Skip to main content
SpringerLink
Log in

Sixty Years of Drug Discovery for Type 2 Diabetes: Where Are We Now?

  • Protocol
  • First Online:
Type 2 Diabetes

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2076))

Abstract

Today, excluding insulin, there are eight classes of anti-diabetic medicines that have been added to the pharmacy since the introduction of metformin in the mid-1950s; the sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, meglitinides, incretins, and sodium glucose transport 2 inhibitors. Does the fact that metformin is still first-line treatment suggest that our drug discovery efforts over the past 60 years have not been good enough? Or does it suggest that diabetes is such a complex disorder that no single treatment, other than gastric bypass surgery, can affect true normalization of not only blood sugar but also the underlying pathologies? Our understanding of the disease has most definitely improved which may bring hope for the future in terms of science, but for it to be beneficial, this science has to be translated into better drug treatments for the disease. In this review, I have examined the eight classes of anti-diabetes drugs from a drug discovery perspective.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Sugiyama Y (2005) Druggability: selecting optimized drug candidates. Drug Discov Today 10:1577–1579

    Article  PubMed  Google Scholar 

  2. Allen MJ, Carey AH (2004) Target identification and validation through genetics. Drug Discov Today TARGETS 3:183–190

    Article  CAS  Google Scholar 

  3. Sams-Dodd F (2005) Target-based drug discovery: is something wrong? Drug Discov Today 10:139–147

    Article  CAS  PubMed  Google Scholar 

  4. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schact AL (2010) How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 9:203–214

    Article  CAS  PubMed  Google Scholar 

  5. Bouzakri K, Koistinen HA, Zierath JR (2005) Molecular mechanisms of skeletal muscle insulin resistance in type 2 diabetes. Curr Diabetes Rev 1:167–174

    Article  CAS  PubMed  Google Scholar 

  6. Gerich JE, Mitrakou A, Kelley D, Mandarino L, Nurjhan N, Reilly J, Jenssen T, Veneman T, Consoli A (1990) Contribution of impaired muscle glucose clearance to reduced postabsorptive systemic glucose clearance in NIDDM. Diabetes 39:211–216

    Article  CAS  PubMed  Google Scholar 

  7. Consoli A (1992) Role of liver in pathophysiology of NIDDM. Diabetes Care 15:430–441

    Article  CAS  PubMed  Google Scholar 

  8. Reaven GM (2014) Pathophysiology of insulin resistance in human disease. Physiol Rev 75:473–486

    Article  Google Scholar 

  9. Reaven GM (1988) Role of insulin resistance in human disease. Diabetes 37:1595–1607

    Article  CAS  PubMed  Google Scholar 

  10. Ritzel RA, Butler AE, Rizza RA, Veldhuis JD, Butler PC (2006) Relationship between b-cell mass and fasting blood glucose concentration in humans. Diabetes Care 29:717–718

    Article  PubMed  Google Scholar 

  11. The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986

    Article  Google Scholar 

  12. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

    Article  Google Scholar 

  13. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853

    Article  Google Scholar 

  14. American Diabetes Association (2011) Executive summary: standards of medical care in diabetes - 2011. Diabetes Care 34:S4–S10

    Article  Google Scholar 

  15. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32:193–203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B (2006) Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the study of diabetes. Diabetes Care 29:1963–1972

    Article  PubMed  Google Scholar 

  17. The ADVANCE Collaborative Group (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572

    Article  Google Scholar 

  18. The Action to Control Cardiovascular Risk in Diabetes Study Group (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559

    Article  PubMed Central  Google Scholar 

  19. Herman WH, Dirani RG, O’Neill MC, Kravitz B, Heise A, Bakst A, Freed.M.I. (2005) Reduction in use of healthcare services with combination sulfonylurea and rosiglitazone: findings from the Rosiglitazone Early vs SULfonylurea Titration (RESULT) study. Am J Manag Care 11:273–278

    PubMed  Google Scholar 

  20. Proks P, Reimann F, Green N, Gribble F, Ashcroft F (2002) Sulfonylurea stimulation of insulin secretion. Diabetes 51:S368–S376

    Article  CAS  PubMed  Google Scholar 

  21. Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism. Nature 440:470–476

    Article  CAS  PubMed  Google Scholar 

  22. Ashcroft FM (2007) ATP-sensitive K channels and disease: from molecule to malady. Am J Physiol Endocrinol Metab 293:E880–E889

    Article  CAS  PubMed  Google Scholar 

  23. Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, Seino S (1996) A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron 16:1011–1017

    Article  CAS  PubMed  Google Scholar 

  24. Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM (2009) SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator. Philos Trans R Soc B 364:257–267

    Article  CAS  Google Scholar 

  25. Gribble FM, Tucker SJ, Seino S, Ashcroft FM (1998) Tissue specificity of sulfonylureas: studies on cloned cardiac and beta-cell K(ATP) channels. Diabetes 47:1412–1418

    Article  CAS  PubMed  Google Scholar 

  26. Zünkler BJ, Lenzen S, Männer K, Panten U, Trube G (2014) Concentration-dependent effects of tolbutamide, meglitinide, glipizide, glibenclamide and diazoxide on ATP-regulated K+ currents in pancreatic b-cells. Naunyn Schmiedebergs Arch Pharmacol 337:225–230

