 5 stages
1st stage-kidney is enlarged and glomerular filteration rate(GFR) is elevated No clinical
symptoms
2nd stage-Normoalbuminuria; albumin excretion <30mg/24h
3rd stage Incipient nephropathy-clinical evediance show;
Microalbuminuria albumin loss at >30mg/24hr <300mg/24hr
BP

4th stage-Overt Diabetic Nephropathy-loss of albumin exceeds 300mg/24hr

patient diagnosed-clinical albuminuria
this stage kidneys demonstrate an inability to filter waste from blood, creatine
urea-nitrogen also elevate

5th stage ESRD (End stage Renal Disease)

advanced nephropathy
glomerulin function is very low
Dialysis required

Nephropathy: prevention and treatment

Log rate per 100
patient-years

(a)

Rate per 100

patient-years

(b)

Probability of
microalbuminuria

(c)

Maintain tight glycaemic and blood

pressure control
Multifactorial disease management:

2
1
0
1
2

1.60
1.85
2.10
2.35
2.60
16
Log glycated haemoglobin (log %)
12
8
4
0

0.8

6
7
8
9
10 11
Glycated haemoglobin (%)

12

6
7
8
9
10 11
Glycated haemoglobin (%)

12

0.6
0.4
0.2
0.0

DCCT. Diabetes 1996;45:128998

antihypertensive agents
good blood glucose control
control of dyslipidaemia
monitoring renal function
lifestyle changes,
STOP smoking

Retinopathy-2 stages
Diabetic retinopathy, 2 stages;

1st stage-Non-proliferative (means no new vessel formation) early

stage but may hemorrhage and small bleeding may occur wet
Retina and protein deposits may be seen- vision can diminish if
fluid present
2nd stage-Proliferative retinopathy-abnormal vessels develop in
Retina and grow towards centre of the eye-vesels regularly bleed
into the vitreous and cause severe problems
scarring
Retina may detach Laser may be used for treatment- stops
leakage but depends on severity

Retinopathy incidence (odds ratio)

Retinopathy: risk factors and classification

Poor glycaemic and blood
pressure control increase the risk
of retinopathy

35

Poor glycaemic and blood

pressure control increase the
risk of retinopathy
Proliferative start with:
pre-proliferative
proliferative
advanced diabetic eye
disease
maculopathy-affects the
macula;

30
25
20
15
10
5
0
4

10

London HbA1c (%)

5.7

6.7

7.7

9.8
10.8
8.8
DCCT HbA1c (%)

Chaturvedi et al. Diabetes Care 2001;24:2849

11.9

Proliferative diabetic retinopathy:

no symptoms

Neuropathy: prevention and treatment

Maintain tight glycaemic
control to reduce the risk or
progression of neuropathy
Exclude or treat contributory
factors:
alcohol excess
vitamin B12 deficiency
Offer pain relief based on
the dominant symptoms

Percentage of cases affected

16
Conventional therapy

12

p<0.001

8
4
Intensified therapy

Time (years)

DCCT. NEJM 1993;329:97786

Diabetic foot

DCCT: intensive therapy reduces microvascular

complications

30
Patients (%)

Patients (%)

40

20

Microalbuminuria*: 34% reduction

Conventional
Intensive

60

Lowering HbA1c by 1% significantly reduces:

20

10

10
Years

10

Reduction in incidence risk

per 1% reduction in HbA1c

Retinopathy: 76% reduction

UKPDS: reducing HbA1c reduces risk

14%*
21%*
37%*
43%*
*p<0.0001

*urinary albumin excretion 40 mg per 24 hours

DCCT. NEJM 1993;329:97786

Stratton et al. BMJ 2000;321:40512

Glycaemic targets: examples for type 2 diabetes

Normal
levels

Targets from:
ADA

IDF

AACE

Fasting plasma
glucose (mmol/
L)

<5.6

7.2

<6.0

<6.1

Postprandial
plasma glucose
(mmol/L)

<7.8

<10.0
(peak)

<8.0
(12 h)

<7.8
(2 h)

HbA1c (%)

<6.0

<7.0

<6.5

6.5

ADA, American Diabetes Association; IDF, International Diabetes Federation; AACE, American
Association of Clinical Endocrinologists

Targets should be individualised what is appropriate for each person?

