Investigational insulin secretagogues for type 2 diabetes

Expert Opinion on Investigational Drugs

Volumn 25, Issue 4, 2016, Pages 405-422

  Scheen, André J ^a,b  

^a UNIVERSITY OF LIÈGE   (Belgium)

^b UNIVERSITY OF LIÈGE   (Belgium)

Author keywords

Beta cell; glucokinase activator; GPR agonist; imeglimin; incretin; insulin secretion; type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; AMG 151; ANTIDIABETIC AGENT; ARRY 403; CARDIOTOXIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; FASIGLIFAM; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 120 AGONIST; GASTRIC INHIBITORY POLYPEPTIDE; GKM 001; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOKINASE; GLUCOKINASE ACTIVATOR; HMS 5552; IMEGLIMIN; INCRETIN; INSULIN DERIVATIVE; MEGLITINIDE; MK 0941; PF 04937319; PF 04991532; PIRAGLIATIN; RO 28 1675; RO 5305552; SULFONYLUREA DERIVATIVE; TMG 123; TTP 399; UNCLASSIFIED DRUG; INSULIN; NEW DRUG; POTASSIUM CHANNEL BLOCKING AGENT;

ANTIDIABETIC ACTIVITY; CELL REGENERATION; CLINICAL TRIAL (TOPIC); DRUG EFFECT; DRUG RESEARCH; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; PANCREAS ISLET BETA CELL; REVIEW; ANIMAL; DIABETES MELLITUS, TYPE 2; METABOLISM; SECRETION (PROCESS);

ANIMALS; DIABETES MELLITUS, TYPE 2; DRUGS, INVESTIGATIONAL; GLUCOKINASE; HUMANS; HYPOGLYCEMIC AGENTS; INCRETINS; INSULIN; INSULIN-SECRETING CELLS; POTASSIUM CHANNEL BLOCKERS; RECEPTORS, G-PROTEIN-COUPLED;

EID: 84959179509     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2016.1152260     Document Type: Review

References (197)

1. DeFronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.
2. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann NY Acad Sci. 2013;1281:64-91.
3. Yabe D, Seino Y, Fukushima M, et al. Beta cell dysfunction versus insulin resistance in the pathogenesis of type 2 diabetes in East Asians. Curr Diab Rep. 2015;15:602.
4. Bhatt HB. Thoughts on the progression of type 2 diabetes drug discovery. Expert Opin Drug Discov. 2015;10:107-110.
5. Ferrannini E, Mari A. Beta-cell function in type 2 diabetes. Metabolism. 2014;63:1217-1227.
6. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.
7. Scheen AJ. A review of gliptins for 2014. Exp Opin Pharmacother. 2015;16:43-62.
8. Bailey CJ. The current drug treatment landscape for diabetes and perspectives for the future. Clin Pharmacol Ther. 2015;98:170-184.
9. Seino S. Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea. Diabetologia. 2012;55:2096-2108.
10. Jitrapakdee S, Wutthisathapornchai A, Wallace JC, et al. Regulation of insulin secretion: role of mitochondrial signalling. Diabetologia. 2010;53:1019-1032.
11. Rorsman P, Braun M. Regulation of insulin secretion in human pancreatic islets. Annu Rev Physiol. 2013;75:155-179.
12. Prentki M, Matschinsky FM, Madiraju SR. Metabolic signaling in fuel-induced insulin secretion. Cell Metab. 2013;18:162-185.
13. Zou CY, Gong Y, Liang J. Metabolic signaling of insulin secretion by pancreatic beta-cell and its derangement in type 2 diabetes. Eur Rev Med Pharmacol Sci. 2014;18:2215-2227.
14. Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000;49:1751-1760.
15. Thule PM, Umpierrez G. Sulfonylureas: a new look at old therapy. Curr Diab Rep. 2014;14:473.
16. Henquin JC. The fiftieth anniversary of hypoglycaemic sulphonamides. How did the mother compound work? Diabetologia. 1992;35:907-912.
17. Zhang CL, Katoh M, Shibasaki T, et al. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science. 2009;325:607-610.
18. Yabe D, Seino Y. Dipeptidyl peptidase-4 inhibitors and sulfonylureas for type 2 diabetes: friend or foe? J Diabetes Investig. 2014;5:475-477.
19. Takahashi H, Shibasaki T, Park JH, et al. Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion. Diabetes. 2015;64:1262-1272.
20. Hirst JA, Farmer AJ, Dyar A, et al. Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Diabetologia. 2013;56:973-984.