    Google Scholar 

  27. Sturgess NC, Kozlowski RZ, Carrington CA, Hales CN, Ashford ML (1988) Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide-sensitive channels in an insulin-secreting cell line. Br J Pharmacol 95:83–94

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Splitter S, Brown FR, Friskey RW, Grindell L, Kinsell LW (1956) Treatment of diabetic patients-observations on the use of carbutamide and tolbutamide. Calif Med 85:285–288

    PubMed Central  PubMed  Google Scholar 

  29. Graal MB, Wolffenbuttel BHR (1999) The use of sulphonylureas in the elderly. Drugs Aging 15:471–481

    Article  CAS  PubMed  Google Scholar 

  30. Malabu UH, Vangaveti VN, Kennedy LR (2014) Disease burden evaluation of fall-related events in the elderly due to hypoglycemia and other diabetic complications: a clinical review. Clin Epidemiol 6:287–294

    Article  PubMed Central  PubMed  Google Scholar 

  31. Bailey CJ, Day C (2004) Metformin: its botanical background. Pract Diabetes Int 21:115–117

    Article  Google Scholar 

  32. Bailey CJ (1992) Biguanides and NIDDM. Diabetes Care 15:755–772

    Article  CAS  PubMed  Google Scholar 

  33. Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF (1981) Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 12:235–246

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Zhou M, Xia L, Wang J (2007) Metformin transport by a newly cloned proton-stimulated organic cation transporter (Plasma Membrane Monoamine Transporter) expressed in human intestine. Drug Metab Dispos 35:1956–1962

    Article  CAS  PubMed  Google Scholar 

  35. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE (2012) Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 22:820–827

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong J, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81–98

    Article  CAS  PubMed  Google Scholar 

  37. Strack T (2008) Metformin: a review. Drugs Today 44:303–314

    Article  CAS  Google Scholar 

  38. Campbell RK, White JR, Saulie BA (1996) Metformin: a new oral biguanide. Clin Ther 18:360–371

    Article  CAS  PubMed  Google Scholar 

  39. DeFronzo RA, Goodman AM (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:541–549

    Article  CAS  PubMed  Google Scholar 

  40. Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334:574–579

    Article  CAS  PubMed  Google Scholar 

  41. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE (1995) Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 333:550–554

    Article  CAS  PubMed  Google Scholar 

  42. Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI (2000) Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49:2063–2069

    Article  CAS  PubMed  Google Scholar 

  43. Klip A, Leiter LA (1990) Cellular mechanism of action of metformin. Diabetes Care 13:696–704

    Article  CAS  PubMed  Google Scholar 

  44. Fryer LGD, Parbu-Patel A, Carling D (2002) The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277:25226–25232

    Article  CAS  PubMed  Google Scholar 

  45. Hardie DG (2008) AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes Relat Metab Disord 32:S7–S12

    Article  CAS  Google Scholar 

  46. Ruderman N, Prentki M (2004) AMP-kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 3:340–351

    Article  CAS  PubMed  Google Scholar 

  47. Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348:607–614

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Sakamoto K, Göransson O, Hardie DG, Alessi DR (2004) Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am J Physiol Endocrinol Metab 287:E310–E317

    Article  CAS  PubMed  Google Scholar 

  49. Golay A (2007) Metformin and body weight. Int J Obes Relat Metab Disord 32:61–72

    Article  CAS  Google Scholar 

  50. Clapham JC, Arch JR (2008) Influencing energy expenditure and substrate utilisation. In: Pharmacotherapy of obesity, Milestones in drug therapy. Birkhäuser, Basel, pp 101–115

    Chapter  Google Scholar 

  51. Paolisso G, Amato L, Eccellente R, Gambardella A, Tagliamonte MR, Varricchio G, Carella C, Giugliano D, D’onofrio F (1998) Effect of metformin on food intake in obese subjects. Eur J Clin Invest 28:441–446

    Article  CAS  PubMed  Google Scholar 

  52. Bruijstens LA, van Luin M, Buscher-Jungerhans PM, Bosch FH (2008) Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment. Neth J Med 66:185–190

    CAS  PubMed  Google Scholar 

  53. Carter D, Howlett HCS, Wiernsperger NF, Bailey CJ (2003) Differential effects of metformin on bile salt absorption from the jejunum and ileum. Diabetes Obes Metab 5:120–125

    Article  CAS  PubMed  Google Scholar 

  54. Davidson J, Howlett H (2004) New prolonged-release metformin improves gastrointestinal tolerability. Br J Diabetes Vasc Dis 4:273–277

    Article  CAS  Google Scholar 

  55. Mallick S (2004) Metformin induced acute pancreatitis precipitated by renal failure. Postgrad Med J 80:239–240

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Alsubaie S, Almalki MH (2013) Metformin induced acute pancreatitis. Derm Endocrinol 5:317–318

    Article  CAS  Google Scholar 

  57. Oprea TI, Bauman JE, Bologa CG, Buranda T, Chigaev A, Edwards BS, Jarvik JW, Gresham HD, Haynes MK, Hjelle B, Hromas R, Hudson L, Mackenzie DA, Muller CY, Reed JC, Simons PC, Smagley Y, Strouse J, Surviladze Z, Thompson T, Ursu O, Waller A, Wandinger-Ness A, Winter SS, Wu Y, Young SM, Larson RS, Willman C, Sklar LA (2011) Drug repurposing from an academic perspective. Drug Discov Today Ther Strat 8:61

