L11.1 Developmental origins of metabolic diseases Flashcards Preview

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Flashcards in L11.1 Developmental origins of metabolic diseases Deck (22)
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1

Relationship of diabetes and CVD

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

2

How does diabetes lead to CVD

  • Due to BV damage from elevated blood glucose

3

Type 1 diabetes

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

4

Type 2 diabetes

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

5

Why don't many people realise they have diabetes?

  • 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…

6

Secretion of insulin

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

7

Insulin

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

8

Glucose homeostasis

  • 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

9

Impaired glucose homeostasis

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

10

Insulin sensitivity vs resistance

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

11

Low birth weight associated with metabolic dysfunction

  • 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

12

When is the critical period for programming of metabolic dysfunction

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

13

Thrifty phenotype hypothesis

  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

14

Mechanisms of low birth weight and diabetes

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

15

Insulin resistant concept

  • 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

16

B-cell apoptosis concept

  • Βcells apoptosis → remaining βcells compensate → exhaust → IFG

17

Islet malformation concept

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

18

Common mechanism leading up to diabetes

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

19

Difference in male/famales glucose tolerance

  • 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

20

Consequences of IUGR

  • 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

21

Gestation diabetes

  •  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

22

Interventions

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