21. Diaz-Garcia CM. The TRPA1 channel and oral hypoglycemic agents: is there complicity in beta-cell exhaustion? Channels. 2013;7:420-422.
22. Rustenbeck I, Krautheim A, Jorns A, et al. Beta-cell toxicity of ATPsensitive K+ channel-blocking insulin secretagogues. Biochem Pharmacol. 2004;67:1733-1741.
23. Dornhorst A. Insulinotropic meglitinide analogues. Lancet. 2001;358:1709-1716.
24. Scott LJ. Repaglinide: a review of its use in type 2 diabetes mellitus. Drugs. 2012;72:249-272.
25. Campbell IW. Nateglinide-current and future role in the treatment of patients with type 2 diabetes mellitus. Int J Clin Pract. 2005;59:1218-1228.
26. Mascarello A, Frederico MJ, Castro AJ, et al. Novel sulfonyl(thio)urea derivatives act efficiently both as insulin secretagogues and as insulinomimetic compounds. Eur J Med Chem. 2014;86:491-501.
27. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-1705.
28. Zhang Y, Hong J, Chi J, et al. Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas - a meta-analysis from randomized clinical trials. Diabetes Metab Res Rev. 2014;30:241-256.
29. Lee YS, Jun HS. Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells. Metabolism. 2014;63:9-19.
30. Meier JJ, Nauck MA. Incretin-based therapies: where will we be 50 years from now? Diabetologia. 2015;58:1745-1750.
31. Barnett AH, Charbonnel B, Moses RG, et al. Dipeptidyl peptidase-4 inhibitors in triple oral therapy regimens in patients with type 2 diabetes mellitus. Curr Med Res Opin. 2015;31:1919-1931.
32. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140-149.
33. Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf. 2015;14:505-524.
34. Scheen AJ, Paquot N. Gliptin versus a sulphonylurea as add-on to metformin. Lancet. 2012;380:450-452.
35. Scheen AJ. Once-weekly DPP-4 inhibitors: do they meet an unmet need? Lancet Diabetes Endocrinol. 2015;3:162-164.
36. McKeage K. Trelagliptin: first global approval. Drugs. 2015;75:1161-1164.
37. Kaku K. First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother. 2015;16:2539-2547.
38. Biftu T, Sinha-Roy R, Chen P, et al. Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes. J Med Chem. 2014;57:3205-3212.
39. Burness CB. Omarigliptin: first global approval. Drugs. 2015;75:1947-1952.
40. Inagaki N, Onouchi H, Sano H, et al. SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:125-132.
41. Inagaki N, Onouchi H, Maezawa H, et al. Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study. Lancet Diabetes Endocrinol. 2015;3:191-197.
42. Sheu W-H-H, Gantz I, Chen M, et al. Safety and efficacy of omarigliptin (MK-3102), a novel once-weekly DPP-4 inhibitor for the treatment of patients with type 2 diabetes. Diabetes Care. 2015;38:2106-2114.
43. Gantz I, Lai E, Suryawhanshi S, et al. Omarigliptin, a once-weekly DPP-4 inhibitor, provides similar glycaemic control to sitagliptin in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetologia. 2015;58(Suppl 1):Abstract 110.
44. Scheen AJ. Which incretin-based therapy for type 2 diabetes? Lancet. 2014;384:1325-1327.
45. Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet. 2014;383:2008-2017.
46. Kumar A. Insulin degludec/liraglutide: innovation-driven combination for advancement in diabetes therapy. Expert Opin Biol Ther. 2014;14:869-878.
47. Berria R, Guerci B, Paranjape S, et al. Improved glucose control without increased hypoglycaemia risk with insulin glargine/lixisenatide fixed-ratio combination (LixiLan) vs insulin glargine alone. Diabetologia. 2015;58(Suppl 1):Abstract 111.
48. Aronson R. Optimizing glycemic control: lixisenatide and basal insulin in combination therapy for the treatment of type 2 diabetes mellitus. Expert Rev Clin Pharmacol. 2013;6:603-612.
49. Henry RR, Rosenstock J, Logan D, et al. Continuous subcutaneous delivery of exenatide via ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes. J Diabetes Complications. 2014;28:393-398.
50. Nauck MA, Petrie JR, Sesti G, et al. A phase 2, randomized, dosefinding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes. Diabetes Care. 2016;39:231-241.
51. Wang MW, Liu Q, Zhou CH. Non-peptidic glucose-like peptide-1 receptor agonists: aftermath of a serendipitous discovery. Acta Pharmacol Sin. 2010;31:1026-1030.