    Article  Google Scholar 

  58. Kasznicki J, Sliwinska A, Drzewoski J (2014) Metformin in cancer prevention and therapy. Ann Transl Med 2:57

    PubMed Central  PubMed  Google Scholar 

  59. Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN (2010) Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol 162:193–212

    Article  CAS  PubMed  Google Scholar 

  60. Scarpello JHB, Howlett HCS (2008) Metformin therapy and clinical uses. Diabetes Vasc Dis Res 5:157–167

    Article  Google Scholar 

  61. Hirst JA, Farmer AJ, Dyar A, Lung TWC, Stevens RJ (2013) Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Diabetologia 56:973–984

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Rydberg T, Jönsson A, Karlsson MO, Melander A (1997) Concentration-effect relations of glibenclamide and its active metabolites in man: modelling of Pharmacokinetics and Pharmacodynamics. Br J Clin Pharmacol 43:373–381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–716

    Article  CAS  PubMed  Google Scholar 

  64. Rosengren A, Jing X, Eliasson L, Renstrøm E (2008) Why treatment fails in type 2 diabetes. PLoS Med 5:e215

    Article  PubMed Central  PubMed  Google Scholar 

  65. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443

    Article  CAS  PubMed  Google Scholar 

  66. Karam JH, Sanz N, Salamon E, Nolte MS (1986) Selective unresponsiveness of pancreatic b-cells to acute sulfonylurea stimulation during sulfonylurea therapy in NIDDM. Diabetes 35:1314–1320

    Article  CAS  PubMed  Google Scholar 

  67. Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, Zimmerman RS (2012) Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab 14:803–809

    Article  CAS  PubMed  Google Scholar 

  68. Rustenbeck I, Wienbergen A, Bleck C, Jörns A (2004) Desensitization of insulin secretion by depolarizing insulin secretagogues. Diabetes 53:S140–S150

    Article  CAS  PubMed  Google Scholar 

  69. Sadikot SM, Mogensen CE (2008) Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. Diabetes Res Clin Pract 82:391–395

    Article  CAS  PubMed  Google Scholar 

  70. Lefer DJ, Nichols CG, Coetzee WA (2009) Sulfonylurea receptor 1 subunits of ATP-sensitive potassium channels and myocardial Ischemia/reperfusion Injury. Trends Cardiovasc Med 19:61–67

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Bell DSH (2006) Do sulfonylurea drugs increase the risk of cardiac events? Can Med Assoc J 174:185–186

    Article  Google Scholar 

  72. Grygiel-Górniak B (2014) Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications - a review. Nutr J 13:17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Glosli H, Gudbrandsen OA, Mullen AJ, Halvorsen B, Røst TH, Wergedahl H, Prydz H, Aukrust P, Berge RK (2005) Down-regulated expression of PPARa target genes, reduced fatty acid oxidation and altered fatty acid composition in the liver of mice transgenic for hTNFa. Biochim Biophys Acta 1734:235–246

    Article  CAS  PubMed  Google Scholar 

  74. Turner NC, Clapham JC (1998) Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanisms and treatment: current status and therapeutic possibilities. Prog Drug Res 51:33–94

    Article  CAS  PubMed  Google Scholar 

  75. Henry RR (1997) Thiazolidinediones. Endocrinol Metab Clin 26:553–573

    Article  CAS  Google Scholar 

  76. Gale EAM (2006) Troglitazone: the lesson that nobody learned? Diabetologia 49:1–6

    Article  PubMed  Google Scholar 

  77. Barnett AH (2009) Redefining the role of thiazolidinediones in the management of type 2 diabetes. Vasc Health Risk Manag 5:141–151

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A (2001) Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 24:308–315

    Article  CAS  PubMed  Google Scholar 

  79. Fonseca V, Rosenstock J, Patwardhan R, Salzman A (2000) Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 283:1695–1702

    Article  CAS  PubMed  Google Scholar 

  80. Poitout V (2004) b-cell lipotoxicity: burning fat into heat? Endocrinology 145:3563–3565

    Article  CAS  PubMed  Google Scholar 

  81. Nolan CJ, Prentki M (2008) The islet b-cell: fuel responsive and vulnerable. Trends Endocrinol Metab 19:285–291

    Article  CAS  PubMed  Google Scholar 

  82. Buckingham RE, Al-Barazanji KA, Toseland CDN, Slaughter M, Connor SC, West A, Bond B, Turner NC, Clapham JC (1998) Peroxisome proliferator-activated receptor-g agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47:1326–1334

    CAS  PubMed  Google Scholar 

  83. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471

    Article  CAS  PubMed  Google Scholar 

  84. Singh S, Loke YK, Furberg CD (2007) Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care 30:2148–2153

    Article  CAS  PubMed  Google Scholar 

  85. Bloomgarden ZT (2007) The avandia debate. Diabetes Care 30:2401–2408

    Article  PubMed  Google Scholar 

  86. Misbin RI (2007) Lessons from the avandia controversy: a new paradigm for the development of drugs to treat type 2 diabetes. Diabetes Care 30:3141–3144

