Treatment with CNX-011-67, a novel GPR40 agonist, delays onset and progression of diabetes and improves beta cell preservation and function in male ZDF rats

BMC Clinical Pharmacology

Madanahalli R Jagannath¹  Baggavalli P Somesh¹  Marikunte V Venkataranganna¹  Mammen O Anup¹  Yoganand Moolemath¹  Mahesh Kumar Verma¹  Kumaraswamy Aparna¹  Manojkumar Sadasivuni¹  Ashokkumar Reddy¹  Venkategowda Sunil¹  Pavagada C Shilpa¹  Mudigere N Lakshmi¹  Vijaya Raghav¹  Sanghamitra Biswas¹  Jaideep Singh¹  Anilkumar Dandu¹  Nagesh Gowda¹ 

[1] Connexios Life Sciences Pvt Ltd, #49, “SHILPA VIDYA” 1st Main, 3rd Phase, JP Nagar, Bangalore 560078, India

关键词: Insulin content;    Glucolipotoxicity;    Rat islets;    Type 2 diabetes;    GSIS;    PDX1;    Zucker diabetic fatty rats;    GPR40;   

Others  :  860592
DOI  :  10.1186/2050-6511-14-28

 received in 2013-01-04, accepted in 2013-05-15,  发布年份 2013

【 摘 要 】

Background

The role of G protein-coupled receptor (GPR40), which is highly expressed in pancreatic beta cells, has been studied extensively in the amelioration of beta cell dysfunction in T2D using rat and mouse islets, beta cell lines and in animal models of diabetes. But its potential as a therapeutic target has not been fully explored. This aim of the study is to evaluate the therapeutic potential of CNX-011-67, a highly selective, potent and orally bioavailable GPR40 agonist, in controlling diabetes and other metabolic parameters.

Methods

Seven week old male ZDF rats were treated with either vehicle or CNX-011-67, 5 mg/kg twice daily, for seven weeks. The animals were subjected to oral glucose tolerance and insulin tolerance tests. Plasma glucose, insulin, triglyceride, HbA1c, fructosamine and free fatty acids were measured at selected time points. Pancreas from control and treated animals were subjected to insulin and pancreatic and duodenal homeobox 1 (PDX1) immunohistochemistry and were also evaluated by electron microscopy. Also the potential impact of CNX-011-67 on islet insulin secretion, content, ATP levels and markers of both glucose oxidation, beta cell health in rat islets under chronic glucolipotoxic conditions was evaluated.

Results

Treatment of male ZDF rats with CNX-011-67 for 7 weeks significantly enhanced insulin secretion in response to oral glucose load, delayed the onset of fasting hyperglycemia by 3 weeks, reduced nonfasting glucose excursions, fasting free fatty acids and triglyceride levels. A significant increase in PDX1 expression and insulin content and reduction in plasma fructosamine, HOMA-IR, and beta cell apoptosis were observed. CNX-011-67 improves glucose mediated insulin secretion, insulin gene transcription and islet insulin content in cultured rat islets under chronic glucolipotoxic condition. Also enhanced glucose oxidation in the form of increased islet ATP content and overall improvement in beta cell health in the form of reduced expression of stress markers (TXNIP and CHOP mRNA) were observed.

Conclusions

These findings, suggest that long-term oral therapy with CNX-011-67 could be of clinical value to provide good glycemic control and improve islet beta cell function.

【 授权许可】

   
2013 Gowda et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Fineman MS, Cirincione BB, Maggs D, Diamant M: GLP-1 based therapies: differential effects on fasting and postprandial glucose. Diabetes Obes Metab 2012, 14:675-688.
• [2]Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH: Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006., 18CD006060
• [3]Sreenan S, Sturis J, Pugh W, Burant CF, Polonsky KS: Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. Am J Physiol 1996, 271:742-747.
• [4]Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, Ammala C, Fornwald JA, Ignar DM, Jenkinson S: Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol 2009, 148:619-628.
• [5]Shapiro H, Shachar S, Sekler I, Hershfinkel M, Walker MD: Role of GPR40 in fatty acid action on the beta cell line INS-1E. Biochem Biophys Res Commun 2005, 335:97-104.
• [6]Fujiwara K, Maekawa F, Yada T: Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am J Physiol Endocrinol Metab 2005, 289:670-677.
• [7]Tan CP, Feng Y, Zhou YP, Eiermann GJ, Petrov A, Zhou C, Lin S, Salituro G, Meinke P, Mosley R, Akiyama TE, Einstein M, Kumar S, Berger JP, Mills SG, Thornberry NA, Yang L, Howard AD: Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes 2008, 57:2211-2219.
• [8]Tsujihata Y, Ito R, Suzuki M, Harada A, Negoro N, Yasuma T, Momose Y, Takeuchi K: TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J Pharmacol Exp Ther 2011, 339:228-327.
• [9]Lin DC, Zhang J, Zhuang R, Li F, Nguyen K, Chen M, Tran T, Lopez E, Lu JY, Li XN, Tang L, Tonn GR, Swaminath G, Reagan JD, Chen JL, Tian H, Lin YJ, Houze JB, Luo J: AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents. PLoS One 2011, 6:e27270.
• [10]Luo J, Swaminath G, Brown SP, Zhang J, Guo Q, Chen M, Nguyen K, Tran T, Miao L, Dransfield PJ, Vimolratana M, Houze JB, Wong S, Toteva M, Shan B, Li F, Zhuang R, Lin DC: A Potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. PLoS One 2012, 7:e46300.
• [11]Burant CF, Viswanathan P, Marcinak J, Cao C, Vakilynejad M, Xie B, Leifke E: TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2012, 379:1403-1411.
• [12]Kaku K, Araki T, Yoshinaka R: Randomized, Double-Blind, Dose-Ranging Study of TAK-875, a Novel GPR40 Agonist, in Japanese Patients With Inadequately Controlled Type 2 Diabetes. Diabetes Care 2013, 36:245-250.
• [13]Tokuyama Y, Sturis J, DePaoli AM, Takeda J, Stoffel M, Tang J, Sun X, Polonsky KS, Bell GI: Evolution of beta cell dysfunction in the male Zucker diabetic fatty rat. Diabetes 1995, 44:1447-1457.
• [14]Yuen VG, Vera E, Battell ML, Li WM, McNeill JH: Acute and chronic oral administration of bis(maltolato) oxovanadium (IV) in Zucker diabetic fatty (ZDF) rats. Diabetes Res Clin Pract 1999, 43:9-19.
• [15]Carter JD, Dula SB, Corbin KL, Wu R, Nunemaker CS: A practical guide to rodent islet isolation and assessment. Biol Proced Online 2009, 11:3-31.
• [16]Luna L: AFIP Manual of Histological Staining Methods. New York: McGraw Hill; 1968.
• [17]Culling CFA, Allison RT, Bair WT: Cellular pathology technique. London: Butterworths; 1985.
• [18]Kerr JFR, Wyllie AH, Currie AR: Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. Br J Cancer 1972, 26:239-257.
• [19]Wyllie AH, Kerr JFR, Currie AR: Cell death: the significance of apoptosis. Int Rev Cytol 1980, 68:251-306.
• [20]Garrity MM, Burgart LJ, Riehle DL, Hill EM, Sebo TJ, Witzig T: Identifying and Quantifying Apoptosis: Navigating Technical Pitfalls. Mod Pathol 2003, 16:389-394.
• [21]Bruin JE, Gerstein HC, Morrison KM, Holloway AC: Increased pancreatic beta cell apoptosis following fetal and neonatal exposure to nicotine is mediated via the mitochondria. Toxicol Sci 2008, 103:362-370.
• [22]Watari N, Tsukagoshi N, Honma Y: The correlative light and electron microscopy of the islets of Langerhans in some lower vertebrates. Arch Histol 1970, 31:371-392.
• [23]Mihail N, Craciun C: An ultrastructural description of the cell types in the endocrine pancreas of the pigeon. Anat Anz Jena 1982, 152:229-237.
• [24]Misawa E, Tanaka M, Nomaguchi K, Nomaguchia K, Yamada M, Toida T, Takase M, Iwatsuki K, Kawada T: Administration of phytosterols isolated from aloe vera gel reduce visceral fat mass and improve hyperglycemia in Zucker diabetic fatty (zdf) rats. Obes Res Clin Pract 2008, 2:239-245.
• [25]Del Prato S: Loss of early insulin secretion leads to postprandial hyperglycaemia. Diabetologia 2003, 46:2-8.
• [26]Rebrin K, Steil GM, Getty L, Bergman RN: Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 1995, 44:1038-1045.
• [27]Koopmans SJ, Sips HC, Bosman J, Radder JK, Krans HM: Antilipolytic action of insulin in adipocytes from starved and diabetic rats during adenosine-controlled incubations. Endocrinology 1989, 125:3044-3050.
• [28]Bajaj M, Suraamornkul S, Romanelli A, Cline GW, Mandarino LJ, Shulman GI, DeFronzo RA: Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty Acyl-CoAs and insulin action in type 2 diabetic patients. Diabetes 2005, 54:3148-3153.
• [29]Sugden MC, Holness MJ: Potential role of peroxisome proliferator-activated receptor-alpha in the modulation of glucose-stimulated insulin secretion. Diabetes 2004, 53(Suppl 1):S71-S81.
• [30]Frigerio F, Brun T, Bartley C, Usardi A, Bosco D, Ravnskjaer K, Mandrup S, Maechler P: Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism. Diabetologia 2010, 53:331-340.
• [31]Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A: Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis. Diabetes 2008, 57:938-944.
• [32]Oslowski CM, Hara T, O’Sullivan-Murphy B, Kanekura K, Lu S, Hara M, Ishigaki S, Zhu LJ, Hayashi E, Hui ST, Greiner D, Kaufman RJ, Bortell R, Urano F: Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab 2012, 16:265-273.
• [33]Reich E, Tamary A, Sionov RV, Melloul D: Involvement of thioredoxin-interacting protein (TXNIP) in glucocorticoid-mediated beta cell death. Diabetologia 2012, 55:1048-1057.
• [34]Chen J, Fontes G, Saxena G, Poitout V, Shalev A: Lack of TXNIP protects against mitochondria-mediated apoptosis but not against fatty acid-induced ER stress-mediated beta-cell death. Diabetes 2010, 59:440-447.
• [35]Rendell M, Stephen PM, Paulsen R, Valentine JL, Rasbold K, Hestorff T, Eastberg S, Shint DC: An interspecies comparison of normal levels of glycosylated hemoglobin and glycosylated albumin. Comp Biochem Physiol B 1985, 81:819-822.
• [36]Wallace TM, Levy JC, Matthews DR: Use and abuse of HOMA modeling. Diabetes Care 2004, 27:1487-1495.
• [37]Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD: Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci USA 1994, 91:10878-10882.
• [38]Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W: Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 1998, 47:358-364.
• [39]Smith SA, Lister CA, Toseland CD, Buckingham RE: Rosiglitazone prevents the onset of hyperglycaemia and proteinuria in the Zucker diabetic fatty rat. Diabetes Obes Metab 2000, 2:363-372.
• [40]Sudre B, Broqua P, White RB, Ashworth D, Evans DM, Haigh R, Junien JL, Aubert ML: Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats. Diabetes 2002, 51:1461-1469.