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)
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