Acta Diabetologica

, Volume 50, Issue 4, pp 479–488 | Cite as

Effects of renin–angiotensin system blockade on the islet morphology and function in rats with long-term high-fat diet

  • Li Yuan
  • Xin Li
  • Jin Li
  • Hai-ling Li
  • Suo-suo Cheng
Original Article


The renin–angiotensin system (RAS) has an important role in the endocrine pancreas. Multiple researches have shown that even in the insulin resistance phase, there are many abnormalities in islets morphology and function. This study aimed at investigating the effects of RAS blockade on the islets function in rats with long-term high-fat diet and its mechanisms. Wistar rats with 16-week high-fat diet were randomly divided into perindopril intervention group (FP, n = 15) and telmisartan intervention group (FT, n = 15). After 8-week intervention, insulin sensitivity and islets function were detected by hyperinsulinemic euglycemic clamp and intravenous glucose tolerance test (IVGTT), respectively. The pancreases were stained by immunohistochemistry technique to qualitatively and/or quantitatively analyze the relative content of insulin (IRC), NF-KB, uncoupling protein 2 (UCP2) and caspase-3 in islets. The apoptosis of islet cells was detected by TUNEL. The expression of angiotensin II receptor 1 (AT1R), interleukin-1β (IL-1β), hypoxia-inducing factor (HIF)-1α and CHOP mRNA in the islets was detected by reverse transcription polymerase chain reaction (RT-PCR). Compared with normal control group (NC, n = 15), the glucose infusion rate (GIR), area under the insulin curve (AUCI) of 0–10 min and IRC were decreased in high-fat control group (FC, n = 15). The relative content of NF-KB, UCP-2 and caspase-3 was increased significantly with the increased number of apoptotic cells in unit islets area. The relative expression of AT1R, IL-1β, HIF-1α and CHOP was also increased evidently (all P < 0.01). After intervention, the GIR, AUCI of 0–10 min and IRC were all increased obviously with the decreased relative concentration of NF-KB, UCP-2, caspase-3 and the number of apoptotic cell in unit islets area. The relative expression of AT1R, IL-1β, HIF-1α and CHOP mRNA was reduced significantly (all P < 0.01 or P < 0.05). There were no significant differences between groups FP and FT. So we concluded that blockade of RAS may protect islet function of rats with long-term high-fat diet via downregulation of islets inflammation, oxidative stress, endoplasmic reticulum stress and apoptosis, which have tight relationship with each other.


Renin–angiotensin system Insulin resistance Islets function Inflammation Oxidative stress Endoplasmic reticulum stress Apoptosis 