52. Yang DH, Zhou CH, Liu Q, et al. Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure. Acta Pharmacol Sin. 2015;36:1033-1042.
53. Tomlinson B, Hu M, Zhang Y, et al. An overview of novel GLP-1 receptor agonists for type 2 diabetes. Exp Opin Investig Drug. 2016;25:145-158.
54. Pols TW, Auwerx J, Schoonjans K. Targeting the TGR5-GLP-1 pathway to combat type 2 diabetes and non-alcoholic fatty liver disease. Gastroenterol Clin Biol. 2010;34:270-273.
55. Kumar DP, Rajagopal S, Mahavadi S, et al. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic beta cells. Biochem Biophys Res Commun. 2012;427:600-605.
56. Briere DA, Ruan X, Cheng CC, et al. Novel small molecule agonist of TGR5 possesses anti-diabetic effects but causes gallbladder filling in mice. PLoS One. 2015;10:e0136873.
57. Duan H, Ning M, Zou Q, et al. Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes. J Med Chem. 2015;58:3315-3328.
58. Zheng C, Zhou W, Wang T, et al. A novel TGR5 activator WB403 promotes GLP-1 secretion and preserves pancreatic beta-cells in type 2 diabetic mice. PLoS One. 2015;10:e0134051.
59. Tatarkiewicz K, Hargrove DM, Jodka CM, et al. A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents. Diabetes Obes Metab. 2014;16:75-85.
60. Petersen N, Reimann F, Van Es JH, et al. Targeting development of incretin-producing cells increases insulin secretion. J Clin Invest. 2015;125:379-385.
61. Grimsby J, Sarabu R, Corbett WL, et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science. 2003;301:370-373.
62. Sarabu R, Bizzarro FT, Corbett WL, et al. Discovery of piragliatin-first glucokinase activator studied in type 2 diabetic patients. J Med Chem. 2012;55:7021-7036.
63. 4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study. J Clin Endocrinol Metab. 2010;95:5028-5036.
64. Zhi J, Zhai S. Effects of piragliatin, a glucokinase activator, on fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus. J Clin Pharmacol. 2016;56:231-238.
65. Meininger GE, Scott R, Alba M, et al. Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care. 2011;34:2560-2566.
66. Kiyosue A, Hayashi N, Komori H, et al. Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:923-930.
67. Wilding JP, Leonsson-Zachrisson M, Wessman C, et al. Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin. Diabetes Obes Metab. 2013;15:750-759.
68. Katz L, Manamley N, Snyder W, et al. AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycemia in patients with type 2 diabetes. Diabetes Obes Metab. 2016; 18:191-195.
69. Chen L, Leng Y, Jin X, et al. Validating the dual modes of action of HMS5552, a novel pancreatic and hepatic-targeting glucokinase activator. Late breaking abstract presented at the 74th Scientific Meeting of the American Diabetes Association; 2014 Jun 13-17; San Francisco; 134-LB.
70. Chen L, Zhang Y, Jin X, et al. Clinical validation of the dual-modes of action of glucokinase activator HMS5552 for type 2 diabetes. Diabetes Metab Res Rev. 2014;30:6, Abstract O873.
71. Zhu D, Ding Y, Xiao D, et al. A novel dual pancreatic and hepatic acting glucokinase activator, HMS5552: phase I studies in healthy subjects and T2DM patients. Diabetes. 2015;64(Suppl 1):A300, Abstract 1165-P.
72. Zhu D, Ding Y, Xiao D, et al. Clinically differentiated glucokinase activator HMS5552: effective control of 24-hour glucose and improvement of β-cell function in T2DM patients. Diabetes. 2015;64(Suppl 1):A301, Abstract 1167-P.
73. Valcarce C. TTP399, a liver selective glucose kinase activator (GKA) lowers glucose and does NOT increase lipids in subjects with type 2 diabetes mellitus (T2DM). Diabetes. 2014;63(Suppl 1):A32, Abstract number 122-OR.
74. Amin NB, Aggarwal N, Pall D, et al. Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes. Diabetes Obes Metab. 2015;17:751-759.
75. Ramanathan V, Vachharajani N, Patel R, et al. GKM-001, a liverdirected/pancreas-sparing glucokinase modulator (GKM), lowers fasting and post-prandial glucose without hypoglycemia in type 2 diabetic (T2D) patients. Diabetes. 2012;61:A76, Abstract 293-OR.
