Overview of diabetes mellitus with a focus on pathophysiological aspects

1. Diabetes
mellitus
Pathophysiology

2. Obesity
Diabetes mellitus
Hypertension
“Obesity is the mother of metabolic
diseases”
The 3 public health scourges of modern times

3. World-wide estimated number of adults with
diabetes by age group and year

4. Diabetes mellitus
is a group of metabolic diseases characterized
by
hyperglycemia
resulting from
• defects in insulin secretion,
• defects in insulin action
(“insulin resistance”),
• or both.
long-term damage, dysfunction, and
failure of various organs, especially the
eyes
kidney
nerves
heart
blood vessels.
“Complications”

5. Classification of diabetes
 Type 1 ( was called “insulin- dependent DM”/ juvenile type of DM) ( 5-10%)
 Type 2 (was called “non insulin- dependent DM” /adult onset DM ) (90-95%)
 The “pre-diabetic stage” (impaired glucose tolerance)
 Gestational DM -any degree of glucose intolerance with onset or first
recognition during pregnancy [in 2-5% of all pregnancies]
 Other specific types (1% - 2%)
– genetic syndromes (affecting insulin secretion or action)
– endocrinopathies (Acromegaly, Cushing’s syndrome, glucagonoma,
pheochromocytoma, thyrotoxicosis)
– diseases of pancreas (chronic pancreatitis, cancer)
– drug- or chemical-induced (corticosteroids, beta-blockers, thiazide
diuretics)
– infections (viral)
The main focus of this plenary

6. Type 1 Diabetes
“insulin- dependent DM”
“ juvenile-onset DM”
Type 2 Diabetes
“Non insulin-
dependent DM”
“ adult-onset DM”

7. Type 1 Diabetes
“insulin- dependent DM”
“ juvenile-onset DM”
Type 2 Diabetes
“Non insulin-
dependent DM”
“ adult-onset DM”
Many require insulin
i.e. insulin- dependent
May develop when
much older
Developing at younger
age groups
(childhood obesity)

8. Type 1 Diabetes Type 2 Diabetes
diabetes due to
insulin resistance and
inadequate compensatory
insulin secretory response
diabetes due to
absolute deficiency of
insulin

9. Positive Family history
Type 1 Diabetes Type 2 Diabetes
(but ”obesity gene” not yet identified)
30 %10 %

10. Pathogenesis
Susceptibility genes identified
e.g. HLA haplotypes DR3 & DR4.
cell-mediated autoimmune
destruction of the beta-cells
of the pancreas by auto-
antibodies
genetic
predisposition environmental factors
viral infections
stress
toxins e.g. rat poison
Type 1 Diabetes
absolute insulin deficiency

11. Sequence of events in the development of
Pathogenesis
Type 1 Diabetes

12. Pathogenesis
genetic
predisposition environmental factors
Diet
Physical inactivity
relative insulin deficiency
 Obesity
insulin resistance and
inadequate compensatory
insulin secretory response
Type 2 Diabetes

13. ?Exhaustion
?Glucotoxicity
? Amyloid deposition
Postreceptor defects
(refer to 2nd messenger
systems mediating insulin
action)
Impaired insulin action
Insulin
Counter regulatory
hormones:
Cortisol
Growth hormone
Anti-insulin action
hyperglycaemia
Inadequate
secretory
response
insulin
resistance
Type 2 DiabetesPathogenesis
Glucagon
Catecholamines
Target
cells
Pancreatic beta-cells:
Hyperglycaemic effect
vs
Diabetogenic effect

14. 2nd messenger systems mediating insulin action
What and where is the postreceptor defect?
• Multiple, but unified hypothesis yet to be made

15. Sympathetic
nervescells
cells
Glucagon
Insulin
receptor (-)
receptor (+)
receptor (+)
receptor (-)
Sympathetic
nerves
Net effect: incr. glucagon secretion
Net effect: decr. insulin secretion
(-)
(+)
Islets of
Langerhans
 Insulin-glucagon interaction in normal conditions
Paracrinepathway
Start here

16. Sympathetic
nerves
Glucagon
Insulin
receptor (-)
receptor (+)
receptor (+)
receptor (-)
Sympathetic
nerves
Net effect: incr. glucagon secretion
Net effect: decr. insulin secretion
Paracrinepathway
(-)
(+)
Islets of
Langerhans
 DM: Hyperglucagonaemia is a feature of DM
 Beta-blockers may further impair insulin secretion
Start here
cells
cells

17. Natural history of Type 2 Diabetes
cell secretory response to
progressive insulin
resistance
(Blood glucose normal)
cells no longer able
to compensate
Type 2 Diabetes

18. Too late?
At the time of diagnosis, 50% of cell function has already been lost
( A study on patients in the UK)
Type 2 Diabetes

19. Clinical presentation of DM
• Asymptomatic (particularly type 2 DM)
• Features resulting from the effects of insulin
deficiency/resistance (review insulin actions)
– The 3 Polys :
• Polyuria / nocturia
• Polydipsia
• Polyphagia (in the presence of unintentional weight loss)
• Complications
– Acute: coma (ketoacidosis) (particularly type 1 DM)
– Chronic: macrovascular and microvascular

20. Pancreas beta cells
Insulin actions
Glucose
entry and
utilization
(oxidation,
storage)
Glucose
entry and
oxidation
TG synthesis
insulin actions: a review

