L11.1 Developmental origins of metabolic diseases

Question 1

Relationship of diabetes and CVD

Answer 1

• CVD is the leading cause of death in patients with diabetes
• 70% of diabetic patients have hypertension

Question 2

How does diabetes lead to CVD

Answer 2

• Due to BV damage from elevated blood glucose

Question 3

Type 1 diabetes

Answer 3

• Insulin dependent (defective insulin production)
• Early onset, 10-15% cases

Question 4

Type 2 diabetes

Answer 4

• Non-insulin dependent
• Insulin resistance
• Late onset, but recently ↑ in children (due to bad diet and lifestyle factors)

Question 5

Why don’t many people realise they have diabetes?

Answer 5

• Symptoms don’t manifest at early stages and blood glucose has been elevated
• Leads to Complications:
  
  • Microvascular
    
    • Damage to BV: Retinopathy/nephropathy
      
      • BV don’t supply to periphery → tissues can’t regenerate and need to be amputated
  • Macrovascular
    
    • Heart diseases/stroke…

Question 6

Secretion of insulin

Answer 6

• Secreted by β-cells in islet cells in pancreas
• β-cell mass is dynamic → changes according to demand
• Biphasic secretion

Question 7

Insulin

Answer 7

• Allows uptake of glucose into cells (via GLUT4)
• Suppress liver glucose production
• Glucose homeostasis

Question 8

Glucose homeostasis

Answer 8

• Food → causes spike in glucose
• Body maintains strict glucose range (~4-~6.5mmol/L)
• Brain is unable to syn/store glucose → constant supply is needed
• Insulin is closely mirrored by glucose → ↑glucose → ↑insulin to ↓glucose
  
  • -ve FB from ↓glucose to inhibit further insulin secretion

Question 9

Impaired glucose homeostasis

Answer 9

• Not secreting insulin/insulin resistance
• Impairment leads to hyperglycaemia and diabetes
  
  • Impaired glucose tolerance does not equal diabetes

Question 10

Insulin sensitivity vs resistance

Answer 10

• Resistance → body does not respond to insulin signals
• Sensitivity → how responsive the body is to insulin signals

Question 11

Low birth weight associated with metabolic dysfunction

Answer 11

• Hyperinsulinaemic → suggesting insulin resistance
• β-cells overcompensate to maintain normal glucose levels
• Genetic factors not contributing to the phenotype
  
  • Intra-uterine condition is what is programming it

Question 12

When is the critical period for programming of metabolic dysfunction

Answer 12

• Developmental insults during late gestation may be a critical period for programming of metabolic dysfunction

Question 13

Thrifty phenotype hypothesis

Answer 13

1. Fetus can adapt to suboptimal intrauterine conditions
   
   • Limited nutritional supply → able to redirect nutrients to important organs like brain at the expense of other organs (pancreas/kidneys)
2. Such events during critical periods → permanently program fetus metabolism to enhance survival in poor nutrition env (even postnatally)
3. Programs itself to a deficient env post-natally as well → if postnatal nutrition is abundant → advantageous adaptation may be lost and may have harmful long-term consequences

Question 14

Mechanisms of low birth weight and diabetes

Answer 14

IUGR/malnutrition/GC leads to:

• ↓β-cell mass & secretion
• ↓glucse uptake/production in liver
• ↓insulin sensitivity in muscles
• ↓insulin inhibition of lipolysis in adipose tissue
  
  • All leads to type 2 diabetes

Question 15

Insulin resistant concept

Answer 15

• Body less sensitive to insulin
• β-cells compensate ↑insulin secretion
• β-cells exhausted (↑apoptosis) → ↓insulin secretion
• Sustained impaired fasting glucose (IFG)
• Further ↓insulin sensitivity, secretion, β-cells
• Sustained type 2 diabetes

Question 16

B-cell apoptosis concept

Answer 16

• Βcells apoptosis → remaining βcells compensate → exhaust → IFG

Question 17

Islet malformation concept

Answer 17

• Most commonly seen in people born small
• Βcell deficient → compensate → insulin resistance with age → sustained IFG

Question 18

Common mechanism leading up to diabetes

Answer 18

• No matter what underlying pathology is, Pancreatic βcells can compensate by ↑insulin secretion in response to declin in insulin sensitivity → until βcell exhaustion → diabetes

Question 19

Difference in male/famales glucose tolerance

Answer 19

• IUGR male rates → loss of insulin secretion even in presence of elevated glucose
• IUGR females rats → normal glucose tolerance
  
  • But pregnant (becomes insulin resistance) → if born small to start with → impaired glucose tolerance during pregnancy

Question 20

Consequences of IUGR

Answer 20

• Structural changes
  
  • ↓pancreas/muscle mass, islet mass (70%), pancreatic vascularisation
• Molecular changes
  
  • Gene/protein changes
  • Mito dysfunction (ATP is critical for insulin prod/release)
• Epigenetic changes

Question 21

Gestation diabetes

Answer 21

• can only happened during pregnancy
• ↑risk of diabetes in offspring
• ↑lifetime risk of diabetes in mother (becomes type2)
  
  • Implication in 2nd pregnancy
  • Transgenerational programming → disease may span multiple generations

Question 22

Interventions

Answer 22

• Improved diet, supplements, drugs, exercise (most important)
  
  • Adult βcell mass restored in growth restricted adult rats after 4 weeks of exercise