76. Kimura T, Sakurai K, Morino K, et al. Pharmacokinetics, pharmacodynamics and tolerability of a novel glucokinase activator TMG-123, after single oral ascending doses in Japanese healthy subjects (Abstract). Diabetologia. 2015;58:S18, Abstract 37
77. Lloyd DJ, St Jean DJ Jr., Kurzeja RJ, et al. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature. 2013;504:437-440.
78. Du X, Hinklin RJ, Xiong Y, et al. C5-alkyl-2-methylurea-substituted pyridines as a new class of glucokinase activators. ACS Med Chem Lett. 2014;5:1284-1289.
79. Park K. Identification of YH-GKA, a novel benzamide glucokinase activator as therapeutic candidate for type 2 diabetes mellitus. Arch Pharm Res. 2012;35:2029-2033.
80. Oh YS, Lee YJ, Park K, et al. Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells. Eur J Pharm Sci. 2014;51:137-145.
81. Matschinsky F, Liang Y, Kesavan P, et al. Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest. 1993;92:2092-2098.
82. DeFronzo RA, Triplitt CL, Abdul-Ghani M, et al. Novel agents for the treatment of type 2 diabetes. Diabetes Spectrum. 2014;27:100-112.
83. Grewal AS, Sekhon BS, Lather V. Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus. Mini Rev Med Chem. 2014;14:585-602.
84. Nakamura A, Terauchi Y. Present status of clinical deployment of glucokinase activators. J Diabetes Investig. 2015;6:124-132.
85. Matschinsky FM. GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol Sci. 2013;34:90-99.
86. Filipski KJ, Pfefferkorn JA, A patent review of glucokinase activators and disruptors of the glucokinase-glucokinase regulatory protein interaction: 2011-2014. Expert Opin Ther Pat. 2014;24:875-891.
87. Matschinsky FM, Zelent B, Doliba NM, et al. Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects. Handb Exp Pharmacol. 2011;203:357-401.
88. Georgy A, Zhai S, Liang Z, et al. Lack of potential pharmacokinetic and pharmacodynamic interactions between piragliatin, a glucokinase activator, and simvastatin in patients with T2DM. J Clin Pharmacol. 2015. doi:10.1002/jcph.640.
89. Zhi J, Zhai S, Georgy A, et al. Exploratory effects of a strong CYP3A inhibitor (ketoconazole), a strong CYP3A inducer (rifampicin), and a concomitant ethanol on piragliatin pharmacokinetics and pharmacodynamics in type 2 diabetic patients. J Clin Pharmacol. 2015. doi:10.1002/jcph.617.
90. Krentz AJ, Morrow L, Petersson M, et al. Effect of exogenously administered glucagon versus spontaneous endogenous counterregulation on glycaemic recovery from insulin-induced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, AZD1656, and metformin. Diabetes Obes Metab. 2014;16:1096-1101.
91. Pfefferkorn JA. Strategies for the design of hepatoselective glucokinase activators to treat type 2 diabetes. Exp Opin Drug Discov. 2013;8:319-330.
92. Erion DM, Lapworth A, Amor PA, et al. The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. PLoS One. 2014;9:e97139.
93. Pfefferkorn JA, Guzman-Perez A, Oates PJ, et al. Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,Ndimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy) pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus. Med Chem Commun. 2011;2:828-839.
94. Ashton KS, Andrews KL, Bryan MC, et al. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept. J Med Chem. 2014;57:309-324.
95. Bourbeau MP, Ashton KS, Yan J, et al. Nonracemic synthesis of GKGKRP disruptor AMG-3969. J Org Chem. 2014;79:3684-3687.
96. Hinklin RJ, Boyd SA, Chicarelli MJ, et al. Identification of a new class of glucokinase activators through structure-based design. J Med Chem. 2013;56:7669-7678.
97. Hinklin RJ, Aicher TD, Anderson DA, et al. Discovery of 2-pyridylureas as glucokinase activators. J Med Chem. 2014;57:8180-8186.
98. Park K, Lee BM, Hyun KH, et al. Discovery of 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus. Bioorg Med Chem. 2014;22:2280-2293.
99. Park K, Lee BM, Hyun KH, et al. Design and synthesis of acetylenyl benzamide derivatives as novel glucokinase activators for the treatment of T2DM. ACS Med Chem Lett. 2015;6:296-301.
100. Li Y, Tian K, Qin A, et al. Discovery of novel urea derivatives as dualtarget hypoglycemic agents that activate glucokinase and PPARgamma. Eur J Med Chem. 2014;76:182-192.