Treatment of
type 2
diabetes

Diabetes treatment

Why hyperglycaemia in type 2

diabetes?
Insulin Secretion Defect

Type 1:

Pancreas

Type 2:

Hyperglycemia
Therapy:

Diet/Exercise
21%

Percent of diagnosed patients industrial world only.

Oral products
54%

Oral/Insulin
7%

Insulin
18%

Muscle

Liver
Increased Hepatic
Glucose Production

Decreased Glucose
Utilization

Insulin Resistance

How can blood glucose be controlled

OAD groups and generic names

Impaired Insulin Secretion

Pancreas
Insulin secretagogues
Sulphonylureas
Meglitinides

Sulphonyl Meglitinides
Biguanides
(PGRs)
ureas (SU)

Hyperglycemia
Liver

Insulin sensitizers
Glitazones
Biguanides
Insulin Resistance

Muscle

Glibenclamide Repaglinide Metformin

Gliclazide
Nateglinide
Glipizide
Glimepiride
Others

Prandial
Glucose
Regulators

Glitazones
Pioglitazone
Rosiglitazone

-glucosidase GLP-1/DPP-IV-inhibitors
inhibitors

Acarbose

Sitagliptin

Insulin Secretion

Sulphonylureas
Sulphonyl Meglitinides
Biguanides
(PGRs)
ureas (SU)

Pancreas
Glitazones

-glucosidase GLP-1/DPP-IV-inhibitors
inhibitors

Stimulate insulin secretion; usually taken 1x

or 2x daily
Side effects: hypoglycaemia and weight gain

Glibenclamide: Daonil (Aventis)

Glipizide: Minidiab (Pfizer)

Insulin Secretion

Meglitinides (glinides)
Sulphonyl Meglitinides
Biguanides
(PGRs)
ureas (SU)

Glitazones

Pancreas
-glucosidase GLP-1/DPP-IV-inhibitors
inhibitors

Stimulate insulin secretion

rapidly and for a short period

taken with each meal (prandial glucose
regulators - PGRs)

Side effects: hypoglycaemia and

weight gain

Diamicron (Servier)
Glimepiride: Amaryl (Aventis)

Repaglinide: NovoNorm (EU), Prandin (US), GlucoNorm (Canada)

- NN

Insulin sensitizers
- Increases glucose
uptake by the muscles
- Decreases liver glucose
production

Liver

Muscle
Sulphonyl Meglitinides
Biguanides
(PGRs)
ureas (SU)

Biguanides

Metformin
Glitazones
Rosiglitazone: Avandia
Pioglitazone: Actos

Side effects:
bowel upset
lactic acidosis

Side effects:
weight gain
water retention
Contraindicated if any history of liver disease or heart failure

Glitazones

-glucosidase GLP-1/DPP-IV-inhibitors
inhibitors

Alpha-glucosidase inhibitors
Primarily control of post-prandial
hyperglycaemia

Poor overall effectiveness

Poorly tolerated by many patients; dose
titration may help tolerance

Insulin Secretion

Pancreas
Sulphonyl Meglitinides
Biguanides
(PGRs)
ureas (SU)

Glitazones

Incretin based therapy:

GLP-1 derivatives

-glucosidase GLP-1/DPP-IV-inhibitors
inhibitors

Sulphonyl Meglitinides
Biguanides
(PGRs)
ureas (SU)

Glitazones

-glucosidase GLP-1/DPP-IV-inhibitors
inhibitors

DPP-IV inhibitors
Inhibit the breakdown of incretin hormones (GLP-1)

Liraglutid

Stimulate beta cell function in pancreas

Exenatide

Reduce levels of glucagone

DPP-IV inhibitors
Sitagliptin

Weight neutral
Cause few adverse events (nausea)
Sitagliptin: Januvia (MSD)

OAD combination therapies

Estimated improvement of glycaemic control

Metformin

Glitazones
Pioglitazone
Rosiglitazone

-glucosidase
-inhibitors
Acarbose

50% of patients would need insulin

6 years after they are diagnosed

DPP-IVinhibitors
Sitagliptin

Combination
Therapy

Sulphonyl Meglitinides
Biguanides
(PGRs)
ureas (SU)

