Pharmacology of Diabetes Mellitus 1

Dr Emma Baker

Consultant Physician/Senior Lecturer in Clinical Pharmacology

Sometime in the 19th century…

• 14 year old boy, obvious weight loss• Passing increased amounts of urine, getting up 4

times at night to empty bladder. Urine sticky and sweet

• Very thirsty, drinking litres of water per day

Questions• What is the diagnosis?• What is going to happen to this boy and why?

Insulin - physiology revisited

Pancreas

Glucose

Insulin

Brain Heart

Liver

Adipose

Muscle

Glucose: Utilised Stored as

glycogen, fat Protein: Increased synthesis, decreased catabolism

GUT

Insulin receptors

No InsulinPancreas

1. Glucose

Brain

Heart Liver

Adipose

Muscle

GUT

Lipase

2. Fatty acids

Used as energy

3. Acetoacetic acid

Cholesterol

Triglycerides

No Insulin• Increased plasma and urinary glucose• Glucose in urine has osmotic effect

• diuresis• dehydration• circulatory collapse

• Increased acetoacetic acid, acidosis• myocardial and cerebral dysfunction• venoconstriction, arterial vasodilation

• Untreated leads to certain death

Insulin

• 11th January 1922 - pancreatic islet cell extract first administered to 14 year old insulin deficient patient

• Bovine and porcine pancreatic extracts

• 1980 human insulin available– amino acid modification of porcine insulin– synthesised by introducing DNA for human

insulin into bacteria or yeast

Sometime in the late 20th century…

• 17 year old girl, obvious weight loss

• Passing increased amounts of urine, getting up 4 times at night to empty bladder.

• Very thirsty, drinking litres of water per day

• Urinalysis glucose ++++, ketones ++++

Questions• What is the diagnosis?

• How should this girl be treated?

• What health problems do you anticipate and how could these be prevented?

Diagnosis

• Diagnosis - ketoacidosis secondary to type 1 diabetes

• Treatment - insulin replacement

Insulin replacement

Pancreas

1. Glucose

Brain

Heart Liver

Adipose

Muscle

GUT

Lipase

2. Fatty acids

Used as energy

3. Acetoacetic acid

Cholesterol

Triglycerides

Insulin

Insulin prevents death from ketoacidosis

But does it restore normal life expectancy???

Type 1 diabetes with insulin replacementInsulin

Carbohydrate metabolism

Prevents dehydration and collapse from hyperglycaemia

BUT

•Does not restore normal glycaemia

•Thickening of basement membrane

•Microvascular disease

Lipid metabolism

Prevents ketoacidosis

BUT

•Increased plasma cholesterol and triglycerides

•Other mechanisms

•Macrovascular disease

Diabetes Control and Complications Trial

• 1441 people with type 1 diabetes mellitus

• Randomised into conventional and intensive therapy

• Trial duration 6.5 years

• Intensive group achieved HBA1C 2.0% lower than conventional group

People receiving intensive therapy were less likely to have:

• Microvascular disease:– Retinopathy

• development OR 0.22, NNT 6

• progression OR 0.39, NNT 5

– Nephropathy OR 0.5, NNT 7– Neuropathy OR 0.36, NNT 13

• Macrovascular disease– reduction from 0.8 to 0.5 per 100 patient years

What problems might be experienced by patients on an

intensive insulin regime?

Intensive insulin regime

• Requires frequent injections

• May be difficult with normal life style

• Increases risks of hypoglycaemia

• Other complications?

Sometime in the 21st century...

• 53 year old Asian woman living in the UK• BMI 38Kg/m2, but recent weight loss• Tired, mild thirst, new nocturia x 2• Known hypertension, hypercholesterolaemia

• Questions• What is the likely cause of her new symptoms?• What is going to happen to this woman and why?

Type 2 diabetes mellitus

Pancreas

Plasma glucose

Insulin

Brain Heart

Liver

Adipose

Muscle

GUT

Some -cell loss

Insulin receptors

Cholesterol Triglycerides

Complications

• Hyperosmolar, non-ketotic coma

• Macrovascular disease– stroke 2x– MI 3-5x– Amputation of foot for gangrene 50x

• Microvascular disease

How could type 2 diabetes be treated?

Type 2 diabetes mellitus

Pancreas

Plasma glucose

Insulin

Brain Heart

Liver

Adipose

Muscle

GUT

Some -cell loss

Insulin receptors

Cholesterol Triglycerides

Treatment of type 2 diabetes mellitus

Pancreas

Plasma glucose

Insulin

Brain Heart

Liver

AdiposeGUT

Some -cell loss

C. Insulin resistance

Weight reduction

Biguanides Glitazones

Muscle Cholesterol Triglycerides

B. Sulphonylureas

Statins Fibrates

D. Acarbose

A. Insulin

UK Prospective Diabetes Study

• 3876 people with type 2 diabetes mellitus

• Randomised controlled trial examining the effects of intensive v conventional glucose control

• Also looked at the effects of controlling other cardiovascular risk factors

• Study duration 10 years

Intensive blood sugar control:

• Reduced microvascular complications– retinopathy OR 0.66, NNT 10– neuropathy OR 0.42, NNT 5

• Did not significantly reduce macrovascular complications

• Control of other cardiovascular risk factors also crucial in reducing morbidity and mortality

Last week...• 48 year old woman with chronic asthma• Complained of tiredness, thirst, weight loss, polyuria• Urinalysis - glucose ++, Plasma glucose 14mmol/l• Medications:

– salbutamol, salmeterol, becloforte inhalers

– prednisolone 10mg daily for 6 months

Question• What is the diagnosis?• Why has this occurred?

Glucocorticoid-induced diabetes mellitus

Pancreas

Glucose

Insulin

Brain

Heart

Liver

GUT

Adipose

MuscleGluco

corticoids

Fatty acidsAmino

acids

Gluco neogenesis

Drugs which cause an increase in plasma glucose

• Glucocorticoids

• Thiazide diuretics

• Loop diuretics

• Oral contraceptive pill

• Diazoxide

Summary

Insulin deficiency Insulin resistance

Type 1 Type 2

Insulin Sulphonylureas Metformin Glitazones

Pathology

Treatment

Acute complications

Ketoacidosis HONC

Drugs used to treat diabetes mellitus

Gut

Food

Absorption

Glucose

Insulin

Pancreas

Insulin stored in -islet cells

Liver

•Reduced gluconeogenesis

•Glycogenesis

•Reduced lipolysis

Receptor (tyrosine kinase)

Complex internalised

Muscle/fat cell

Stimulates glucose uptake

Adipose cell

Insulin receptor

Peroxisome proliferator-

activated receptor

Insulin

Sulphonylureas

Metformin

Acarbose

Glitazones