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“ Angiotensin -Insulin Cross Talk” Implications For Insulin Resistance

“ Angiotensin -Insulin Cross Talk” Implications For Insulin Resistance. Sharma Prabhakar MD MBA FACP FASN Professor and Chief, Nephrology Division Texas Tech University Health Sciences Center. A True Story From Bedside to the Bench. Insulin Resistance. Type II diabetes

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“ Angiotensin -Insulin Cross Talk” Implications For Insulin Resistance

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  1. “Angiotensin-Insulin Cross Talk”Implications For Insulin Resistance Sharma Prabhakar MD MBA FACP FASN Professor and Chief, Nephrology Division Texas Tech University Health Sciences Center

  2. A True Story From Bedside to the Bench

  3. Insulin Resistance Type II diabetes Metabolic syndrome (Obesity, hyperlipidemia, hypertension, proteinuria) Essential hypertension is also an insulin resistant state in most patients. RAAS and Angiotensin II is activated in all these states Evidence of cross talk at several steps between signaling pathways that mediate AII and Insulin actions.

  4. 1 (Ser/Thr) 2 tyrosine phosphorylation (pY) 4 5 3

  5. Angiotensin II Signaling Pathways

  6. O2 O2  NO The Role of Angiotensin II in Endothelial Dysfunction and Atherosclerosis Angiotensin II Activation of NADH Oxidase in EC O2 Generation Oxidized LDL  LOX-1 Receptors  LDL Oxidation and Uptake by Macrophages  Uptake of Oxidized LDL Accumulation of Lipids in Plaques Interference With Endothelium-Dependent Vasodilation Formation of Foam Cells EC Injury NADH = nicotinamide adenine dinucleotide; EC = endothelial cell.

  7. Angiotensin II Plays a Central Role in Organ Damage Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction Stroke Hypertension A II LV hypertrophy Fibrosis Remodeling Apoptosis Heart Failure MI Death GFR Proteinuria Aldosterone release Glomerular sclerosis Renal Failure *Preclinical data. LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate. Adapted from Willenheimer R et al. Eur Heart J . 1999;20:997–1008; Dahlöf B. J Hum Hypertens. 1995;9(suppl 5):S37–S44; Daugherty A et al. J Clin Invest. 2000;105:1605–1612; Fyhrquist F et al. J Hum Hypertens. 1995;9(suppl 5):S19–S24;Booz GW, Baker KM. Heart Fail Rev. 1998;3:125–130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy.17th ed. Whitehouse Station, NJ: Merck Research Laboratories. 1999:1682–1704; Anderson S. Exp Nephrol . 1996;4(suppl 1):34–40;Fogo AB. Am J Kidney Dis. 2000;35:179–188.

  8. ACE Inhibition Versus AT1 Blockade in the Renin-Angiotensin System Kininogen Angiotensinogen Kallikrein Renin ACE Inhibitors Nitric Oxide Bradykinin Angiotensin I   ACE Inactive Peptides Angiotensin II  ARBs ↓ Blood Pressure ↓ Vascular Proliferation ↓ Oxidative Stress ↓ Vascular Inflammation ↓ Thrombogenesis ARB AT1 ACE-I ARB Adapted with permission from Brown NJ, et al. Circulation. 1998;97:1411-1420.

  9. Inhibitors of RAS and antidiabetic effects

  10. RAAS inhibition and antidiabetic effects Meta-analysis of 10 RCT in 75, 950 pts with HT or CHF showed a 22% risk reduction of NODM with ACEi/ARB therapy after a mean follow up of 4.5 yrs (Sheen AJ DiabMetab 2004) Glycemic indices in diabetic pts were much better in pts treated with ACEi/ARB vs other anti HTN therapies -Pollare et al NEJM 1989, -UKPDS study, BMJ 1998 -Velasquez MT et al Metabolism 1998

  11. Karin et al J Hypertension 2006

  12. NAVIGATOR STUDY N Engl J Med 2010;362:1477-90. Examine if drugs inhibiting RAS would reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance (IGT). Double blind randomized 2x2 factorial design 9306 subjects with IGT with CV disease or risk factors randomized to receive valsartan or placebo Median follow up 5 years

  13. NAVIGATOR STUDY N Engl J Med 2010;362:1477-90. Results Cumulative incidence of development of diabetes 33.1 % ( valsartan group) vs 36.8% (placebo) HR 0.86, p<0.001 Cardiovascular outcomes 14.4% vs. 14.8% HR = 0.96 p=0.43

  14. NAVIGATOR STUDY N Engl J Med 2010;362:1477-90. Conclusions Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events.