101. Lu J, Lei L, Huan Y, et al. Design, synthesis, and activity evaluation of GK/PPARgamma dual-target-directed ligands as hypoglycemic agents. ChemMedChem. 2014;9:922-927.
102. Kaku K. Fasiglifam as a new potential treatment option for patients with type 2 diabetes. Expert Opin Pharmacother. 2013;14:2591-2600.
103. Burant CF, Viswanathan P, Marcinak J, et al. 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.
104. Anunpindi R, Dixit A, Deshmukh N, et al. P11187, a potent and novel GPR40 agonist, potentiates glucose stimulated insulin secretion and improves glucose tolerance in rodent models of type 2 diabetes. Diabetes. 2014;63(Suppl 1):A456. Abstract 1763-P.
105. Takano R, Yoshida M, Inoue M, et al. Discovery of DS-1558: a potent and orally bioavailable GPR40 agonist. ACS Med Chem Lett. 2015;6:266-270.
106. Tanaka H, Yoshida S, Oshima H, et al. Chronic treatment with novel GPR40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion. J Pharmacol Exp Ther. 2013;346:443-452.
107. Guo DY, Li DW, Ning MM, et al. Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models. Biochem Biophys Res Commun. 2015;466:740-747.
108. Gowda N, Dandu A, Singh J, et al. 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 Pharmacol Toxicol. 2013;14:28.
109. Sunil V, Verma MK, Oommen AM, et al. CNX-011-67, a novel GPR40 agonist, enhances glucose responsiveness, insulin secretion and islet insulin content in n-STZ rats and in islets from type 2 diabetic patients. BMC Pharmacol Toxicol. 2014;15:19.
110. Ma Z, Lin DC-H, Sharma R, et al. Discovery of the imidazole-derived GPR40 agonist AM-3189. Bioorg Med Chem Lett. 2016;26:15-20.
111. Ha TY, Kim YS, Kim CH, et al. Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus. Arch Pharm Res. 2014;37:671-678.
112. Oshima H, Yoshida S, Ohishi T, et al. Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice. Life Sci. 2013;92:167-173.
113. Nunez DJ, Bush MA, Collins DA, et al. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies. PLoS One. 2014;9:e92494.
114. He Y, Davis L, Bhad P, et al. LEZ763, a novel GPR119 agonist, increases GLP-1, GIP, PYY, and glucagon, but has minimal effects on glucose in patients with type 2 diabetes. Late breaking abstract presented at the 75th Scientific Meeting of the American Diabetes Association; 2015 Jun 5-9; Boston, MA; 122-LB.
115. Kim BG. LGLS120-A, a potent, selective, and structurally novel GPR120 agonist, provides superior glycemic control to DPP-4 inhibitor in animal model of type 2 diabetes. Diabetes. 2015;64(Suppl 1):A334, Abstract 1284-P.
116. Urban C, Hamacher A, Partke HJ, et al. In vitro and mouse in vivo characterization of the potent free fatty acid 1 receptor agonist TUG-469. Naunyn Schmiedebergs Arch Pharmacol. 2013;386:1021-1030.
117. Hudson BD, Shimpukade B, Mackenzie AE, et al. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol Pharmacol. 2013;84:710-725.
118. Sekiguchi H, Kasubuchi M, Hasegawa S, et al. A novel antidiabetic therapy: free fatty acid receptors as potential drug target. Current Diabetes Reviews. 2015;11:107-115.
119. Milligan G, Alvarez-Curto E, Watterson KR, et al. Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4. Br J Pharmacol. 2015;172:3254-3265.
120. Mancini AD, Poitout V, The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol Metab. 2013;24:398-407.
121. Nagasumi K, Esaki R, Iwachidow K, et al. Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes. 2009;58:1067-1076.
122. Poitout V, Lin DC-H. Modulating GPR40: therapeutic promise and potential in diabetes. Drug Discov Today. 2013;18:1301-1308.
123. Feng XT, Leng J, Xie Z, et al. GPR40: a therapeutic target for mediating insulin secretion (review). Int J Mol Med. 2012;30:1261-1266.
124. Burant CF. Activation of GPR40 as a therapeutic target for the treatment of type 2 diabetes. Diabetes Care. 2013;36 Suppl 2: S175-S179.
125. Kaku K, Araki T, Yoshinaka R. Randomized, double-blind, doseranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care. 2013;36:245-250.
126. Watterson KR, Hudson BD, Ulven T, et al. Treatment of type 2 diabetes by free fatty acid receptor agonists. Front Endocrinol (Lausanne). 2014;5:137.