  1. 1.
    Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR (1992) Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 340(8825):925–929PubMedCrossRefGoogle Scholar
  2. 2.
    Porte D Jr (2001) Clinical importance of insulin secretion and its interaction with insulin resistance in the treatment of type 2 diabetes mellitus and its complications. Diabetes Metab Res Rev 17(3):181–188PubMedCrossRefGoogle Scholar
  3. 3.
    Prentki M, Joly E, El-Assaad W, Roduit R (2002) Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 51(Suppl 3):S405–S413PubMedCrossRefGoogle Scholar
  4. 4.
    Leahy JL (2005) Pathogenesis of type 2 diabetes mellitus. Arch Med Res 36(3):197–209PubMedCrossRefGoogle Scholar
  5. 5.
    Poitout V, Robertson RP (2002) Minireview: Secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology 143(2):339–342PubMedCrossRefGoogle Scholar
  6. 6.
    Weyer C, Bogardus C, Mott DM, Pratley RE (1999) The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104(6):787–794PubMedCrossRefGoogle Scholar
  7. 7.
    Steil GM, Trivedi N, Jonas JC, Hasenkamp WM, Sharma A, Bonner-Weir S, Weir GC (2001) Adaptation of beta-cell mass to substrate oversupply: enhanced function with normal gene expression. Am J Physiol Endocrinol Metab 280(5):E788–E796PubMedGoogle Scholar
  8. 8.
    Jetton TL, Lausier J, LaRock K, Trotman WE, Larmie B, Habibovic A, Peshavaria M, Leahy JL (2005) Mechanisms of compensatory beta-cell growth in insulin-resistant rats: roles of Akt kinase. Diabetes 54(8):2294–2304PubMedCrossRefGoogle Scholar
  9. 9.
    Liu YQ, Jetton TL, Leahy JL (2002) Beta-Cell adaptation to insulin resistance. Increased pyruvate carboxylase and malate-pyruvate shuttle activity in islets of nondiabetic Zucker fatty rats. J Biol Chem 277(42):39163–39168PubMedCrossRefGoogle Scholar
  10. 10.
    Chen C, Hosokawa H, Bumbalo LM, Leahy JL (1994) Mechanism of compensatory hyperinsulinemia in normoglycemic insulin-resistant spontaneously hypertensive rats. Augmented enzymatic activity of glucokinase in beta-cells. J Clin Invest 94(1):399–404PubMedCrossRefGoogle Scholar
  11. 11.
    Kanauchi M, Kimura K, Kanauchi K, Saito Y (2005) Beta-cell function and insulin sensitivity contribute to the shape of plasma glucose curve during an oral glucose tolerance test in non-diabetic individuals. Int J Clin Pract 59(4):427–432PubMedCrossRefGoogle Scholar
  12. 12.
    Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307(5708):384PubMedCrossRefGoogle Scholar
  13. 13.
    Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, Brownlee M (2003) Inhibition of GAPDH activity by poly (ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 112(7):1049–1057PubMedGoogle Scholar
  14. 14.
    Brownlee M (2003) A radical explanation for glucose-induced beta cell dysfunction. J Clin Invest 112(12):1788PubMedGoogle Scholar
  15. 15.
    Krauss S, Zhang CY, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST, Lowell BB (2003) Superoxide- mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 112(12):1831–1842PubMedGoogle Scholar
  16. 16.
    Despres JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444:881–887PubMedCrossRefGoogle Scholar
  17. 17.
    Casas S, Gomis R, Gribble FM, Altirriba J, Knuutila S, Novials A (2007) Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis. Diabetes 56(9):2284–2294PubMedCrossRefGoogle Scholar
  18. 18.
    Leung PS (2003) Pancreatic renin-angiotensin system: a novel target for the potential treatment of pancreatic diseases? JOP 4:89–91PubMedGoogle Scholar
  19. 19.
    Carlsson PO (2001) The renin-angiotensin system in the endocrine pancreas. JOP 2:26–32PubMedGoogle Scholar
  20. 20.
    Gillespie EL, White CM, Kardas M, Lindberg M, Coleman CI (2005) The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes. Diabetes Care 28(9):2261–2266PubMedCrossRefGoogle Scholar
  21. 21.
    McFarlane SI, Provilus A, Shin JJ (2007) Diabetes prevention between RAAS inhibition and PPAR-gamma stimulation: the diabetes reduction assessment with ramipril and rosiglitazone medication (DREAM) trial. J Cardiometab Syndr 2(2):149–150PubMedCrossRefGoogle Scholar
  22. 22.
    NAVIGATOR Study Group, McMurray JJ, Holman RR et al (2010) Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 362(16):1477–1490PubMedCrossRefGoogle Scholar
  23. 23.
    Rouyer O, Zoll J, Daussin F et al (2007) Effect of angiotensin-converting enzyme inhibition on skeletal muscle oxidative function and exercise capacity in streptozotocin-induced diabetic rats. Exp Physiol 92:1047–1056PubMedCrossRefGoogle Scholar
  24. 24.
    Schäfer A, Flierl U, Vogt C et al (2007) Telmisartan improves vascular function and reduces platelet activation in rats with streptozotocin-induced diabetes mellitus. Pharmacol Res 56:217–223PubMedCrossRefGoogle Scholar
  25. 25.
    Kraegen EW, James DE, Bennet SP, Chisholm DJ (1983) In vivo insulin sensitivity in the rat determined by euglycemic clamp. Am J Physiol 245:E1–E7PubMedGoogle Scholar
  26. 26.
    Ferrario CM, Strawn WB (2006) Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 98(1):121–128PubMedCrossRefGoogle Scholar
  27. 27.
    Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 17(1):4–12PubMedGoogle Scholar
  28. 28.
    Takai S, Jin D, Kimura M, Kirimura K, Sakonjo H, Tanaka K, Miyazaki M (2007) Inhibition of vascular angiotensin-converting enzyme by telmisartan via the peroxisome proliferator-activated receptor gamma agonistic property in rats. Hypertens Res 30(12):1231–1237PubMedCrossRefGoogle Scholar
  29. 29.
    Ceolotto G, Gallo A, Papparella I, Franco L, Murphy E, Iori E, Pagnin E, Fadini GP, Albiero M, Semplicini A, Avogaro A (2007) Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. Arterioscler Thromb Vasc Biol 27(12):2627–2633PubMedCrossRefGoogle Scholar
  30. 30.
    De Souza CT, Araújo EP, Stoppiglia LF, Pauli JR, Ropelle E, Rocco SA, Marin RM, Franchini KG, Carvalheira JB, Saad MJ, Boschero AC, Carneiro EM, Velloso LA (2007) Inhibition of UCP2 expression reverses diet-induced diabetes mellitus by effects on both insulin secretion and action. FASEB J 21(4):1153–1163PubMedCrossRefGoogle Scholar
  31. 31.
    Srinivasan S, Ohsugi M, Liu Z, Fatrai S, Bernal-Mizrachi E, Permutt MA (2005) Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3 beta in mouse insulinoma cells. Diabetes 54(4):968–975PubMedCrossRefGoogle Scholar
  32. 32.
    Kharroubi I, Ladrière L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL (2004) Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145(11):5087–5096PubMedCrossRefGoogle Scholar
  33. 33.
    Iwase M, Uchizono Y, Tashiro K, Goto D, Iida M (2002) Islet hyperperfusion during prediabetic phase in OLETF rats, a model of type 2 diabetes. Diabetes 51(8):2530–2535PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Li Yuan
    • 1
  • Xin Li
    • 2
  • Jin Li
    • 1
  • Hai-ling Li
    • 1
  • Suo-suo Cheng
    • 1
  1. 1.Department of Endocrinology, Union HospitalTongji Medical College of HuaZhong Science & Technology UniversityWuhanChina
  2. 2.Department of Endocrinology, Zhongnan HospitalWuhan UniversityWuhanChina

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