  15. ZSF rat Obese ZDFxSHHF-fa/facp model was developed by crossing lean female Zucker Diabetic Fatty (ZDF ./fa) and lean male Spontaneously Hypertensive Heart Failure (SHHF/Mcc-facp, ./fa) rats. Phenotypically normal until 8 weeks Develops progressive obesity, hyperglycemia and hypertension after 8 weeks. Other features are nephropathy, heart failure and hyperlipidemia.

  16. Table 1. Characteristics of ZSF1 rats at 8 weeks and 20 weeks. N=12 in each group, * P<0.01 vs. 8 wks ZSF1-8 wk rats, ‡ P<0.001 vs. ZSF1 -8 wk rats

  17. RAAS inhibition and glycemic control in ZSF rats * P<0.01 vs. control ‡ P<0.05 vs. ZSF 20 wks,

  18. Effects of losartan therapy on (3H)-2-Deoxy-D-glucose uptake by of ZSF1 ratmyoocytes * P<0.05 vs. C. n=6 in both groups 1. C – 30 min 2. L- 30 min 3. C-60 min 4. L-60 min 5. C-90 min 6. L-90 min 7. C.120 min 8. L-120 min Prabhakar et al JASN 2003 ( abstract)

  19. Prabhakar et al JASN 2003 ( abstract)

  20. Proposed molecular mechanisms of Ang II–induced insulin resistance. phosphorylation of Ser612 and Ser302 are involved in dissociation of IRS-1 from the p85 subunit of PI3-K Ser307 phosphorylation inhibits the binding of IRS-1 to the insulin receptor and triggers IRS-1 degradation. 26S proteasome degradative pathway Prolonged loss of IRS 1 protein

  21. IRS-1 Phospho-tyrosine expression in ZSF rat muscle 1 2 3 4 Phospho-tyrosine - Actin 1. Obese ZSF 2. Lean ZSF 3. Obese +losartan 4. Positive control Prabhakar et al JASN 2007 ( abstract)

  22. IRS-1 Phospho-serine expression in ZSF rat muscle 1 2 3 4 Phospho-serine - Actin 1. Lean ZSF 2. Obese ZSF 3. Obese +losartan 4. Positive control Prabhakar et al JASN 2007 ( abstract)

  23. Prabhakar et al JASN 2007 ( abstract)

  24. Prabhakar et al JASN 2008 ( abstract)

  25. Expression of AdipoR2 expression in ZSF rat liver † Intensity (relative to lean at same age) * *P,0.01 vs. lean † P<0.05 vs. lean 1.Obese 2. lean 3. Obese 4. + control + losartan AdipoR2 Prabhakar et al JASN 2008 ( abstract)

  26. 8 weeks 12 weeks Obese + losartan Lean Obese Lean Obese P-AMPK Obese + losartan Lean Obese Lean Obese IP – AMPK Sood et al JASN 20038( abstract)

  27. SUMMARY • Angiotensin inhibition improves insulin resistance by multiple mechanisms which include • Increased insulin secretion from pancreatic islets • Increased IRS tyrphosphorylation • Increased adiponectin receptor signaling • Increased AMPK activity

  28. ANGIOTENSIN INHIBITION Increased secretion Tyr phosphorylation Ser phosphorylation X

  29. Questions to ponder on Is the therapeutic benefit of RAAS inhibition (HTN control, target organ damage, cardiorenal protection etc) partly due to antidiabetic effects? Is RAAS activation the basis of systemic hypertension in most patients - even salt retention? Does HTN and DM represent two clinical expressions of RAAS activation ?

  30. Story to be continued…..

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