    Article  PubMed  Google Scholar 

  87. Bhatt DL, Chew DP, Grines C, Mukherjee D, Leesar M, Gilchrist IC, Corbelli JC, Blankenship JC, Eres A, Steinhubl S, Tan WA, Resar JR, Al Mahameed A, Abdel-Latif A, Tang HW, Brennan D, McErlean E, Hazen SL, Topol EJ (2007) Peroxisome proliferator-activated receptor g agonists for the prevention of adverse events following percutaneous coronary revascularizationG-results of the PPAR study. Am Heart J 154:137–143

    Article  CAS  PubMed  Google Scholar 

  88. McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM (2007) Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidem Drug Safe 16:711–725

    Article  Google Scholar 

  89. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Dargie H, Komajda M, Gubb J, Biswas N, Jones NP (2005) Rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes (RECORD): study design and protocol. Diabetologia 48:1726–1735

    Article  CAS  PubMed  Google Scholar 

  90. Hillaire-Buys D, Faillie JL, Montastruc JL (2011) Pioglitazone and bladder cancer. Lancet 378:1543–1544

    Article  PubMed  Google Scholar 

  91. Grey A (2009) Thiazolidinedione-induced skeletal fragility - mechanisms and implications. Diabetes Obes Metab 11:275–284

    Article  CAS  PubMed  Google Scholar 

  92. Oshitari T, Asaumi N, Watanabe M, Kumagai K, Mitamura Y (2008) Severe macular edema induced by pioglitazone in a patient with diabetic retinopathy: a case study. Vasc Health Risk Manag 4:1137–1140

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Liazos E, Broadbent DM, Beare N, Kumar N (2008) Spontaneous resolution of diabetic macular oedema after discontinuation of thiazolidenediones. Diabet Med 25:860–862

    Article  CAS  PubMed  Google Scholar 

  94. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH, Brand-Miller J (2005) Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 81:341–354

    Article  CAS  PubMed  Google Scholar 

  95. Prentice AM, Jebb SA (1995) Obesity in Britain: gluttony or sloth? Br Med J 311:437–439

    Article  CAS  Google Scholar 

  96. Röder PV, Geillinger KE, Zietek TS, Thorens B, Koepsell H, Hannelore D (2014) The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS One 9:e89977

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Caspary WF (1992) Physiology and pathophysiology of intestinal absorption. Am J Clin Nutr 55:299S–308S

    Article  CAS  PubMed  Google Scholar 

  98. Chiba S (1997) Molecular mechanism in alpha-glucosidase and glucoamylase. Biosci Biotechnol Biochem 61:1233–1239

    Article  CAS  PubMed  Google Scholar 

  99. Göke B, Fuder H, Wieckhorst G, Theiss U, Stridde E, Littke T, Kleist P, Arnold R, Lücker PW (1995) Voglibose (AO-128) is an efficient a-glucosidase inhibitor and mobilizes the endogenous GLP-1 reserve. Digestion 56:493–501

    Article  PubMed  Google Scholar 

  100. Standl E, Schernthaner G, Rybka J, Hanefeld M, Raptis SA, Naditch L (2001) Improved glycaemic control with miglitol in inadequately-controlled type 2 diabetics. Diabetes Res Clin Pract 51:205–213

    Article  CAS  PubMed  Google Scholar 

  101. Hanefeld M, Fischer S, Schulze J, Spengler M, Wargenau M, Schollberg K, Fücker K (1991) Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 14:732–737

    Article  CAS  PubMed  Google Scholar 

  102. Salman S, Salman F, Satman I, Yilmaz Y, Özer E, Sengül A, Özer H, Demirel HO, Karsidag K, Dinççag N, Yilmaz MT (2001) Comparison of acarbose and gliclazide as first-line agents in patients with type 2 diabetes. Curr Med Res Opin 16:296–306

    Article  CAS  PubMed  Google Scholar 

  103. Wang G, Liu J, Yang N, Gao X, Fan H, Xu Y, Yang W (2014) MARCH2:comparative assessment of therapeutic effects of acarbose and metformin in newly diagnosed type 2 diabetes patients. PLoS One 9:e105698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Dabhi AS, Bhatt NR, Shah MJ (2013) Voglibose: an alpha glucosidase inhibitor. J Clin Diagn Res 7:3023–3027

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Standl E, Theodorakis MJ, Erbach M, Schnell O, Tuomilehto J (2014) On the potential of acarbose to reduce cardiovascular disease. Cardiovasc Diabetol 13:81

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Ceriello A, Taboga C, Giacomello R, Stel L, Motz E, Pirisi M (1996) Post-meal coagulation activation in diabetes mellitus: the effect of acarbose. Diabetologia 39:469–473

    Article  CAS  PubMed  Google Scholar 

  107. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H (1999) Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 34:146–154

    Article  CAS  PubMed  Google Scholar 

  108. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104:2673–2678

    Article  CAS  PubMed  Google Scholar 

  109. Caumo A, Luzi L (2004) First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am J Physiol Endocrinol Metab 287:E371–E385