127. Defossa E, Wagner M. Recent developments in the discovery of FFA1 receptor agonists as novel oral treatment for type 2 diabetes mellitus. Bioorg Med Chem Lett. 2014;24:2991-3000.
128. Mancini AD, Poitout V. GPR40 agonists for the treatment of type 2 diabetes: life after 'TAKing' a hit. Diabetes Obes Metab. 2015;17:622-629.
129. Tanaka H, Yoshida S, Minoura H, et al. Novel GPR40 agonist AS2575959 exhibits glucose metabolism improvement and synergistic effect with sitagliptin on insulin and incretin secretion. Life Sci. 2014;94:115-121.
130. Nakashima R, Yano T, Ogawa J, et al. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists. Eur J Pharmacol. 2014;737:194-201.
131. Ohishi T, Yoshida S. The therapeutic potential of GPR119 agonists for type 2 diabetes. Exp Opin Drug Discov. 2012;21:321-328.
132. Liu P, Hu Z, DuBois BG, et al. Design of potent and orally active GPR119 agonists for the treatment of type II diabetes. ACS Med Chem Lett. 2015;6:936-941.
133. Dai X, Stamford A, Liu H, et al. Discovery of the oxazabicyclo[3.3.1] nonane derivatives as potent and orally active GPR119 agonists. Bioorg Med Chem Lett. 2015;25:5291-5294.
134. Ichimura A, Hara T, Hirasawa A. Regulation of energy homeostasis via GPR120. Front Endocrinol (Lausanne). 2014;5:111.
135. Moran BM, Abdel-Wahab YH, Flatt PR, et al. Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic beta-cells. Diabetes Obes Metab. 2014;16:1128-1139.
136. Suckow AT, Polidori D, Yan W, et al. Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role for GPR120 in glucagon secretion. J Biol Chem. 2014;289:15751-15763.
137. Zhang D, Leung PS. Potential roles of GPR120 and its agonists in the management of diabetes. Drug Des Devel Ther. 2014;8:1013-1027.
138. Cornall LM, Mathai ML, Hryciw DH, et al. GPR120 agonism as a countermeasure against metabolic diseases. Drug Discov Today. 2014;19:670-679.
139. Liu HD, Wang WB, Xu ZG, et al. FFA4 receptor (GPR120): A hot target for the development of anti-diabetic therapies. Eur J Pharmacol. 2015;763:160-168.
140. Winzell MS, Myhre S, Sundström L, et al. The glucose lowering effect of small molecule GPR120 agonists is driven by glucagonlike peptide-1. Diabetologia. 2015;58(Suppl 1):S272, Abstract 559
141. Shimpukade B, Hudson BD, Hovgaard CK, et al. Discovery of a potent and selective GPR120 agonist. J Med Chem. 2012;55:4511-4515.
142. Li A, Li Y, Du L. Biological characteristics and agonists of GPR120 (FFAR4) receptor: the present status of research. Future Med Chem. 2015;7:1457-1468.
143. Pirags V, Lebovitz H, Fouqueray P. Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients. Diabetes Obes Metab. 2012;14:852-858.
144. Fouqueray P, Pirags V, Inzucchi SE, et al. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care. 2013;36:565-568.
145. Fouqueray P, Pirags V, Diamant M, et al. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. Diabetes Care. 2014;37:1924-1930.
146. Fouqueray P, Bolze S, Pirags V, et al. Dose-ranging study to determine the optimum dose for imeglimin, a novel treatment for type 2 diabetes. Diabetes. 2015;64(Suppl 1):A301, Abstract 1169-P.
147. Fouqueray P, Bolze S, Pirags V, et al. Imeglimin, a new oral antihyperglycemic agent controls both fasting and post-prandial glucose through an improvement in both insulin secretion and insulin sensitivity. Poster presented at the 13rd World Congress on Insulin Resistance, Diabetes and Cardiovascular Diseases (WCIRDCVD); 2015 Nov 19-21; Los Angeles, CA.
148. Vuylsteke V, Chastain LM, Maggu GA, et al. Imeglimin: a potential new multi-target drug for type 2 diabetes. Drugs R&D. 2015;15:227-232.
149. Bolze S, Fouqueray P, Hallakou-Bozec S Imeglimin, a new mitochondria targeted agent for type 2 diabetes treatment. Oral presentation at World Congress on Targeting Mitochondria; 2015. Available from: http://journal.medsys-site.com/index.php/WMS/arti cle/view/314.
150. Vial G, Chauvin MA, Bendridi N, et al. Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model. Diabetes. 2015;64:2254-2264.