Monotherapy

Insulin sensitizers

Insulin secretagogues

Glibenclamide Repaglinide
Gliclazide
Glipizide
Glimepiride
Others

Antidiabetic treatment

Sulphonylurea
Metformin
Repaglinide
Acarbose
Pioglitazone
Rosiglitazone
Sulphonylurea + Metformin
Sulphonylurea + Pioglitazone
Sulphonylurea + Acarbose
Metformin + Repaglinide
Metformin + Pioglitazone
Metformin + Rosiglitazone
Insulin monotherapy
Insulin + oral agents

HbA1c

FBG (mmol/l)

1.5% - 2.0%
1.0% - 2.0%
0.8% - 1.7%
0.5% - 1.0%
0.6% - 1.9%
0.7% - 1.8%

2.8 - 3.3
2.8 - 3.3
1.7 - 2.2
1.1 - 1.7
3.1 - 3.3
3.1 - 3.3

~1.7%
~1.2%
~1.3%
~1.4%
~0.7%
~0.8%

~ 3.6
~ 2.8
~ 2.2
~ 2.2
~ 2.2
~ 2.8

open to target
open to target

open to target
open to target

Contents
History of diabetes and insulin
Diabetes and
Insulin

Insulin types
Insulin treatment regimens
Designer insulins

Discovery of insulin

First treated patient

Crude extract of beef pancreas

January 1922. Toronto hospital

14-year-old boy (30 kg, dying)

Experiments in Toronto
University
FG Banting, surgeon
CH Best, medical college
student
30 July 1921

11 January 1922: First extract

small hypoglycaemic effect
abscess in injection site

23 January 1922: Purified

extract.
glucose normalized

Leonard Thompson
(1908-1935)

Insulin characterisation
Connecting peptide

1955: Frederick Sanger

identified the amino acid

sequence of insulin

Insulin is a small protein: 51

amino acids in two chains: A

and B

Insulin is a natural hormone,

produced in the pancreatic
gland

History of insulin preparations

s-s
s-s

A-chain

1923 : Novo Nordisk production of insulin

1936 : PZI (Protamine Zinc Insulin) surplus
Protamine, zinc added

ss
B-chain

1946 : NPH (Neutral Protamine Hagedorn).

Isophane: (Insulin) = (Protamine)
1953 : Lente , Semilente, Ultralente.
Insulin zinc suspensions.
Amorphous / crystalline various timings.

History of insulin preparations

1961 : First neutral soluble insulin: Actrapid.
1964 : First premixed insulin: Mixtard.
1973 : Monocomponent (MC) purity

Origin of insulin
Animal
Beef
Pork

1982 : Human Monocomponent HM

1985 : First insulin pen: NovoPen with Penfill.
1999: NovoRapid: rapid acting insulin analogue
2002: NovoMix: dual acting insulin analogue
2004: Levemir: long acting insuiln analogue

Human

- Extracted from animal pancreas

- Increased incidence of allergic problems
- Less antigenic than beef
- Available as purified insulin
- Genetically engineered using either
yeast or e.coli

Analogue - Genetically modified to alter absorption rate

(faster or slower)

UK/DB/0711/0351 Date of Preparation July 2011

Types of insulin

Animal insulin (Since 1922)

Short-acting

Mixtures of short and intermediate-acting

Human insulin (Since 1982)

Short-acting (regular)

Intermediate-acting

Intermediate-acting
Mixtures of short and intermediate- acting (biphasic)

Insulin analogues (Since 1996)

Rapid-acting

Insulin concentration
All insulin marketed in the UK is 100 IU/ml*
For example a pack with 5 x 3ml cartridges:
5 x 3ml x 100 units = 1500 units
With average daily consumption of 55 units/day (including air
shots) the pack lasts around 25 days

*Human and animal insulin: IU (International Units)

Analogue insulin: U (Units)

Long-acting (basal insulin)

Mixtures of rapid and intermediate-acting (biphasic)
UK/DB/0711/0351 Date of Preparation July 2011

UK/DB/0711/0351 Date of Preparation July 2011

Insulin dosage is individual

Routes of insulin administration

Type 1:
Adults:
Adolescents:
Honey moon:

Type 2:

Mainly adults

0,5 1,0 IU/kg

0,7 1,5 IU/kg
< 0,5 IU/kg
0,4 0,7 IU/kg

An average patient use 40 50 IU/day

Insulin resistance* = High dose segments: 100 - 200 IU/day

*) Due to either puberty in Type 1 or obesity in Type 2 patients

Subcutaneous injections
Intravenous administration
Injection sites must be rotated
Insulin should be injected
subcutaneously (sc)

into a lifted skin fold

Insulin may be injected

intramuscularly (im)

can be painful, faster action

Actrapid and NovoRapid may be

given intravenously (iv) by Health
care providers

in emergencies, only

Insulin secretion in a healthy person

Insulin developments

Meal

DCCT

Meal

Meal

400

pmol/min

Lispro

Human insulin

Purified insulin

Lente insulin

NPH insulin

PZI

Discovery of insulin

Insulin aspart,
Insulin glargine

200

1920

1930

1940

1950

1960

1970

1980

1990 2000
00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00

Time

Adapted from Polonsky et al.1988

Normal insulin profiles

Daily requirements

Time action profiles

Insulin/glucose levels
in the blood

Breakfast

Blood sugar

Mealtime
insulin

Lunch

Evening Meal

Stylised format showing

Onset
Peak
Duration

Intended as a guide ONLY

Background insulin

UK/DB/0711/0351 Date of Preparation July 2011

Action

UK/DB/0711/0351 Date of Preparation July 2011

Time

Short-acting human insulin

Soluble

Action

Clear
Onset

30 minutes

Peak

1 - 3 hours

Duration of action up to 8
hours

Crystals in suspension (need to re-suspend prior to injection)

Cloudy
NPH or Isophane (NPH = Neutral Protamine Hagedorn)
Onset
1 1/2 hours
Peak
4 - 12 hours
Duration of action up to 24 hours

Time

Note: The graphical representation above is for educational and illustrative purposes only
UK/DB/0711/0351 Date of Preparation July 2011

Intermediate-acting human insulin

Action

Time
Note: The graphical representation above is for educational and illustrative purposes only
UK/DB/0711/0351 Date of Preparation July 2011

Insulin treatment regimens in

patients with diabetes

Types of insulin products

Once daily
Twice daily

Fast acting: Actrapid.

Dual acting (premixed) insulin or individual mixtures

Three times daily

Combinations of long, rapid and/or premixed

Mealtime regimen= Basal/bolus:

Injections: long acting at bedtime, rapid/fast at meals

Insulin pump (CSII): basal rate + mealtime bolus

Rapid acting analogue: NovoRapid

Long acting: Insulatard (Isophane, NPH),
Dual acting: Mixtard, NovoMix
Long acting analogue: Levemir

Novo Nordisk human insulin range:

action profiles
Type of insulin

Onset of
action

Maximum
effect

Duration

Within 0.5 hours

13 hours

8 hours

Insulatard

1.5 hours

412 hours

24 hours

Monotard

2.5 hours

715 hours

24 hours

4 hours

824 hours

28 hours

0.5 hours

28 hours

24 hours

Short-acting
Actrapid
Intermediate

Long-acting
Ultratard
Premixed *
Mixtard

Introduction
to insulin
analogues

Properties of ideal analogues

What are insulin analogues?
Structure of insulin is modified
Pharmacokinetic properties modified to mimic
physiology
Molecular pharmacology of human insulin
retained

Properties of an ideal mealtime (bolus) analogue:

Fast onset
Short duration of action
Predictability
Properties of an ideal basal analogue:
Long duration of action
Flat profile (no peak)
Predictability

Factors determining insulin

absorption rate
Insulin preparation

Dose, concentration and

volume
Physical state (solution or
suspension)

Currently available insulin analogues

Injection site factors

Region of injection
Injection device
Depth of injection/
injection technique
Lipodystrophy
Insulin state
- self-association
- precipitation

Rapid-acting
analogues

Basal
analogues

Bloodflow changes, e.g.

- temperature
- exercise

Metabolic state, e.g.

- hypoglycaemia
- ketoacidosis

Biphasic
premixed
analogues

Generic name

Trade name

Manufacturer

Insulin aspart

NovoRapid

Novo Nordisk

Insulin lispro

Humalog

Lilly

Insulin glulisine

Apidra

Sanofi

Insulin detemir

Levemir

Novo Nordisk

Insulin glargine

Lantus

Sanofi

Biphasic insulin
aspart

NovoMix

Novo Nordisk

Biphasic insulin
lispro

Humalog Mix

Lilly

Rapid-acting insulin analogues

Insulin Aspart (NovoRapid)

Insulin Lispro (Humalog)

Action profiles of insulin and

rapid-acting insulin analogues
Novorapid Approved for Pregnancy, a major
advantage
Onset (min)

Peak (min)

Duration (h)

Regular human
insulin1

3060

120180

68

Insulin lispro

152

30702

2-5

Insulin aspart

10203

40903

35

Insulin glulisine

204

555

Not available

1Oiknine.