    Article  CAS  PubMed  Google Scholar 

  110. Lewis GF, Zinman B, Groenewoud Y, Vranic M, Giacca A (1996) Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in Humans. Diabetes 45:454–462

    Article  CAS  PubMed  Google Scholar 

  111. Calles-Escandon J, Robbins DC (1987) Loss of early phase of insulin release in humans impairs glucose tolerance and blunts thermic effect of glucose. Diabetes 36:1167–1172

    Article  CAS  PubMed  Google Scholar 

  112. Del Prato S, Miccoli R, Penno G (2005) The importance of effective early phase insulin secretion. Br J Diabetes Vasc Dis 5:198–202

    Article  Google Scholar 

  113. Gerich JE (2002) Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? Diabetes 51:S117–S121

    Article  CAS  PubMed  Google Scholar 

  114. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW (1988) Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes. Diabetes 37:736–744

    Article  CAS  PubMed  Google Scholar 

  115. Luzio SD, Owens DR, Vora J, Dolben J, Smith H (1991) Intravenous insulin simulates early insulin peak and reduces post-prandial hyperglycaemia/hyperinsulinaemia in type 2 (non-insulin-dependent) diabetes mellitus. Diabetes Res 16:63–67

    CAS  PubMed  Google Scholar 

  116. Owens DR, Luzio SD, Ismail I, Bayer T (2000) Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. Diabetes Care 23:518–523

    Article  CAS  PubMed  Google Scholar 

  117. Gromada J, Dissing S, Kofod H, Frøkjær-Jensen J (1995) Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in TC3 cells and rat pancreatic beta cells. Diabetologia 38:1025–1032

    Article  CAS  PubMed  Google Scholar 

  118. Hu S, Wang S, Fanelli B, Bell PA, Dunning BE, Geisse S, Schmitz R, Boettcher BR (2000) Pancreatic b-cell K ATP channel activity and membrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide. J Pharmacol Exp Ther 293:444–452

    CAS  PubMed  Google Scholar 

  119. Moses RG, Gomis R, Frandsen KB, Schlienger JL, Dedov I (2001) Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive Type 2 diabetes. Diabetes Care 24:11–15

    Article  CAS  PubMed  Google Scholar 

  120. Rosenstock J, Hassman DR, Madder RD, Brazinsky SA, Farrell J, Khutoryansky N, Hale PM (2004) Repaglinide versus nateglinide monotherapy: a randomized, multicenter study. Diabetes Care 27:1265–1270

    Article  CAS  PubMed  Google Scholar 

  121. Hansen AM, Christensen IT, Hansen JB, Carr RD, Ashcroft FM, Wahl P (2002) Differential interactions of nateglinide and repaglinide on the human b-cell sulphonylurea receptor 1. Diabetes 51:2789–2795

    Article  CAS  PubMed  Google Scholar 

  122. Madsbad S, Kilhovd B, Lager I, Mustajoki P, Dejgaard A, for the Scandinavian Repaglinide Group (2001) Comparison between repaglinide and glipizide in type 2 diabetes mellitus: a 1-year multicentre study. Diabet Med 18:395–401

    Article  CAS  PubMed  Google Scholar 

  123. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR (2012) Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 35:1364

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  124. Ekström N, Svensson AM, Miftaraj M, Andersson SK, Cederholm J, Zethelius B, Eliasson B, Gudbjörnsdottir S (2015) Durability of oral hypoglycemic agents in drug naïve patients with type 2 diabetes: report from the Swedish National Diabetes Register (NDR). BMJ Open Diabetes Res Care 3:e000059

    Article  PubMed Central  PubMed  Google Scholar 

  125. Moses R, Slobodniuk R, Boyages S, Colagiuri S, Kidson W, Carter J, Donnelly T, Moffitt P, Hopkins H (1999) Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 22:119–124

    Article  CAS  PubMed  Google Scholar 

  126. Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, Hansen ML, Fosbøl EL, Køber L, Norgaard ML, Madsen M, Hansen PR, Torp-Pedersen C (2011) Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 32:1900–1908

    Article  CAS  PubMed  Google Scholar 

  127. Creutzfeldt W (2005) The [pre-] history of the incretin concept. Regul Pept 128:87–91

    Article  CAS  PubMed  Google Scholar 

  128. Vilsbøll T, Krarup T, Madsbad S, Holst JJ (2003) Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 114:115–121

    Article  CAS  PubMed  Google Scholar 

  129. Eissele R, Göke R, Willemer S, Harthus HP, Vermeer H, Arnold R, Göke B (1992) Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest 22:283–291

    Article  CAS  PubMed  Google Scholar 

  130. Gorboulev V, Schürmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, Veyhl-Wichmann M, Srinivasan A, Balen D, Breljak D, Rexhepaj R, Parker HE, Gribble FM, Reimann F, Lang F, Wiese S, Sabolic I, Sendtner M, Koepsell H (2012) Na+-d-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61:187–196

    Article  CAS  PubMed  Google Scholar 

  131. Thorens B (1992) Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A 89:8641–8645

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, Yoo-Warren H, Permutt MA, Boyd AE (1993) Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor. Endocrinology 133:1907–1910

    Article  CAS  PubMed  Google Scholar 

  133. Gremlich S, Porret A, Hani EH, Cherif D, Vionnet N, Froguel P, Thorens B (1995) Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 44:1202–1208

