Type II Diabetes

Question 1

How does muscle insulin resistance lead to impaired glucose tolerance and diabetes?

Answer 1

. Factors (obesity, ageing, genes) contribute to insulin resistance
. Causes increased lipolysis in visceral fat (increased fatty acids) and β-cell compensation (hyperinsulinemia)
. Leads to increased gluconeogenesis in liver
. β-cell decompensation leads to impaired glucose tolerance
. Decreased insulin secretion –> DIABETES

Question 2

Describe endocrine signalling from adipose tissue.

Answer 2

. Adipose tissue secretes FFAs and inflammatory cytokines
. Leads to:
- Increased glucose output in liver
- Decreased glucose uptake in muscle

Question 3

How does adipocyte hypertrophy lead to Type II Diabetes?

Answer 3

. Adipocyte hypertrophy means more inflammatory cytokines, FFAs, leptin and glycerol produced
. Leads to insulin and leptin resistance, chronic inflammation, and Lipotoxicity
. Results in liver dysfunction, increased apoptosis of β-cells, decreased secretion of insulin, which results in T2D

Question 4

What effect does obesity have on adipocytes?

Answer 4

Leads to adipocytic hypertrophy (adipocytes increase in size, thus secreting a greater amount of FFAs and inflammatory cytokines)

Question 5

How do FFAs cause insulin resistance?

Answer 5

. FFAs converted to LCACoA (long chain acyl CoA)
. LCACoA can be converted to ceramides, DAG, hexosamines (second messengers)

. Ceramide activates CAPP (ceramide activated protein phosphatase), CAPK (ceramide activated protein kinase), PKC (protein kinase C)
. DAG activates PKC
. Hexosamines activates PKC, protein modification, gene transcription

. All this results in insulin resistance
(Note: ceramide activated protein phosphatase/kinase can play a role in regulating the action of pyruvate dehydrogenase)

Question 6

How do FFAs and inflammatory cytokines inhibit insulin signalling?

Answer 6

. FFAs, TNFα, and insulin activate mediators (including JNK)

. Phosphorylation of serine 307, 612, 632 (related to IRS1)