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
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
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
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
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.