    Article  CAS  PubMed  Google Scholar 

  134. Seino Y, Fukushima M, Yabe D (2010) GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Invest 1:8–23

    Article  CAS  Google Scholar 

  135. Salon JA, Lodowski DT, Palczewski K (2011) The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacol Rev 63:901–937

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  136. Wang MW, Liu Q, Zhou C (2010) Non-peptidic glucose-like peptide-1 receptor agonists: aftermath of a serendipitous discovery. Acta Pharmacol Sin 31:1026–1030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  137. Su H, He M, Li H, Liu Q, Wang J, Wang Y, Gao W, Zhou L, Liao J, Young AA, Wang MW (2008) Boc5, a non-peptidic glucagon-like peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice. PLoS One 3:e2892

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  138. Chen D, Liao J, Li N, Zhou C, Liu Q, Wang G, Zhang R, Zhang S, Lin L, Chen K, Nan F, Young AA, Wang MW (2007) A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. Proc Natl Acad Sci U S A 104:943–948

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Kolterman OG, Kim DD, Shen L, Ruggles JA, Nielsen LL, Fineman MS, Baron AD (2005) Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm 62:173–181

    Article  CAS  PubMed  Google Scholar 

  140. Agersø H, Jensen LB, Elbrønd B, Rolan P, Zdravkovic M (2002) The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 45:195–202

    Article  PubMed  Google Scholar 

  141. Cai Y, Wei L, Ma L, Huang X, Tao A, Liu Z, Yuan W (2013) Long-acting preparations of exenatide. Drug Des Devel Ther 7:963–970

    PubMed Central  PubMed  Google Scholar 

  142. Hansen KB, Vilsbøll T, Knop FK (2010) Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes - a review. Diabetes Metab Syndr Obes 17:155–163

    Google Scholar 

  143. Pinkney J, Fox T, Ranganath L (2010) Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide. Ther Clin Risk Manag 6:401–411

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Schlögl H, Kabisch S, Horstmann A, Lohmann G, Müller K, Lepsien J, Busse-Voigt F, Kratzsch J, Pleger B, Villringer A, Stumvoll M (2013) Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. Diabetes Care 36:1933–1940

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  145. Edwards CM, Stanley SA, Davis R, Brynes AE, Frost GS, Seal LJ, Ghatei MA, Bloom SR (2001) Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 281:E155–E161

    Article  CAS  PubMed  Google Scholar 

  146. Ando T, Haraguchi A, Matsunaga T, Natsuda S, Yamasaki H, Usa T, Kawakami A (2014) Liraglutide as a potentially useful agent for regulating appetite in diabetic patients with hypothalamic hyperphagia and obesity. Intern Med 53:1791–1795

    Article  PubMed  Google Scholar 

  147. Zoicas F, Droste M, Mayr B, Buchfelder M, Schöfl C (2013) GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases. Eur J Endocrinol 168:699–706

    Article  CAS  PubMed  Google Scholar 

  148. Matveyenko AV, Butler PC (2008) Relationship between b-cell mass and diabetes onset. Diabetes Obes Metab 10:23–31

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Demeterco C, Hao E, Lee SH, Itkin-Ansari P, Levine F (2009) Adult human b-cell neogenesis? Diabetes Obes Metab 11:46–53

    Article  CAS  PubMed  Google Scholar 

  150. Bunck MC, Cornér A, Eliasson B, Heine RJ, Shaginian RM, Taskinen MR, Smith U, Yki-Järvinen H, Diamant M (2011) Effects of exenatide on measures of b-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 34:2041–2047

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  151. Kjems LL, Holst JJ, Vølund A, Madsbad S (2003) The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52:380–386

    Article  CAS  PubMed  Google Scholar 

  152. Mondragon A, Davidsson D, Kyriakoudi S, Bertling A, Gomes-Faria R, Cohen P, Rothery S, Chabosseau P, Rutter GA, da Silva Xavier G (2014) Divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia. PLoS One 9:e104873

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  153. Rutti S, Sauter NS, Bouzakri K, Prazak R, Halban PA, Donath MY (2012) In vitro proliferation of adult human beta-cells. PLoS One 7:e35801

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  154. Toso C, McCall M, Emamaullee J, Merani S, Davis J, Edgar R, Pawlick R, Kin T, Knudsen LB, Shapiro AMJ (2010) Liraglutide, a long-acting human glucagon-like peptide 1 analogue, improves human islet survival in culture. Transpl Int 23:259–265

    Article  CAS  PubMed  Google Scholar 

  155. Bregenholt S, Møldrup A, Blume N, Karlsen AE, Friedrichsen BN, Tornhave D, Knudsen LB, Petersen JS (2005) The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits b-cell apoptosis in vitro. Biochem Biophys Res Commun 330:577–584

    Article  CAS  PubMed  Google Scholar 

  156. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) b-Cell deficit and Increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110

    Article  CAS  PubMed  Google Scholar 

  157. Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, Muller YD, Giovannoni L, Parnaud G, Berney T (2010) Unique arrangement of α- and β-cells in human Islets of Langerhans. Diabetes 59:1202–1210