21. Pancreas beta cells
Insulin actions
Glucose
entry and
utilization
(oxidation,
storage)
Glucose
entry and
oxidation
TG synthesis
Metabolic consequences of insulin deficiency/resistance

22. Clinical Features of DM due to insulin lack
Polyphagia
(decr. leptin?)
Starvation in the
midst of plenty
Hyperosmolar
hyperglycemic
syndrome (HHS)
Lactic
acidosis
Lactic
acidosis
Muscle protein breakdown
Acetoacetate,0H-butyrate, acetone

23. • Ketoacidosis - Life threatening – medical emergency!
Stressful situation
Positive feedback cycleStart here

24. Stressful situation
Positive feedback cycleStart here
• Treatment: Fluids(normal saline), I.V. insulin. Monitor plasma
glucose (and K+ as insulin promotes uptake of glucose and K+ by
muscles and adipose tissue)
Insulin
pump
Rehydration -
fluids

25. • hyperglycaemia
• Excess glucose  attaches nonenymatically
to amino acids of proteins *“glycosylation”+
• Glycosylation of haemoglobin  HbA1C 
refects glycaemic control for the past 2
months (half life for RBCs)
• Glycosylation of plasma proteins 
fructosamine levels  refects glycaemic
control for the past 6 weeks(shorter half life)
Complications: pathogenesis

26. Complications: pathogenesis
• Hyperglycaemia
•  Excess entry of glucose into non-insulin dependent
tissues
– Nerves
– Lens
– Kidneys
– Blood vessels
• Increased intracellular glucose metabolized to
sorbitol  fructose  increased osmotic load 
influx of water  osmotic cell injury
• E.g. lens  cataract

27. Vascular complications: pathogenesis
• “glyocosylation”of collagen and other long-lived
proteins in tissues
•  Irreversible formation of advanced
glycosylation end products (AGEs)
accumulation of AGEs over the lifetime of blood
vessel walls 
– Protein cross-linking and trapping of plasma
lipoproteins in blood vessel walls
– Reduction in protein breakdown
– AGE binding to cell receptors/ endothelial dysfunction
•  vasculopathy

28. Microvascular complications
• Retinopathy
• Nephropathy
• Neuropathy
• Impaired skin healing  foot ulcers

29. Microvascular complications
• Diabetic Retinopathy:
– Capillary microanuerysms
– Macular oedema
– neovascularization
–  partial or total vision loss

30. Microvascular complications
• Diabetic nephropathy:
– Thickening of glomerular basement membrane
– Mesangial cell expansion
– glomerulosclerosis
Glomerular hypertension
Progressive decline in glomerular filtration rate
 nephrotic syndrome (leakage of albumin)/ renal
failure

31. Microvascular complications
• Diabetic neuropathy
– also due to direct effects of hyperglycaemia and
intracellular metabolic changes
•  impaired nerve function (sensory, motor)
– Symmetric polyneuropathy (distal feet and hands)
– Autonomic neuropathy
– Cranial neuropathy
– Mononeuropathy (median neerve, peroneal nerve)
– “diabetic foot”

32. Macrovascular complications
• Large vessel atherosclerosis (due to
hyperinsulinaemia, dyslipidaemia,
hyperglycaemia)
• Coronary arteries  myocardial ischaemia
/infarction
• Cerebral arteries  transient ischaemic
attacks; cerebrovascular events  stroke
• Peripheral artery disease  ischaemia
intermittent claudication

33. (1) Symptoms (thirst, increased urination,
unexplained weight loss) + a random plasma glucose
concentration >200 mg/dL (11.1 mmol/L).
(2) Fasting plasma glucose (FPG) >126 mg/dL (7.0
mmol/L) after an overnight (at least 8-hour) fast
(3) Two-hour plasma glucose greater than 200 mg/dL
(11.1 mmol/L) during a standard 75-g oral glucose
tolerance test (OGTT)
[ should be confirmed on a later day with one of the
three methods listed]

34. Oral Glucose Tolerance Test (OGTT)
(how much one can tolerate a glucose load without undue rise in
plasma glucose levels; reflects how efficiently insulin can handle
the glucose load))
Procedure
Overnight fast
75 g glucose in 300 ml water given orally over 5 minutes
Basal plasma glucose & every 30 minutes for 2 hours
Urine tested for sugar
Indications
Borderline fasting (FPG) or postprandial PG
Persistent glycosuria
Glycosuria of pregnancy
Pregnant women with family history of DM or had large babies

35. Plasmaglucose(mmol/l)

36. Symptoms of HYPOGLYCAEMIA
AUTONOMIC
• Sweating
• Trembling
• Pounding heart
• Hunger
• Anxiety
NUEROGLYCOPENIC
• Confusion
• Drowsiness
• Speech difficulty
• Inability to concentrate
• In-coordination
NON-SPECIFIC: Nausea, tiredness, headache
Diabetics on
Insulin therapy
“Hypoglycaemia
awareness”

37. American diabetic association. Diagnosis and classification of diabetes
mellitus. Diabetic care, 2004, 27 (Suppl. 1); 55-60.
Robbins Pathologic basis of disease. Pocket companion. Saunders.
Holt RIG and Hanley N. Essential Endocrinology and Diabetes. 5th ed.
2007, Blackwell.
Merck Manual. iPhone app. Agile Parters. www.Merck Manuals.com.
Diabetes power point file. Prof. Hla-Yee-Yee, IMU.