151. Pacini G, Mari A, Fouqueray P, et al. Imeglimin increases glucosedependent insulin secretion and improves beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:541-545.
152. Robertson RP, Halter JB, Porte D Jr. A role for alpha-adrenergic receptors in abnormal insulin secretion in diabetes mellitus. J Clin Invest. 1976;57:791-795.
153. Broadstone VL, Pfeifer MA, Bajaj V, et al. Alpha-adrenergic blockade improves glucose-potentiated insulin secretion in non-insulindependent diabetes mellitus. Diabetes. 1987;36:932-937.
154. Ostenson CG, Pigon J, Doxey JC, et al. Alpha 2-adrenoceptor blockade does not enhance glucose-induced insulin release in normal subjects or patients with noninsulin-dependent diabetes. J Clin Endocrinol Metab. 1988;67:1054-1059.
155. Tang Y, Axelsson AS, Spegel P, et al. Genotype-based treatment of type 2 diabetes with an alpha2A-adrenergic receptor antagonist. Sci Transl Med. 2014;6(257):257ra139-257ra139.
156. Scheen AJ. Towards a genotype-based approach for a patientcentered pharmacologic therapy of type 2 diabetes. Ann Transl Med. 2015;3:S36.
157. Coughlan KA, Valentine RJ, Ruderman NB, et al. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metabol Syndr Obes. 2014;7:241-253.
158. Fu A, Eberhard CE, Screaton RA. Role of AMPK in pancreatic beta cell function. Mol Cell Endocrinol. 2013;366:127-134.
159. Dufer M, Noack K, Krippeit-Drews P, et al. Activation of the AMPactivated protein kinase enhances glucose-stimulated insulin secretion in mouse beta-cells. Islets. 2010;2:156-163.
160. Pasternak L, Meltzer-Mats E, Babai-Shani G, et al. Benzothiazole derivatives augment glucose uptake in skeletal muscle cells and stimulate insulin secretion from pancreatic beta-cells via AMPK activation. Chem Commun (Camb). 2014;50:11222-11225.
161. Kim JW, You YH, Ham DS, et al. The paradoxical effects of AMPK on insulin gene expression and glucose-induced insulin secretion. J Cell Biochem. 2016;117:239-246.
162. Sugawara K, Shibasaki T, Takahashi H, et al. Structure and functional roles of Epac2 (Rapgef4). Gene. 2016;575:577-583.
163. Shibasaki T, Takahashi T, Takahashi H, et al. Cooperation between cAMP signalling and sulfonylurea in insulin secretion. Diabetes Obes Metab. 2014;16 Suppl 1:118-125.
164. Song WJ, Mondal P, Li Y, et al. Pancreatic beta-cell response to increased metabolic demand and to pharmacologic secretagogues requires EPAC2A. Diabetes. 2013;62:2796-2807.
165. Ohtani M, Ohura K, Oka T. Involvement of P2X receptors in the regulation of insulin secretion, proliferation and survival in mouse pancreatic beta-cells. Cell Physiol Biochem. 2011;28:355-366.
166. Pacheco PA, Ferreira LG, Alves LA, et al. Modulation of P2 receptors on pancreatic beta-cells by agonists and antagonists: a molecular target for type 2 diabetes treatment. Curr Diab Rev. 2013;9:228-236.
167. Burnstock G, Novak I. Purinergic signalling and diabetes. Purinergic Signal. 2013;9:307-324.
168. Tengholm A. Purinergic P2Y1 receptors take centre stage in autocrine stimulation of human beta cells. Diabetologia. 2014;57:2436-2439.
169. Ojo OO, Abdel-Wahab YH, Flatt PR, et al. Tigerinin-1R: a potent, non-toxic insulin-releasing peptide isolated from the skin of the Asian frog, Hoplobatrachus rugulosus. Diabetes Obes Metab. 2011;13:1114-1122.
170. Srinivasan DK, Ojo OO, Owolabi BO, et al. [I10W]tigerinin-1R enhances both insulin sensitivity and pancreatic beta cell function and decreases adiposity and plasma triglycerides in high-fat mice. Acta Diabetol. 2015.. doi:10.1007/s00592-015-0783-3.
171. Ojo OO, Srinivasan DK, Owolabi BO, et al. Beneficial effects of tigerinin-1R on glucose homeostasis and beta cell function in mice with diet-induced obesity-diabetes. Biochimie. 2015;109:18-26.