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  158. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A 103:2334–2339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  159. Steiner DJ, Kim A, Miller K, Hara M (2010) Pancreatic islet plasticity: interspecies comparison of islet architecture and composition. Islets 2:135–145

    Article  PubMed  Google Scholar 

  160. Butler PC, Elashoff M, Elashoff R, Gale EAM (2013) A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care 36:2118–2125

    Article  PubMed Central  PubMed  Google Scholar 

  161. Perfetti R, Zhou J, Doyle ME, Egan JM (2000) Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose intolerant rats. Endocrinology 141:4600–4605

    Article  CAS  PubMed  Google Scholar 

  162. Nauck MA, Friedrich N (2013) Do GLP-1-based therapies increase cancer risk? Diabetes Care 36:S245–S252

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  163. Noel RA, Braun DK, Patterson RE, Bloomgren GL (2009) Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care 32:834–838

    Article  PubMed Central  PubMed  Google Scholar 

  164. David F, Bernard AM, Pierres M, Marguet D (1993) Identification of serine 624, aspartic acid 702, and histidine 734 as the catalytic triad residues of mouse dipeptidyl-peptidase IV (CD26). A member of a novel family of nonclassical serine hydrolases. J Biol Chem 268:17247–17252

    CAS  PubMed  Google Scholar 

  165. Lankas GR, Leiting B, Roy RS, Eiermann GJ, Beconi MG, Biftu T, Chan CC, Edmondson S, Feeney WP, Huaibing H, Ippolito DE, Kim D, Lyons KA, Ok HO, Patel RA, Petrov AN, Pryor KA, Qian X, Reigle L, Woods A, Wu JK, Zaller D, Zhang X, Zhu L, Weber AE, Thornberry NA (2005) Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 54:2988–2994

    Article  CAS  PubMed  Google Scholar 

  166. Lambeir A-M, Durinx C, Scharpé S, De Meester I (2013) Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPPIV. Crit Rev Clin Lab Sci 40:209–294

    Article  Google Scholar 

  167. Durinx C, Lambeir AM, Bosmans E, Falmagne JB, Berghmans R, Haemers A, Scharpé S, De Meester I (2000) Molecular characterization of dipeptidyl peptidase activity in serum. Eur J Biochem 267:5608–5613

    Article  CAS  PubMed  Google Scholar 

  168. Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O’Hare JP, Carlsson L, Kumar S, McTernan PG (2009) DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue. Diabetes Obes Metab 11:285–292

    Article  CAS  PubMed  Google Scholar 

  169. Engel M, Hoffmann T, Wagner L, Wermann M, Heiser U, Kiefersauer R, Huber R, Bode W, Demuth HU, Brandstetter H (2003) The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc Natl Acad Sci U S A 100:5063–5068

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  170. Aertgeerts K, Ye S, Tennant MG, Kraus ML, Rogers J, Sang BC, Skene RJ, Webb DR, Prasad GS (2004) Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Sci 13:412–421

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  171. Sebokova E, Christ AD, Boehringer M, Mizrahi J (2015) Dipeptidyl peptidase IV inhibitors: the next generation of new promising therapies for the management of type 2 diabetes. Curr Top Med Chem 7:547–555

    Article  Google Scholar 

  172. Shubrook J, Colucci R, Guo A, Schwartz F (2011) Saxagliptin: a selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. Clin Med Insights Endocrinol Diab 4:1–12

    CAS  Google Scholar 

  173. Toth PP (2015) Overview of saxagliptin efficacy and safety in patients with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease. Vasc Health Risk Manag 11:9–23

    CAS  PubMed  Google Scholar 

  174. Banerjee M, Younis N, Soran H (2009) Vildagliptin in clinical practice: a review of literature. Expert Opin Pharmacother 10:2745–2757

    Article  CAS  PubMed  Google Scholar 

  175. Dhillon S (2010) Sitagliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs 70:489–512

    Article  CAS  PubMed  Google Scholar 

  176. Ahrén B (2014) Insulin plus incretin: a glucose-lowering strategy for type 2-diabetes. World J Diabetes 5:40–51

    Article  PubMed Central  PubMed  Google Scholar 

  177. Pratley RE, Schweizer A, Rosenstock J, Foley JE, Banerji MA, Pi-Sunyer FX, Mills D, Dejager S (2008) Robust improvements in fasting and prandial measures of b-cell function with vildagliptin in drug-naïve patients: analysis of pooled vildagliptin monotherapy database. Diabetes Obes Metab 10:931–938

    Article  CAS  PubMed  Google Scholar 

  178. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA (2011) Effect of linagliptin monotherapy on glycaemic control and markers of b-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab 13:258–267

    Article  PubMed  Google Scholar 

  179. Ahrén B, Pacini G, Tura A, Foley JE, Schweizer A (2007) Improved meal-related insulin processing contributes to the enhancement of b-cell function by the DPP-4 inhibitor vldagliptin in patients with type 2 diabetes. Horm Metab Res 39:826–829

    Article  CAS  PubMed  Google Scholar 

  180. Yeom JA, Kim ES, Park HS, Ham DS, Sun K, Kim JW, Cho JH, Yoon KH (2011) Both sitagliptin analogue & pioglitazone preserve the beta-cell proportion in the islets with different mechanism in non-obese and obese diabetic mice. BMB Rep 44:713–718