Drugs 2005;65:32540

2Prescribing

information, insulin lispro

3Prescribing

information, insulin aspart

4Becker.

Exp Clin Endocrinol Diabetes 2005;113:2927

5Becker.

Diabetes 2004;53(Suppl.2):A119

Basal insulin analogues

Insulin aspart: safety issues

Insulin receptor affinity and
mitogenicity

Mitogenic potency less than human

insulin

Hypoglycaemia

Incidence similar or lower than with

human insulin

Hypoglycaemic awareness

Physiological responses were

preserved and equivalent for aspart
compared with human insulin

Immunogenicity

Transient increase in antibodies. No

correlation with efficacy or safety

Adverse events

Similar to soluble human insulin

Insulin Detemir
(Levemir)

Insulin Glargine
(Lantus)

Action profiles of insulin and

basal analogues
Strategies for protraction
Modification of isoelectric point: precipitation at pH 7.4
Insulin glargine
Acylation with hydrophobic residues (and albumin binding)
Insulin detemir

Onset (h)

Peak (h)

Duration (h)

NPH insulin1

12

57

1318

Insulin
glargine

121

No peak2

20301

Insulin
detemir3

123

683

244

1Oiknine.

Drugs 2005;65:32540

2Prescribing

information, insulin glargine

3Prescribing
4Heise.

information, insulin detemir

Diabetes Obes Metab 2007;9(8):64859

Receptor affinity and mitogenic

potency less than human insulin

Safety of albumin binding of

insulin detemir

Insulin detemir has negligible

impact on the binding capacity of
the serum albumin pool

Hypoglycaemia

Incidence of hypoglycaemia,
especially nocturnal hypoglycaemia,
generally lower than with human
insulin

Immunogenicity

No immunogenicity concerns

Adverse events

Similar to NPH

Rapid-acting
insulin aspart

Intermediate-acting
protamine-crystallised
insulin aspart

NovoMix 30

Insulin receptor affinity and

mitogenicity

Biphasic premixed insulin analogues

Premixed
suspension

Insulin detemir: safety issues

 rapid absorption

70% protamine-crystallised aspart

addresses basal insulin needs
Fewer injections

slower absorption

Protamine-crystallised
insulin aspart

No

vo
M

ix

ix
vo
M
No

ix
M
vo
30% soluble aspart
covers prandial insulin needs

Soluble insulin aspart

No

Biphasic suspension of:

30%
50%
70%

50%

70

50

The composition of the dual-release

analogues
30

Biphasic premixed insulin analogues

70%

30%

The dual-release insulin concept

Action profiles of insulin and

premixed analogues

Physiological insulin profile:

- meal-related peak

Rapid-acting insulin
analogue together with
a basal insulin analogue
provide physiological
insulin replacement

Premix analogues such as

NovoMix 30 mimic
physiological insulin
secretion

Onset (min)

Peak (h)

Duration (h)

Biphasic
human
premixed

3060

28

1424

Biphasic
insulin aspart

1020

1-4

Up to 24

Biphasic
insulin lispro

1020

1-4

12-20

Profiles are
schematic

- basal component

Physiological insulin profile

Soluble insulin aspart
Protamine crystallised
insulin aspart
NovoMix 30

NovoMix30
STAND ALONE MONOTHERAPY

Controls all glycaemic parameters effectively (PPG-FBGHbA1c)

Devices: FlexPen & NovoPen for increased
compliance, accurate injections & decreased pain
Convenient dosing: just before meals or 10 minutes
after a meal
Tendency towards lower hypoglycaemia/nocturnal
hypoglycaemia when compared with NPH

New features evolve FlexPen into the

Next Generation FlexPen
Safety improvements
New Labels

New Packaging material

Coloured cartridges

Simplicity improvements
Lower dose force

Next Generation FlexPen

Colour-coded
packaging

Next Generation FlexPen

Next Generation FlexPen

Full colour labels

Colour-coded
cartridges

Presentation title
Modern Insulin Training Camp

May 2008
Date

Slide no 24

Next Generation FlexPen