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1

Structure and synthesis of insulin

2

Normal blood glucose values

Fasting: 72 – 100 mg/dl (4.0 – 5.7 mmol/L)

Random: < 180 mg/dl (10 mmol/L)

3

Other causes of DM

 

Hormonal/ Genetic syndromes 

– Pancreatic disease

– Hormonal antagonists to insulin (eg, cortisol,

growth hormone, catecholamines)

– Drug - &chemical-induced

– Genetic syndromes: Down’s, turner’s

4

 Gestational DM is typically resolved

after delivery

5

Features of type1 and type 2 DM

6

Etiology of Type I DM

caused by immune- mediated destruction of the pancreas

7

Genetic Etiology of Type I DM

concordance between monozygotic twins is 40%

– association with

HLA-DR3  

DR4/DQA1

DQB1

8

Environmental factors Type I DM

 

Viruses 

Association with viruses: coxsackie B4, Rubella, Mumps

and some drugs and toxins

 

To destroy insulin Rub your Mumps b4 you get kicked in your coxsackie

9

Etiology of Type I DM (2)

• Autoimmunity

islet cell antibodies (ICA), other antibodies against pancreatic components and infiltration of the pancreatic islets by T-cells

– There is a long pre-diabetic phase during which the destruction of Beta cells continues

10

autoimmune system which destroys the pancreas is triggered by

viral or chemical attack on beta cells, leading to exposing new proteins or due to molecular mimicry between viral and beta cell structures. The HLA system is relevant because it is involved in antigen presentation.

11

Etiology and Pathogenesis: Type 2 DM GeneticFactors

– stronger than Type 1 - (80 % concordance in identical

twins).

– no HLA associations

– typically a polygenic disorder: depends on the simultaneous presence of several genes but environmental factors (eg obesity) are involved

12

Etiology and Pathogenesis: Type 2 DM(2) • Environmental factors

– Obesity is associated with around 80% of patients with Type 2 DM.

– More than half of patients with diabetes have BMI between 25 – 29 kg/m2

– Relative risk (RR) for DM for BMI >35kg/m2 100- fold than BMI <22 kg/m2

– DM is rare at BMI 21-22

13

How does obesity lead to DM

Increased production of insulin antagonists, such as fatty acids and tumour necrosis factor (TNF) by adipose

tissue, specially in central obesity

14

Pancreatic pathology in DM

• Type 1 DM

– selective destruction of insulin-secreting beta cells.

– insulitis, a chronic inflammatory infiltrate of the islets affecting primarily insulin containing islets.

15

Pancreatic pathology in DM

Type 2 DM

– Moderate reduction islet tissue

– Variable degrees of deposition of amyloid

16

Long-term complications diabetes

– Including : nephropathy, neuropathy, eye disease, heart disease, stroke and problems of feet.

17

Biohemical signs in DM

• Hyperglycaemia: • Glycosuria

• Ketoacidosis

• Ketonuria

• Hyperlactatemia

• Hyperlipidemia

• Hypovolemia

• Hyperosmolarity

18

Diagnosis of DM

• A1c > 6.5% OR

• Fasting plasma glucose (FPG) level > 126 mg/dL (7 mmol/L) OR

• Two-hour plasma glucose > 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT)

OR

• Classical signs and symptoms (polyuria, polydipsia and unexplained weight loss), plus random glucose level > 200 mg/dL (11.1 mmol/L)

19

Diagnosis of DM

• OGTT (oral glucose tolerance test):

– Patient fasts overnight

– Take basal glucose level

– Give 75 gram glucose and measure blood glucose level at 120 minutes

20

Oral Glucose Tolerance Test (OGTT) graph

21

Prediabetic states • Impaired fasting glycaemia (IFG)

– A fasting plasma glucose above normal and below the diabetic range i.e. FPG > 100mg/dl but < 126 mg/dl (between 5.6 mmol/L and 6.9 mmol/L)

22

Prediabetic states Impaired glucose tolerance (IGT)

– A 2-h value in the OGTT of > 140 mg/dl but < 200

mg/dl (between 7.8 and 11.1 mmol/L, during an OGTT)

23

Prediabetic states A1c level

5.7–6.4%

24

Prediabetic states epi

• 10 -25% of Western populations are IGT or IFG

• 4 - 9% annual conversion of prediabetic state to clinical diabetes

• It is possible to prevent this conversion by

encouraging weight loss through diet, exercise

and medications

25

Glycosylated hemoglobin method

Hemoglobin reacts with glucose non-enzymatically to produce HbA1. HbA1c is the major fraction of glycosylated hemoglobin ( about 5% of total hemoglobin concentration ). HbA1c levels give an integrated measure of glucose concentrations over the previous 2 -3 months

26

Elution profile of glycosylated hemoglobin

27

Acute complications of DM

• Hypoglycemia

– Is a complication of diabetes treatment • Diabetic ketoacidosis

• Hyperosmolar nonketotic coma

• Lactic acidosis

28

Diabetic Ketoacidosis (DKA) • Precipitating factors

– Infection or acute illness

– Trauma

– Emotional disturbance

– Missed insulin dose

29

pathophys of DKA 

30

Pathophysiology of DKA

• Acute insulin deficiency, and the rise in stress hormones levels lead to progressive hyperglycaemia; severe hyperglycemia cause a huge osmotic diuresis and gross dehydration.

• Acute insulin deficiency and the rise in levels of stress hormones (due to cellular starvation and hypovolemia) lead to development of ketosis. Ketosis cause vomiting.

• Electrolyte disturbance is caused by (i) insulin deficiency (ii) osmotic diuresis (iii)vomiting

• Acidosis is caused by (i) ketosis (ii) lactic acidosis, caused by dehydration and vasoconstriction by stress hormones.