Mutation in Insulin Receptor Attenuates Oxidative Stress and Apoptosis in Pancreatic Beta-Cells Induced by Nutrition Excess: Reduced Insulin Signaling and ROS

Abstract

Type 2 diabetes results from the failure of beta-cells to adequately compensate for insulin resistance. Although the reduction of beta-cell mass is because of increased cell death and/or inadequate replication or neogenesis, the mechanism underlying beta-cell mass reduction is not fully understood. Here, we clarify the role of insulin signaling pathway in the beta-cell apoptosis using insulin resistant model mice. Wild-type mice and those carrying a mutation in the insulin receptor (mIR) were fed either regular chow or a high-fat diet for 6 weeks and subsequently investigated for beta-cell apoptosis, endoplasmic reticulum stress, and oxidative stress. Insulin tolerance tests revealed that mIR mice fed a high-fat diet (mIRHF) had higher insulin resistance. Beta-cell apoptosis was increased 2-fold in the wild-type mice fed a high-fat diet (wHF) compared with control mice, whereas beta-cell apoptosis in mIRHF mice did not increase compared with that in mIR mice. The expression of endoplasmic reticulum stress markers in isolated islets did not differ between the groups. Staining of 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal in islets of wHF mice significantly increased, but the staining in mIRHF mice was not different from that in control group. Gene expression of the antioxidant enzyme MnSOD was significantly higher in mIRHF mice than those in the other 3 groups. A mutation in the insulin receptor attenuated the oxidative stress and apoptosis in beta-cells even though high caloric nutrient was loaded. Our results suggest that reduced insulin signaling protects beta-cells thorough decline of oxidative stress.

Key words

insulin resistance - manganese superoxide dismutase - endoplasmic reticulum stress

