Case 6 Flashcards

1
Q

What are the genetic causes of TIDM?

A
  • 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
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2
Q

What are the Environmental causes of TIDM?

A
  • 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
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3
Q

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

A
  • Decreased glucose uptake
  • decreased glycogen breakdown and gluconeogenesis
  • conversion of of fatty acids to ketone bodies
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4
Q

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

A
  • decreased glucose uptake
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5
Q

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

A
  • decreased glucose uptake and storage
  • increased breakdown of fat and release of Fatty acids
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6
Q

Describe and explain the pathogeneisis of TIDM?

A
  • 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
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7
Q

What are the symptoms of TIDM?

A
  • 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
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8
Q

What is T2DM?

A
  • 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
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9
Q

What is sarcopenia and what are its effects?

A
  • Loss of muscle mass
  • results in increased insulin resistance
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10
Q

What are the non-modifable risks associated with T2DM?

A
  • Age
  • Ethnicity
    • Afro-Caribean
    • Middle Eastern
    • Asian
  • Family history of T2DM
  • history of gestational diabetes
  • polycystic ovary syndrome
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11
Q

Whare are the modifiable risk factors of T2DM?

A
  • Obesity/Overweight
  • Sedentary lifestyle
  • Glucose intolerance
  • dietary factors
  • intrauterine environment
  • inflammation
  • metabolic syndrome
    • Hypertension
    • Decreased HDL cholesterol
    • Increased triglycerides
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12
Q

What is the minimum blood sugar level for diabetic patients

A
  • 4mmol/L
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13
Q

What are the effects of a low blood sugar level?

A
  • Neuroglycopenia
  • mild cognitive impairement below that level
  • activation of autonomic systems
    • sweting
    • tremor
    • elevated HR
  • Coma
  • death
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14
Q

What are the symptoms of hyperglycaemia?

A
  • Ketoacidosis in T2DM
  • polydipsia
  • polyphagia
  • diabetic retinopathy leads to blindness
  • fatigue
  • headache
  • blurred vision
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15
Q

Explain the mechanism of insulin release from beta cells?

A
  • 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
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16
Q

Explain the pathophysiology of macrovascular complications of T2DM?

A
  • 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
17
Q

What is diabetic retinopathy?

A
  • Retinal capillary microaneurysms and macular oedema
  • Symptoms:
    • focal blurring
    • vitreous or retinal detachment
    • partial or total vision loss
18
Q

What is diabetic nepropathy?

A
  • Thickening of the glomerular basement membrane, mesangial expansion and glomerular sclerosis
  • the changes cause glomerular hypertension and system decrease in GFR
19
Q

What is diabetic neuropathy?

A
  • Nerve ischaemia, direct effects of hyperglycaemia on neurones and intraceullular metabolic changes that impair nerve function
20
Q

What type of glutamine transporter is present in pancreatic beta cells

A
  • Express GLUT-2 receptors which permit rapid glucose uptake regardless of extracellular sugar concentration
21
Q

Explain the mechanism of inflammatory conditions leading to insulin reistance?

A
  • 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, TNFa (proinflamamtory)
  • Activation of NF-KB in livers results in liver and muscle insulin resistance - diabetes
22
Q

Explain the mechanism that results in insulin resistance?

A
  • 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