Case 6

Question 1

What are the genetic causes of TIDM?

Answer 1

• loss of self tolerance among T cells that attack the beta cells antigens therefore t cells call other t cells to have a coordinated attack on beta cells
• HLA system on chromosome 6 that code for MHC complex which is important for self tolerance
• many diabetic patients have the genes
  
  • HLA -DR3
  • HLA-DR4
• Susceptibility genes:
  
  • DQB1*0201
  • DQBI*0302

Question 2

What are the Environmental causes of TIDM?

Answer 2

• Viruses: directly infect and destory betal cells or may cause betal cells destruction indirectly by exposing autoantigens activating autoreactive lymphocytes
• Diet: exposure of infants to cow’s milk
  
  • low vit D
  • early or late exposure to gluten

Question 3

What are the effects of a lack of unsulin on the liver?

Answer 3

• Decreased glucose uptake
• decreased glycogen breakdown and gluconeogenesis
• conversion of of fatty acids to ketone bodies

Question 4

What are the effects of a lack of insulin on the muscle?

Answer 4

• decreased glucose uptake

Question 5

Whar are the effects of a lack of insulin on adipose tissue?

Answer 5

• decreased glucose uptake and storage
• increased breakdown of fat and release of Fatty acids

Question 6

Describe and explain the pathogeneisis of TIDM?

Answer 6

• Genetic predisposition linked to HLA
• Environmental challenge possibly viral causes onset leading to inflammation of islets (insulitis) and changes the nature of beta cells so that they become a target for the immune system
• Beta cell destruction
• As a result from the lack of insulin blood glucose levels are raised both before and after a meal in the fasting state
• The cells cannot uptake the glucose available int he blodo therefore the body is in astate of hypoglycaemia
• all regulatory mechanisms against hypoglycaemia are activated:
  
  • increase in lipolysis - resulting in plasma FFA
  • increase in ketone bodies - ketoacidosis
• compensated by Kussmaul’s respiration

Question 7

What are the symptoms of TIDM?

Answer 7

• Hyperglycaemia
• loss of glucose in urine
• osmotic drag of glucose on water
• water and glucose lost in urine - glycosuria
• electrolytes lost along with water
• increased urine - polyuria and nocturia
• dehydration - increased thirst - polyuria
• eating a lot - polyphagia

Question 8

What is T2DM?

Answer 8

• A syndrome due to insulin receptor insensitivity, igher levels of insulin are required to achieve the same effect, a disorder of insulin deficiency
• progressive decline in beta cell function

Question 9

What is sarcopenia and what are its effects?

Answer 9

• Loss of muscle mass
• results in increased insulin resistance

Question 10

What are the non-modifable risks associated with T2DM?

Answer 10

• Age
• Ethnicity
  
  • Afro-Caribean
  • Middle Eastern
  • Asian
• Family history of T2DM
• history of gestational diabetes
• polycystic ovary syndrome

Question 11

Whare are the modifiable risk factors of T2DM?

Answer 11

• Obesity/Overweight
• Sedentary lifestyle
• Glucose intolerance
• dietary factors
• intrauterine environment
• inflammation
• metabolic syndrome
  
  • Hypertension
  • Decreased HDL cholesterol
  • Increased triglycerides

Question 12

What is the minimum blood sugar level for diabetic patients

Answer 12

• 4mmol/L

Question 13

What are the effects of a low blood sugar level?

Answer 13

• Neuroglycopenia
• mild cognitive impairement below that level
• activation of autonomic systems
  
  • sweting
  • tremor
  • elevated HR
• Coma
• death

Question 14

What are the symptoms of hyperglycaemia?

Answer 14

• Ketoacidosis in T2DM
• polydipsia
• polyphagia
• diabetic retinopathy leads to blindness
• fatigue
• headache
• blurred vision

Question 15

Explain the mechanism of insulin release from beta cells?

Answer 15

• Brain is dependent on glucose
• Insulin is produced from pancreatic beta cells which have calcium and k-ATPase channels
• glucose enters the cell and is broken down to produce ATP
• The ATP deactivates the K-ATPase channel shutting it down therefore the cell retains potassium and depolarises the membrane
• calcium channel opens
• calcium influx results in insulin granules being re;eased
• in the absence of glucose beta cells don’t produce insulin

Question 16

Explain the pathophysiology of macrovascular complications of T2DM?

Answer 16

• Glycosylation of serum and tissue proteins with formation of advanced glycation and products
• Superoxide production. Activation of PKC a signalling molecule that increases vascular permeability and causes endothelial dysfunction
• sorbitol accumulation within tissues, hypertension and dyslipideamia that accompanies diabetes
• Arterial microthromboses
• Pro-inflammatory and prothrombotic effects of hyperglycaemia and hyperinsulinemia that impair vascular autoregulation

Question 17

What is diabetic retinopathy?

Answer 17

• Retinal capillary microaneurysms and macular oedema
• Symptoms:
  
  • focal blurring
  • vitreous or retinal detachment
  • partial or total vision loss

Question 18

What is diabetic nepropathy?

Answer 18

• Thickening of the glomerular basement membrane, mesangial expansion and glomerular sclerosis
• the changes cause glomerular hypertension and system decrease in GFR

Question 19

What is diabetic neuropathy?

Answer 19

• Nerve ischaemia, direct effects of hyperglycaemia on neurones and intraceullular metabolic changes that impair nerve function

Question 20

What type of glutamine transporter is present in pancreatic beta cells

Answer 20

• Express GLUT-2 receptors which permit rapid glucose uptake regardless of extracellular sugar concentration

Question 21

Explain the mechanism of inflammatory conditions leading to insulin reistance?

Answer 21

• Low level chronic inflammation is linked to diabetes
• High doses of salicytes (apirin)
  
  • reverse insulin reistance and idabtetes
  • preserve B cell function
• high fat diets or obesity activate transcription factor NF-_KB and increase production of IL-6, IL-1beta, TNF_a (proinflamamtory)
• Activation of NF-KB in livers results in liver and muscle insulin resistance - diabetes

Question 22

Explain the mechanism that results in insulin resistance?

Answer 22

• Insulin binds to to insulin receptor which requires a docking protein (insulin receptor substrate)
• IRS proteins contian serines and tyrosines which act as substrates for phosphorylation
• When insulin binds to the receptor, the IRS is acitvated and tyrosine is phosphorylated and this activates P13 -K
• this causes an increase in glucose transport, shuts down hepatic glucose production and lipolysis
• lipid infusion causes a decrease in IRS tyrosine phosphorylation leading to a decreased in p13-K associated activity
• increase in membrane bound active protein kinase Cq via diacyglycerol DAG activates PrKc in presence of calcium
• causes supression of IRS sctivity by causing phosphorylation of serine proteins instead of tyrosine ones
• inflammatory mediators IL-6, TNFa induce insulin resistance via this mechanism
• the transport channels trnaslocated to the membrane are GLUT-4