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

1. 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 in atherosclerosclerosis of Type II diabetics

3. 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

4. Dysregulation of lipid metabolism in the “Metabolic Syndrome” If insulin resistant- why are some obese?

5. 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 insulin sensitive glucose transport

6. From Medical Physiology, (eds Boron & Boulpaep) page 999 • Insulin targets: • - ↑ endothelial cell LPL → ↑ plasma FFA • ↑ hepatic & adipose TG synthesis from FFA • (prevents FFA entry into mitochondria for oxidation by • increasing malonyl CoA) • ↓ lipolysis in adipose tissue by inhibition of • hormone sensitive lipase • - ↑ LDL endocytosis

7. 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.

8. If insulin resistant, why obese? • -elevated insulin to normalize glucose • Insulin inhibition of lipolysis is most • Insulin-sensitive parameter

9. 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 “Metabolic Syndrome”

10. 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 approach Obesity → decreased insulin receptor concentration Decreased insulin-sensitive glucose uptake → hyper-insulinemia to normalize blood glucose Hyper-insulinemia with “normal” insulin sensitivity on inhibition of lipolysis → abnormally greater inhibition of lipolysis Hyper-insulinemia with “normal” insulin sensitivity in liver → greater inhibition of lipid oxidation, greater ↑TG & LDL

11. 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

12. 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)

13. Attached references: AMP Kinase Foam Cell Formation

14. Normal flow of chylomicrons → VLDL → LDL → HDL • 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* • 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 • .