Goals:

1) Understand the mechanism for ↑LDL in Type II diabetes

2) Having previously established the link between endothelial cell damage(loss of inhibitory GAG) and abnormal smooth muscle migration & proliferation,

Integrate ↑LDL into scheme of atherosclerosis- accumulation of LDL cholesterol in the macrophage

to form “foam cells”

Final Exam: Explain abnormal accumulations of smooth muscle and lipid inatherosclerosclerosis of Type II diabetics

Approach:

-normal regulation of lipid metabolism by insulin(↑ TG in adipose tissue)

- theoretical abnormalities in lipid metabolism with insulin resistance

- “insulin-resistant syndrome”: why ↑TG, ↑LDL & obesity ??

- hyperglycemia & AMP Kinase

- selective insulin resistance

-lipid-centric approach-obesity represents the epigenetic cause of insulin resistance in

susceptible individuals

Dysregulation of lipid metabolism in the “Metabolic Syndrome”

If insulin resistant- why are some obese?

Insulin resistance of Type II diabetes

- reduced receptor concentration with hyperinsulinemia

- reduced signaling due to abnormal phosphorylation of insulin receptor substrate 1

- increased FFA with “metabolic syndrome” impairs insulinsensitive glucose transport

Insulin targets:- ↑ endothelial cell LPL → ↑ plasma FFA-↑ hepatic & adipose TG synthesis from FFA

(prevents FFA entry into mitochondria for oxidation byincreasing malonyl CoA)

-↓ lipolysis in adipose tissue by inhibition of hormone sensitive lipase

- ↑ LDL endocytosis

From Medical Physiology, (eds Boron & Boulpaep) page 999

Insulin & lipid metabolism:

clear plasma of TG & store energy as fat

- prevents FFA oxidation by ↑ malonyl CoA & preventing FFA entry into mitochondria for oxidation**

- facilitates hepatic TG synthesis (TG appear in plasma as VLDL)

- stimulates lipoprotein sensitive lipase on endothelium to release FFA from TG

- inhibits lipolysis via inhibition of hormone-sensitive lipase

___________________________________________________________________________________________

Insulin resistance & dyslipidemia in the Metabolic Syndrome↑ TG & ↑ small density LDL ↓ HDL

**If insulin resistant, why ↑plasma TG, LDL & obesity? Should mobilize fat stores & oxidize fat.

If insulin resistant, why obese?

-elevated insulin to normalize glucose-Insulin inhibition of lipolysis is most

Insulin-sensitive parameter

“Metabolic Syndrome”

If insulin resistant, should oxidize FFA, & in adipose tissue, have less lipogenesis & greater lipolysis (maybe not greater lipolysis)

If insulin resistant, why obese with ↑plasma TG &LDL?

-hyperglycemia (acting through AMP kinase & increased substrate→ ↑ malonyl CoA → ↑ TG)

-Insulin resistance may not exist in liver (↑ malonyl CoA → ↑ TG & LDL)

Additional components with metabolic syndrome:

-sedentary lifestyle- ↓ exercise; through AMP kinase, ↑

malonyl CoA- “emotional stress”

- ↑ cortisol → ↑appetite & ↑insulin resistance → ↑ glucose

- aging & obesity - ↓ exercise- ↓ activity of hormone sensitive lipase

(mobilize less “central” fat)

- leptin resistance- ↑ appetite

- obesity/depression- ↑ appetite

Obesity as the epi-genetic cause of insulin resistance in genetically susceptible individuals

Obesity:1) Decreased sensitivity of glucose-induced insulin secretion

- can manifest as hyperinsulinemia with normal blood glucose(J Clin Inves 81:442,1988)

lipo-centric approachObesity → decreased insulin receptor concentrationDecreased insulin-sensitive glucose uptake → hyper-insulinemia to normalize blood glucoseHyper-insulinemia with “normal” insulin sensitivity on inhibition of lipolysis → abnormally greater

inhibition of lipolysisHyper-insulinemia with “normal” insulin sensitivity in liver → greater inhibition of lipid oxidation,

greater ↑TG & LDL

Insulin resistance

• “most, if not all, of the other tissues of the body retain normal insulin sensitivity in the face of muscle and adipose tissue insulin resistance” (Endo Metab Clin N Am 34:49,2005)

• Hence: with increased insulin (response to hyperglycemia secondary to insulin resistance in sk mus & fat), exagerated inhibition of hepatic FFA oxidation and enhanced TG synthesis

Final Exam Preparation:

Compose a cohesive explanation for the pathophysiology & pharmacological prophylaxis of atherosclerosis in the insulin-resistant (metabolic) syndrome.

Suggestions:

- lipocentric approach (obesity → decreased insulin-sensitive glucose uptake → hyper-insulinemia)

- increased plasma concentration of LDL(ex: possible hyperglycemia effects on AMP kinase & normal insulin sensitivity in liver → reduced lipid oxidation, ↑ TG & LDL)

- significance of elevated LDL(ex: induces endothelial binding of monocytes, which infiltrate sub-endothelial space, differentiate into macrophages,

incorporate LDL and present as “foam cell”)

-endothelial damage & loss of inhibitory ECM GAG leading to abnormal SMC proliferation(ex: summarize evidence discussed regarding loss of inhibitory heparan sulfate GAG)

Attached references:

AMP Kinase

Foam Cell Formation

1) Intestinal chylomicrons (85% triglycerides & 3% cholesterol)→lymph→plasma- lipoprotein lipase* on vascular endothelium releases FFA from TG on chylomicrons- FFA transported into skeletal muscle and adipose tissue*

2) Liver processes remnant chylomicrons (TG depleted & cholesterol rich) & exports VLDL (triglyceride rich) to plasma

- hepatic FFA oxidation inhibited* & TG synthesized- lipoprotein lipase* on vascular endothelium releases FFA from TG on VLDL*

3) FFA diffuse into adipose tissue → ↑TG - lipolysis inhibited*

4) Plasma triglyceride depleted VLDL = LDL (cholesterol rich)

5) Small/dense LDL formed (exchange of some LDL cholesterol with TG of VLDL; subsequent hydrolysis of TG generates dense LDL)

6) LDL (cholesterol rich) enter cells by receptor-mediated endocytosis*

7) HDL accumulate cholesterol from LDL & cell membranes; liver extracts & excretes cholesterol from HDL

* Insulin sensitive.

Normal flow of chylomicrons → VLDL → LDL → HDL