• References

• 1 Lingohr MK, Buettner R, Rhodes CJ. Pancreatic beta-cell growth and survival – a role in obesity-linked type 2 diabetes?. Trends Mol Med 2002; 8: 375-384
• 2 Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102-110
• 3 Kusminski CM, Shetty S, Orci L, Unger RH, Scherer PE. Diabetes and apoptosis: lipotoxicity. Apoptosis 2009; 14: 1484-1495
• 4 Styskal J, Van Remmen H, Richardson A, Salmon AB. Oxidative stress and diabetes: what can we learn about insulin resistance from antioxidant mutant mouse models?. Free Radic Biol Med 2012; 52: 46-58
• 5 Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia 2002; 45: 85-96
• 6 Tang C, Han P, Oprescu AI, Lee SC, Gyulkhandanyan AV, Chan GN, Wheeler MB, Giacca A. Evidence for a role of superoxide generation in glucose-induced beta-cell dysfunction in vivo. Diabetes 2007; 56: 2722-2731
• 7 Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 1996; 20: 463-466
• 8 Kaneto H, Kajimoto Y, Miyagawa J, Matsuoka T, Fujitani Y, Umayahara Y, Hanafusa T, Matsuzawa Y, Yamasaki Y, Hori M. Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Diabetes 1999; 48: 2398-2406
• 9 Numazawa S, Sakaguchi H, Aoki R, Taira T, Yoshida T. Regulation of the susceptibility to oxidative stress by cysteine availability in pancreatic beta-cells. Am J Physiol Cell Physiol 2008; 295: C468-C474
• 10 Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457-461
• 11 Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 2008; 29: 42-61
• 12 Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y. Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. J Mol Med (Berl) 2005; 83: 429-439
• 13 Ogino J, Sakurai K, Yoshiwara K, Suzuki Y, Ishizuka N, Seki N, Koseki H, Shirasawa T, Hashimoto N, Yagui K, Saito Y. Insulin resistance and increased pancreatic beta-cell proliferation in mice expressing a mutant insulin receptor (P1195L). J Endocrinol 2006; 190: 739-747
• 14 Baba T, Shimizu T, Suzuki Y, Ogawara M, Isono K, Koseki H, Kurosawa H, Shirasawa T. Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice. J Biol Chem 2005; 280: 16417-16426
• 15 Ihara Y, Toyokuni S, Uchida K, Odaka H, Tanaka T, Ikeda H, Hiai H, Seino Y, Yamada Y. Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. Diabetes 1999; 48: 927-932
• 16 Szot GL, Koudria P, Bluestone JA. Murine pancreatic islet isolation. J Vis Exp 2007; 255
• 17 Cerf ME. High fat diet modulation of glucose sensing in the beta-cell. Med Sci Monit 2007; 13: RA12-RA17
• 18 Akiyama M, Hatanaka M, Ohta Y, Ueda K, Yanai A, Uehara Y, Tanabe K, Tsuru M, Miyazaki M, Saeki S, Saito T, Shinoda K, Oka Y, Tanizawa Y. Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice. Diabetologia 2009; 52: 653-663
• 19 Hofer T, Karlsson HL, Moller L. DNA oxidative damage and strand breaks in young healthy individuals: a gender difference and the role of life style factors. Free Radic Res 2006; 40: 707-714
• 20 Li X, Chen H, Epstein PN. Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species. J Biol Chem 2004; 279: 765-771
• 21 Marchetti P, Del Prato S, Lupi R, Del Guerra S. The pancreatic beta-cell in human Type 2 diabetes. Nutr Metab Cardiovasc Dis 2006; 16 (Suppl. 01) S3-S6
• 22 Honda Y, Honda S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J 1999; 13: 1385-1393
• 23 Taguchi A, White MF. Insulin-like signaling, nutrient homeostasis, and life span. Annu Rev Physiol 2008; 70: 191-212
• 24 Pedulla M, d’Aquino R, Desiderio V, de Francesco F, Puca A, Papaccio G. MnSOD mimic compounds can counteract mechanical stress and islet beta cell apoptosis, although at appropriate concentration ranges. J Cell Physiol 2007; 212: 432-438
• 25 Bertera S, Crawford ML, Alexander AM, Papworth GD, Watkins SC, Robbins PD, Trucco M. Gene transfer of manganese superoxide dismutase extends islet graft function in a mouse model of autoimmune diabetes. Diabetes 2003; 52: 387-393
• 26 Krautbauer S, Eisinger K, Neumeier M, Hader Y, Buettner R, Schmid PM, Aslanidis C, Buechler C. Free fatty acids, lipopolysaccharide and IL-1alpha induce adipocyte manganese superoxide dismutase which is increased in visceral adipose tissues of obese rodents. PLoS One 2014; 9: e86866
• 27 Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 2002; 419: 316-321
• 28 Brand MD, Esteves TC. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2005; 2: 85-93
• 29 Kikuchi O, Kobayashi M, Amano K, Sasaki T, Kitazumi T, Kim HJ, Lee YS, Yokota-Hashimoto H, Kitamura YI, Kitamura T. FoxO1 gain of function in the pancreas causes glucose intolerance, polycystic pancreas, and islet hypervascularization. PLoS One 2012; 7: e32249
• 30 Kitamura YI, Kitamura T, Kruse JP, Raum JC, Stein R, Gu W, Accili D. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab 2005; 2: 153-163
• 31 Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir GC, Eizirik DL, Cnop M. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 2007; 50: 2486-2494
• 32 Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, Tsubamoto Y, Komeda K, Nakano R, Miki H, Satoh S, Sekihara H, Sciacchitano S, Lesniak M, Aizawa S, Nagai R, Kimura S, Akanuma Y, Taylor SI, Kadowaki T. Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 2000; 49: 1880-1889
• 33 Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999; 96: 329-339
• 34 Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391: 900-904
• 35 Kulkarni RN, Mizrachi EB, Ocana AG, Stewart AF. Human beta-cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes 2012; 61: 2205-2213
• 36 Taylor SI. Lilly Lecture: molecular mechanisms of insulin resistance. Diabetes 1992; 41: 1473-1490
• 37 Bruning JC, Winnay J, Cheatham B, Kahn CR. Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. Mol Cell Biol 1997; 17: 1513-1521
• 38 Shigeyama Y, Kobayashi T, Kido Y, Hashimoto N, Asahara S, Matsuda T, Takeda A, Inoue T, Shibutani Y, Koyanagi M, Uchida T, Inoue M, Hino O, Kasuga M, Noda T. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol Cell Biol 2008; 28: 2971-2979