172. Srinivasan D, Ojo OO, Abdel-Wahab YHA, et al. Insulin-releasing and cytotoxic properties of the frog skin peptide, tigerinin-1R: a structure-activity study. Peptides. 2014;55:23-31.
173. Nguyen TTN, Folch B, Letourneau M, et al. Cardiotoxin-I: an unexpectedly potent insulinotropic agent. Chembiochem. 2012;13:1805-1812.
174. Nguyen TTN, Folch B, Letourneau M, et al. Design of a truncated cardiotoxin-I analogue with potent insulinotropic activity. J Med Chem. 2014;57:2623-2633.
175. Zhang F, Dey D, Branstrom R, et al. BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner. Am J Physiol Cell Physiol. 2009;296:C346-C354.
176. Zhang Q, Zhang F, Sjoholm A. BLX-1002 restores glucose sensitivity and enhances insulin secretion stimulated by GLP-1 and sulfonylurea in type 2 diabetic pancreatic islets. Physiol Rep. 2014;2:e12014-e12014.
177. Shaghafi MB, Barrett DG, Willard FS, et al. The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structureactivity relationships. Bioorg Med Chem Lett. 2014;24:1031-1036.
178. Ludwig B, Barthel A, Reichel A, et al. Modulation of the pancreatic islet-stress axis as a novel potential therapeutic target in diabetes mellitus. Vitam Horm. 2014;95:195-222.
179. Song I, Muller C, Louw J, et al. Regulating the beta cell mass as a strategy for type-2 diabetes treatment. Curr Drug Targets. 2015;16:516-524.
180. Tortosa F, Dotta F. Incretin hormones and beta-cell mass expansion: what we know and what is missing? Arch Physiol Biochem. 2013;119:161-169.
181. Takebayashi K, Inukai T. Effect of proton pump inhibitors on glycemic control in patients with diabetes. World J Diabetes. 2015;6:1122-1131.
182. Boj-Carceller D. Proton pump inhibitors: impact on glucose metabolism. Endocrine. 2013;43:22-32.
183. Inci F, Atmaca M, Ozturk M, et al. Pantoprazole may improve beta cell function and diabetes mellitus. J Endocrinol Invest. 2014;37:449-454.
184. Gonzalez-Ortiz M, Martinez-Abundis E, Mercado-Sesma AR, et al. Effect of pantoprazole on insulin secretion in drug-naive patients with type 2 diabetes. Diabetes Res Clin Pract. 2015;108:e11-e13.
185. Hove KD, Brons C, Faerch K, et al. Effects of 12 weeks' treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study. Diabetologia. 2013;56:22-30.
186. Wan Y, Wang Q, Prud'homme GJ. GABAergic system in the endocrine pancreas: a new target for diabetes treatment. Diabetes Metab Syndr Obes. 2015;8:79-87.
187. Purwana I, Zheng J, Li X, et al. GABA promotes human beta-cell proliferation and modulates glucose homeostasis. Diabetes. 2014;63:4197-4205.
188. Tian J, Dang H, Chen Z, et al. Gamma-aminobutyric acid regulates both the survival and replication of human beta-cells. Diabetes. 2013;62:3760-3765.
189. Rutter GA, Hodson DJ. Beta cell connectivity in pancreatic islets: a type 2 diabetes target? Cell Mol Life Sci. 2015;72:453-467.
190. Rutter GA, Hodson DJ. Minireview: intraislet regulation of insulin secretion in humans. Mol Endocrinol. 2013;27:1984-1995.
191. Cigliola V, Chellakudam V, Arabieter W, et al. Connexins and betacell functions. Diabetes Res Clin Pract. 2013;99:250-259.
192. Hedrington MS, Davis SN. Discontinued in 2013: diabetic drugs. Expert Opin Investig Drugs. 2014;23:1703-1711.
193. Colca JR. Discontinued drug therapies to treat diabetes in 2014. Expert Opin Investig Drugs. 2015;24:1241-1245.
194. Neithercott T. The future is near. 14 diabetes products suggest big things to come. Diabetes Forecast. 2015;68:33-35.
195. Ahren B, Creative use of novel glucose-lowering drugs for type 2 diabetes: where will we head in the next 50 years? Diabetologia. 2015;58:1740-1744.
196. Kahn SE, Buse JB. Medications for type 2 diabetes: how will we be treating patients in 50 years? Diabetologia. 2015;58:1335-1339.
197. Weir GC, Bonner-Weir S. Islet beta cell mass in diabetes and how it relates to function, birth, and death. Ann N Y Acad Sci. 2013;1281:92-105.