Diabetes Mellitus

Question 1

Describe etiology of type I diabetes

Answer 1

1. Autoimmune disease with islet cell destruction
2. Environmental factors esp infections (mumps, rubella, coxB) may be due to molecular mimcry)

Question 2

Mention Abs in type I diabetes

Answer 2

1. zICA: islet cell cytoplasmic Ab
2. GADA: Glutamate decarboxylase Ab

Question 3

Describe etiology of type II diabetes

Answer 3

A. Genetic factors: diabetogenic genes
B. Environmental: sedentary lifestyle, dietary habits, apple-shaped or visceral obesity.

Question 4

List symptoms marking onset of DM

Answer 4

1. Hyperglycemia (more than 126 mg/dl fasting)
2. Polyuria due to glucosuria
3. Polydipsia due to polyuria
4. Polyphagia due to dec entry of glucose into cells of satiety center which is insulin dependent

Question 5

Mwntion labs for diagnosis & follow up of DM

Answer 5

Diagnosis:
1. FBG more than or equal to 126 mg/dl (n=100)
2. Random BG m/e to 200 mg/dl
3. Type 1 when uncertain test for Abs
Follow-up:
1. HbA1c gives an idea about control in previous few months (n is less than 6%)
2. Frucrosamine estimation in blood (every 2-3 wks)
3. Albumin ti check for nephropathy

Question 6

GR: Oral glucose tolerance test is not routinely used

Answer 6

Bec it is difficult to perform in practice & results are highly variable: however, it is used to screen pregnant women for gestational diabetes.

Question 7

Explain occurrence of hypertriacylgltcerolemia in type I DM

Answer 7

Not all fatty acids can be disposed by oxidation or ketone body synthesis, thus excess fatty acids are pachaged & secreted in VLDL. CMs which are formed in intestine after meal and VLDL level rise due to low lipoprotein lipase (as insulin inc its synthesis) resulting in this condition.

Question 8

Explain mechanism of insulin resistance

Answer 8

Obesity leads to over release of FFAs & other mediators (leptin, adiponectin) from adipocytes leading oxidative stress & inflammatory responses in pancreas & target cells leading to dec insulin sensitivity, through activation of serine/threonine kinase which phosphorylates beta polypeptide chain of RTK insulin receptor inhibiting its autophosphorylation upon insulin binding. Also FFA in macrophages & beta cells cytoplasm leads to secretion of cytokine IL-IBwhich mediates release of additional pro-inflammatory cytokines & promotes insulin resistance.

Question 9

Mention 2 insulin sensitising substances

Answer 9

1. Adiponectin is an adipokine with insulin sensitizing activity acts by dampening inflammatory response, it is dec in obesity.
2. Peroxisome proliferator-activated receptor-g

Question 10

The final fate on islets with long-standing type 2 DM

Answer 10

Amyloid replacement of islets

Question 11

GR: Ketosis is minimal in type 2 diabetes

Answer 11

Because presence of insulin even in presence if insulin resistance diminishes hepatic ketogenesis

Question 12

Describe role glucagon in DKA

Answer 12

Inc glucose causing polyuria & dehydration
Inc lipolysis thus inc ketone bodies & acidosis

Question 13

C/P of type 2 diabetes

Answer 13

Coma, normal pulse, dry skin, hyperventilation (Kussmaul breathing), acetone odor in mouth, acidosis&epinepherine dec GIT motility causing NVA

Question 14

Describe lab data of DKA

Answer 14

High blood glucose
Glucose & acetone in urine
Inc KB in blood

Question 15

List steps of DKA management

Answer 15

1. Fluid replacement (3-5 L)
2. Insulin therapy
3. Potassium replacement
4. Bicarbonate (rarely used)
5. Treat underlying cause

Question 16

Describe fluid replacement therapy in DKA & its importance

Answer 16

1. Isotonic saline initially followed by half tonic solution if serum Na+ rises
2. 5% glucose if blood falls to 250 mg/dl to maintain plasma osmolality thus avoiding brain edema & hypoglycemia
   Brain edema can occur since the decline of glucose level inside the brain is much less than other tissues since it’s insulin independent will lead to gap between brain osmolarity & plasma of blood leading to withdrawal of water.

Question 17

GR: K+ replacement in DKA

Answer 17

Initial K+ is often high due to acidosis & there is no need for K+, insulin reverses acidosis dec K+ so requiring KCl administration.

Question 18

What is indication HCO3-?

Answer 18

Severe acidosis (less than 7.1) stopped when reaches 7.2, as mild acidosis is corrected by insulin

Question 19

Glucose levels in HHC is usually……

Answer 19

More than or e to 300 mg/dl

Question 20

What is the mechanism of HHC?

Answer 20

High glucose blood glucose causes severe dehydration, inc in osmolarity as water is osmotically drawn out of cells into the blood & loss of glucose into urine. There is dangerous electrolyte disturbance & lethargy ultimately leading to coma.

Question 21

Why does strenuous exercise cause hypoglycemia?

Answer 21

Exercise promotes glucose uptake into muscle & dec the need for exogenous insulin

Question 22

C/P of hypoglycemic coma

Answer 22

1. Rapid strong pulse
2. Moist skin
3. Many symptoms of sympathetic activation of autonomic nervous system. Consciousness can be altered or even lost in extreme cases, leading to coma, seizures, or even brain damage & death.
4. No hyperventillation or acetone odor
5. May cause brain edema
6. Patients rely on epinepherine secretion to prevent hypoglycemia. However, as the disease progresses type 1 diabetes patients show diabetic autonomic neuropathy.

Question 23

List pathways involved in long term effect of diabetes

Answer 23

1. Formation of advanced glycation end products
2. Disturbances in polyol pathway
3. Activation of protein kinase C

Question 24

Describe role of AGE in complications of diabetes

Answer 24

1. Bind to a specific receptor RAGE which is expressed on inflammatory cells (macrophages & T cells) & in endothelium & vascular smooth muscles the effects of AGE-RAGE signaling axis are:
   -Release of pro-inflammatory cytokines & growth factors from intimal macrophages
   -Generation of ROS in endothelial cells
   -Inc procoagulant activity on endothelial cells & macrophages
   -Enhanced proliferation of vascular smooth muscles
2. AGE can diretly cross link ECM proteins dec protein removal & enhancing deposition e.g. LDL gets trapped in AGE-modified large blood vessels accelerating atherosclerosis, albumin gets trapped in capillaries acounting for BM thickening & diabetic microangiopathy.

Question 25

Role of polyol pathways in complications of diabetes

Answer 25

In tissues not reuiring insulin for glucose transport as nerves, lens, kidney, blood vessels,, hyperglycemia activates aldose reductase forming sorbitol & eventually fructose a reaction that uses NADPH as cofactor. Sorbitol accumulates in retina, lens, kidney & nerve cells causing strong osmotic effects & cell swelling as result of water retention. Also this pathway consumes NADPH which is required for regeneration & reduction of glutathione thus this decreases tissue resistance to oxidative stress.

Question 26

Role of protein kinase C in complications of diabetes

Answer 26

Intracellular hyperglycemia can stimulated de novo synthesis of DAG from glycolytic intermediates & Intracellular PKC is activated by Ca & DAG. Downstream effects of PKC activation are production of VEGF & profibrigenic molecules such as TGFB leading inc ECM deposition & BM material.

Question 27

List the 4 most important tissue damage in diabetes

Answer 27

1. Blood vessels (macro & microangiopathy)
2. Kidney (nephropathy)
3. Eye (retinopathy)
4. Neurons (neuropathy)