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Pharmacology of Diabetes
Mellitus 2
Dr Emma Baker
Consultant Physician/Senior Lecturer
in Clinical Pharmacology
Patient 1 - 21 year old woman
• Drowsy and vomiting
• Appears breathless
On examination
• Pulse 120 reg, BP 80/50mmHg, RR 24/min
• Chest clear
• Urinalysis Glucose +++, ketones +++
What is the most likely diagnosis?
How do you explain her clinical signs?
Investigations
• Biochemistry
Na 141mmol/l (135-145)
K 6.0mmol/l (3.5 - 4.5)
Urea 11mmol/l (2.5 - 6.5)
Creatinine 120mmol/l (60-110)
Bicarbonate 5mmol/l (22-28)
• Arterial gases
pH 7.14 (7.35 - 7.45)
pO2 12 (10 - 13.1)
pCO2 2.5 (4.1 - 6.0)
Do these results confirm the diagnosis?
How should she be treated?
Treatment of diabetic ketoacidosis
Insulin
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Route of administration?
Duration of action?
Metabolism and elimination?
Effects on biochemistry?
Effects of Insulin
• Biochemistry
Na 141mmol/l (135-145)
K 6.0mmol/l (3.5 - 4.5)
Urea 11mmol/l (2.5 - 6.5)
Creatinine 120mmol/l (60-110)
Bicarbonate 5mmol/l (22-28)
• Arterial gases
pH 7.14 (7.35 - 7.45)
pO2 12 (10 - 13.1)
pCO2 2.5 (4.1 - 6.0)
What else does he need?
Treatment of diabetic ketoacidosis
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Insulin
Fluid
Potassium (high in plasma, low total body)
Subcutaneous heparin
Careful monitoring - consider ITU
Patient 1 - 2 days later
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Considerable improvement
Eating and drinking normally
Biochemical abnormalities corrected
Still on IV sliding scale insulin for newly
diagnosed diabetes
Questions
• What are her insulin needs going to be?
• What treatment regime would you suggest and
why?
Insulin needs
• Normal daily pancreatic output 30-40U/day
• Diabetics usually need 30-50U/day (best to
start lower and build up)
• Need continuous background level of
insulin with larger amounts at the time of
meals and snacks
Physiological Insulin Levels
Insulin
Levels
Breakfast
Lunch
Dinner
Insulin regimes
• Soluble insulin at the time of meals
• Intermediate or long acting insulin to
provide background cover
• Minimise number of injections
Questions
• How do soluble, intermediate and long
acting insulin differ?
Twice daily injections e.g. Humulin M3
Insulin
Levels
Breakfast
Lunch
Dinner
3-4 daily injections - more physiological profile
Insulin
Levels
Breakfast
Lunch
Dinner
Flexible insulin
Insulin Lispro
• Change in 2 amino acids from physiological
insulin
• Molecules dissociate and are absorbed from
injection sites more quickly
• can be given immediately before eating rather than
30 minutes before food
Injection devices
• Insulin pen devices
Patient 2 - 45 year old man
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Newly diagnosed diabetes mellitus
3 months on diabetic diet
Fasting plasma glucose 9 mmol/l, HBA1C 9.4%
Weight 97Kg, BMI 30Kg/m2
Questions
• Are you happy with his diabetic control?
• If necessary, which drug would you choose to
lower blood sugar in this man?
• What else do you want to ask/ measure?