    Article  CAS  PubMed  Google Scholar 

  181. Girgis CM, Champion BL (2011) Vildagliptin-induced acute pancreatitis. Endocr Pract 17:e48–e50

    Article  PubMed  Google Scholar 

  182. Lee CF, Sun MS, Tai YK (2014) Saxagliptin-induced recurrent acute pancreatitis. Intern Med 53:1351–1354

    Article  PubMed  Google Scholar 

  183. Chang CH, Lin JW, Chen ST, Lai MS, Cuang LM, Chang YC (2016) Dipeptidyl peptidase-4 inhibitor use is not associated with acute pancreatitis in high-risk type 2 diabetic patients: a nationwide cohort study. Medicine 95:e2603–e2609

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  184. Karagiannis T, Bekiari E, Boura P, Tsapas A (2015) Cardiovascular risk with DPP-4 inhibitors: latest evidence and clinical implications. Ther Adv Drug Saf 7:36–38

    Article  PubMed Central  PubMed  Google Scholar 

  185. Brunton S (2014) GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other? Int J Clin Pract 68:557–567

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  186. Wright EM, Loo DDF, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91:733–794

    Article  CAS  PubMed  Google Scholar 

  187. Wright EM (2001) Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 280:F10–F18

    Article  CAS  PubMed  Google Scholar 

  188. Mackenzie B, Loo DDF, Panayotova-Heiermann M, Wright EM (1996) Biophysical characteristics of the pig kidney Na+/Glucose cotransporter SGLT2 reveal a common mechanism for SGLT1 and SGLT2. J Biol Chem 271:32678–32683

    Article  CAS  PubMed  Google Scholar 

  189. Wells RG, Pajor AM, Kanai Y, Turk E, Wright EM, Hediger MA (1992) Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am J Physiol Renal Physiol 263:F459–F465

    Article  CAS  Google Scholar 

  190. Kanai Y, Lee WS, You G, Brown D, Hediger MA (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93:397–404

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  191. DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, Morrow LA, Leslie BR, Boulton DW, Ching A, LaCreta FP, Griffen SC (2013) Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 36:3169–3176

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  192. Calado J, Soto K, Clemente C, Correia P, Rueff J (2004) Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. Hum Genet 114:314–316

    Article  PubMed  Google Scholar 

  193. van den Heuvel L, Assink K, Willemsen M, Monnens L (2002) Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet 111:544–547

    Article  CAS  PubMed  Google Scholar 

  194. Gallo LA, Wright EM, Vallon V (2015) Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diabetes Vasc Dis Res 12:78–89

    Article  CAS  Google Scholar 

  195. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA (1987) Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 79:1510–1515

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  196. Isaji M (2011) SGLT2 inhibitors: molecular design and potential differences in effect. Kidney Int 79:S14–S19

    Article  CAS  Google Scholar 

  197. Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, Tsuda-Tsukimoto M (2010) Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes Mellitus. J Med Chem 53:6355–6360

    Article  CAS  PubMed  Google Scholar 

  198. Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN (2008) Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 51:1145–1149

    Article  CAS  PubMed  Google Scholar 

  199. Neumiller JJ (2014) Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. Drugs Context 3:212262

    PubMed Central  PubMed  Google Scholar 

  200. Hummel CS, Lu C, Liu J, Ghezzi C, Hirayama BA, Loo DDF, Kepe V, Barrio JR, Wright EM (2011) Structural selectivity of human SGLT inhibitors. Am J Physiol Cell Physiol 302:C373–C382

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  201. Valentine V (2015) The role of the kidney and sodium-glucose cotransporter-2 inhibition in diabetes management. Clin Diab 30:151–155

    Article  Google Scholar 

  202. Kalra S (2014) Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther 5:355–366

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  203. Dietrich E, Powell J, Taylor JR (2013) Canagliflozin: a novel treatment option for type 2 diabetes. Drug Des Devel Ther 7:1399–1408

    Article  PubMed Central  PubMed  Google Scholar 

  204. Aylsworth A, Dean Z, VanNorman C, Okere AN (2014) Dapagliflozin for the treatment of type 2 diabetes mellitus. Ann Pharmacother 48:1202–1208

    Article  CAS  PubMed  Google Scholar 

  205. Heise T, Seman L, Macha S, Jones P, Marquart A, Pinnetti S, Woerle HJ, Dugi K (2013) Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther 4:331–345

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  206. Kasichayanula S, Liu X, LaCreta F, Griffen SC, Boulton DW (2014) Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet 53:17–27

    Article  CAS  PubMed  Google Scholar 

  207. Ghezzi C, Hirayama BA, Gorraitz E, Loo DDF, Liang Y, Wright EM (2014) SGLT2 inhibitors act from the extracellular surface of the cell membrane. Physiol Rep 2:e12058

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  208. Anderson SL (2014) Dapagliflozin efficacy and safety: a perspective review. Ther Adv Drug Saf 5:242–254

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  209. Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S (2011) Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metabol 97:1020–1031

    Article  CAS  Google Scholar 

  210. Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, Parikh SJ (2011) Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 34:2015–2022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  211. Strojek K, Yoon KH, Hruba V, