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Chronic inhibition of dipeptidyl peptidase-IV with ASP8497 improved the HbA1c level, glucose intolerance, and lipid parameter level in streptozotocin–nicotinamide-induced diabetic mice

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Abstract

Dipeptidyl peptidase-IV (DPP-IV) is the primary inactivator of glucoregulatory incretin hormones, and DPP-IV inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the chronic in vivo profile of the DPP-IV inhibitor ASP8497. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 was administered orally for 3 weeks at 1, 3, or 10 mg/kg once daily, which improved the hemoglobin A1c, non-fasting plasma insulin, fasting blood glucose levels, glucose intolerance, and lipid profiles (plasma triglyceride, non-esterified fatty acid and total cholesterol) with neutral effect on body weight. The pancreatic insulin content and hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity recovered dose-dependently in ASP8497-treated groups. These results revealed that ASP8497 was successful in improving glycemic control and metabolic parameters in streptozotocin-nicotinamide-induced diabetic mice. It is therefore suggested that ASP8497 may be a potential agent for the treatment of type 2 diabetes.

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References

  • American Diabetes Association (2001) Postprandial blood glucose. Diabetes Care 24:775–778

    Article  Google Scholar 

  • American Diabetes Association (2004) Standards of medical care in diabetes. Diabetes Care 27(Suppl.1):S15–35

    Google Scholar 

  • Asplund K, Wiholm BE, Lithner F (1983) Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia 24:412–417

    Article  PubMed  CAS  Google Scholar 

  • Basu R, Chandramouli V, Dicke B, Landau B, Rizza R (2005) Obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis. Diabetes 54:1942–1948

    Article  PubMed  CAS  Google Scholar 

  • Boden G, Chen X, Stein P (2001) Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 280:E23–E30

    PubMed  CAS  Google Scholar 

  • Deacon CF, Johnsen AH, Holst JJ (1995a) Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol 80:952–957

    Article  CAS  Google Scholar 

  • Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ (1995b) Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44:1126–1131

    Article  PubMed  CAS  Google Scholar 

  • Drucker DJ (2001) Development of glucagon-like peptide-1 based pharmaceuticals as therapeutic agents for the treatment of diabetes. Curr Pharm Des 7:1399–1412

    Article  PubMed  CAS  Google Scholar 

  • Drucker DJ (2007) The role of gut hormones in glucose homeostasis. J Clin Invest 117:24–32

    Article  PubMed  CAS  Google Scholar 

  • Ebert R, Nauck M, Creutzfeldt W (1991) Effect of exogenous or endogenous gastric inhibitory polypeptide (GIP) on plasma triglyceride responses in rats. Horm Metab Res 23:517–521

    Article  PubMed  CAS  Google Scholar 

  • Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, Perfetti R (2002) Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 143:4397–4408

    Article  PubMed  CAS  Google Scholar 

  • Hansen L, Deacon CF, Orskov C, Holst JJ (1999) Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140:5356–5363

    Article  PubMed  CAS  Google Scholar 

  • Harrower AD (1994) Comparison of efficacy, secondary failure rate, and complications of sulfonylureas. J Diabet Complications 8:201–203

    Article  CAS  Google Scholar 

  • Holst JJ, Deacon CF (1998) Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47:1663–1670

    Article  PubMed  CAS  Google Scholar 

  • Holst JJ, Deacon CF (2004) Glucagon-like-peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus. Curr Opin Pharmacol 4:589–596

    Article  PubMed  CAS  Google Scholar 

  • Kieffer TJ, McIntoch CH, Pederson RA (1995) Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide-1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136:3585–3596

    Article  PubMed  CAS  Google Scholar 

  • Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Grémeaux T, Drucker DJ, Kahn R, Girard J, Tanti JF, Delzenne NM, Postic C, Burcekin R (2005) Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest 115:3554–3563

    Article  PubMed  CAS  Google Scholar 

  • Kosaka K, Kuzuya T, Hagura R (1994) Insulin secretary response in Japanese type 2 (non-insulin-dependent) diabetic patients. Diabetes Res Clin Pract 24:S101–110

    Article  PubMed  Google Scholar 

  • Li L, Yang G, Li Q, Tan X, Liu H, Tang Y, Boden G (2008) Exenatide prevents fat-induced insulin resistance and raises adiponectin expression and plasma levels. Diabetes Obes Metab (in press)

  • Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that b-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51:1437–1442

    Article  PubMed  CAS  Google Scholar 

  • Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buys D et al (1998) Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes 47:224–229

    Article  PubMed  CAS  Google Scholar 

  • Matikainen N Mänttäri S, Schweizer A, Ulvestad A, Mills D, Dunning BE, Foley JE, Taskinen M-R (2006) Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia 49:2049–2057

    Article  CAS  Google Scholar 

  • Matsuyama-Yokono A, Tahara A, Nakano R, Someya Y, Nagase I, Hayakawa M, Shibasaki M (2008) ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity. Biochem Pharmcol 76:98–107

    Article  CAS  Google Scholar 

  • Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  PubMed  CAS  Google Scholar 

  • Meier JJ, Nauck MA (2006) Incretins and the development of type 2 diabetes. Curr Diab Rep 6:194–201

    Article  PubMed  CAS  Google Scholar 

  • Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regul Pept 85:9–24

    Article  PubMed  CAS  Google Scholar 

  • Morifuji M, Sakai K, Sugiura K (2005) Dietary whey protein modulates liver glycogen level and glycoregulatory enzyme activities in exercise-trained rats. Exp Biol Med 230:23–30

    CAS  Google Scholar 

  • Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, Feng Y, Zhu, Li C, Howard AD, Moller DE, Thornberry NA, Zhang BB (2006) Chronic inhibition of dipeptidyl peptidase-4 with sitagliptin analog preserves pancreatic {beta}-cell mass and function in a rodent model of type 2 diabetes. Diabetes 55:1695–1704

    Article  PubMed  CAS  Google Scholar 

  • Pederson RA, White HA, Schlenzig D, Pauly RP, McIntoch CH, Deemuth H-U (1998) Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes 47:1253–1258

    Article  PubMed  CAS  Google Scholar 

  • Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, Frank BH, Galloway JA, Van Cauter E (1988) Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med 318:1231–1239

    PubMed  CAS  Google Scholar 

  • Porte D (1991) b-cells in type II diabetes mellitus. Diabetes 40:166–180

    Article  PubMed  Google Scholar 

  • Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, Piteau S, Demuth HU, McIntoch CH, Pederson RA (2003) Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 52:741–750

    Article  PubMed  CAS  Google Scholar 

  • Qin X, Shen H, Liu M, Yang Q, Zheng S, Sabo M, D’Alessio DA, Tso P (2005) GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol 288:G943–949

    Article  PubMed  CAS  Google Scholar 

  • Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, Sitagliptin Study 023 Group (2006) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 49:2564–2571

    Article  PubMed  CAS  Google Scholar 

  • Reimer MK, Holst JJ, Ahren B (2002) Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur J Endocrinol 146:717–727

    Article  PubMed  CAS  Google Scholar 

  • Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A (2007) Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care 30:217–223

    Article  PubMed  CAS  Google Scholar 

  • Someya Y, Tahara A, Nakano R, Matsuyama-Yokono A, Nagase I, Fukunaga Y, Takasu T, Hayakawa M, Shibasaki M (2008) Pharmacological profile of ASP8497, a novel, selective, and competitive dipeptidyl peptidase-IV inhibitor, in vitro and in vivo. Naunyn Schmiedebergs Arch Pharmacol 377:209–217

    Article  PubMed  CAS  Google Scholar 

  • Stahl M, Berger W (1999) Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. Diabet Med 16:586–590

    Article  PubMed  CAS  Google Scholar 

  • Sudre B, Broqua P, White RB, Ashworth D, Evans DM, Haigh R, Junien JL Aubert ML (2002) Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male Zucker diabetic fatty rats. Diabetes 51:1461–1469

    Article  PubMed  CAS  Google Scholar 

  • Taylor SI, Accili D, Imai Y (1994) Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes 43:735–740

    PubMed  CAS  Google Scholar 

  • Trumper A, Trumper K, Trusheim H, Arnold R, Goke B, Horsch D (2001) Glucose-dependent insulinotropic polypeptide is a growth factor for b (INS-1) cells by pleiotropic signaling. Mol Endocrinol 15:1559–1570

    Article  PubMed  CAS  Google Scholar 

  • Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical implications. Diabetes 44:863–870

    Article  PubMed  CAS  Google Scholar 

  • Wasada T, McCorkle K, Virginia H, Kawai K, Howard B, Unger RH (1981) Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. J Clin Invest 68:1106–1107

    Article  PubMed  CAS  Google Scholar 

  • Weyer C, Bogardu 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 104:787–794

    Article  PubMed  CAS  Google Scholar 

  • Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M (1999) Glucose-Lowering and Insulin-Sensitizing Actions of Exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats and diabetic rhesus monkeys (Macaca mulatta). Diabetes 48:1026–1034

    Article  PubMed  CAS  Google Scholar 

  • Zhou YP, Grill VE (1994) Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 93:870–876

    Article  PubMed  CAS  Google Scholar 

  • Zimmerman BR (1997) Sulfonylureas. Endocrinol Metab Clin North Am 26:511–522

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Drs. Toichi Takenaka, Isao Yanagisawa, Yasuaki Shimizu, Tetsuo Matsui, and Yutaka Yanagita (Astellas Pharma Inc.) for their valuable comments and continuing encouragement. The authors would also like to thank Mr. Masanori Yokono (Astellas Pharma Inc.) for his suggestions regarding the preparation of this manuscript.

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  1. Drug Discovery Research, Astellas Pharma Inc., 5-2-3, Toukoudai, Tsukuba, Ibaraki, 300-2698, Japan

    Akiko Matsuyama-Yokono, Atsuo Tahara, Ryosuke Nakano, Yuka Someya, Masahiko Hayakawa & Masayuki Shibasaki

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  1. Akiko Matsuyama-Yokono
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  2. Atsuo Tahara
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  3. Ryosuke Nakano
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Correspondence to Akiko Matsuyama-Yokono.

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Matsuyama-Yokono, A., Tahara, A., Nakano, R. et al. Chronic inhibition of dipeptidyl peptidase-IV with ASP8497 improved the HbA1c level, glucose intolerance, and lipid parameter level in streptozotocin–nicotinamide-induced diabetic mice. Naunyn-Schmied Arch Pharmacol 379, 191–199 (2009). https://doi.org/10.1007/s00210-008-0348-x

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