Diabetic control
• Normal HBA1C 3.5 - 6.5%
• Targets
HBA1c
Low
risk
Macrovascular
risk
Microvascular
risk
<6.5
Fasting plasma
glucose
<5.5
>6.5
>5.5
>7.5
>6.0
Choice of medication
• Increased body weight increases insulin resistance
– Insulin is “anabolic” and will increase body weight
– Diabetics on insulin or sulphonylureas (increase insulin
secretion) will therefore put on weight
– This could make diabetes worse
• Treatment of overweight diabetics
– weight loss (13.5Kg - HBA1c 8.1% to 5.8%)
– Drugs that reduce insulin resistance
Drugs that reduce insulin
resistance
• Metformin (Biguanide)
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oral
t 1/2 5 hours
given 3 times daily
Main side effect
• LACTIC ACIDOSIS
• Does NOT cause hypoglycaemia
Patient 2 - follow up
• On Metformin
• Fasting plasma glucose 7mmol/l, HBA1C 8.4%
• Weight 96Kg (1Kg)
Questions
• Are you happy with his control?
• What other treatment options does he have?
Combination therapy for type 2 DM
• Sulphonylureas (gliclazide, glibenclamide, glimepiride)
– oral hypoglycaemics, promote insulin secretion
– variable half life and excretion
– main side effect WEIGHT GAIN, HYPOGLYCAEMIA
• Glitazones (rosiglitazone)
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oral hypoglycaemics, reduce insulin resistance
not used alone
eliminated by liver and kidney
main side effect WEIGHT GAIN, HYPOGLYCAEMIA
monitor liver function tests
• Acarbose
Drugs used to treat diabetes mellitus
Glitazones
Gut
Adipose cell
Food
Insulin
Absorption
Acarbose
Peroxisome
proliferatoractivated
receptor
Glucose
Pancreas
Insulin stored
in b-islet cells
Sulphonyl
ureas
Stimulates
glucose uptake
Insulin
receptor
Insulin
Complex
internalised
Receptor
(tyrosine
kinase)
Muscle/fat cell
•Reduced
gluconeogenesis
•Glycogenesis
•Reduced lipolysis
Liver
Metformin
Patient 3 - 75 year old man
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Known type 2 diabetic on glibenclamide
Ischaemic heart disease, on heart failure medication
Unconscious
Blood glucose stick testing unrecordable
Biochemistry
Urea 55mmol/l (2.5 - 6.5), Creatinine 810mmol/l (60-110)
Questions
– Why is he unconscious?
– How would you treat this?
– Why did this problem occur?
Diagnosis
• Glibenclamide is a sulphonylurea
• This drug increases insulin secretion from the
pancreas
• It is eliminated via the kidney, hence can
accumulate in the elderly or in renal failure
• Accumulation of glibenclamide causes
hypoglycaemia
• Renal impairment may be caused by poor renal
perfusion, heart failure medication in this patient
Patient 4 - 48 year old woman
• Admitted unconscious, smelling of alcohol
• Pulse 60bpm, blood glucose unrecordable
From partner
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Diabetes since age 17, insulin twice daily
4th admission with hypoglycaemia in past month
Recent anxiety and depression
Propranolol 40mg tds,  alcohol intake
Questions
• Why have her hypoglycaemic attacks got more
frequent and required admission recently
Drug interactions and diabetes
• Increase risk of hypoglycaemia
– beta blockers, alcohol, sulphonamides,
monoamine oxidase inhibitors
• Decrease awareness of hypoglycaemia
– beta blockers
• Raise blood glucose
– corticosteroids, oral contraceptive, thiazides,
loop diuretics, diazoxide
Special prescribing in diabetes
• A carefully designed insulin (+ glucose, +K+)
regime is usually used in diabetics who:
– are acutely ill, have had myocardial infarction
– are fasting e.g. for an operation
– are pregnant
• Care should be taken with oral hypoglycaemics
in diabetics who:
– are elderly
– have renal/hepatic impairment
Summary
• Diabetes mellitus is a complicated spectrum
of conditions
• Each patient requires tailored therapy
depending on:
– pathology of diabetes
– lifestyle
– special circumstances/ill health
Summary 2
• Drugs that lower blood sugar form only part
of the treatment of diabetes
• Attention must be paid to many other
aspects including:
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lifestyle
diet/alcohol consumption
cardiovascular risk factors
foot care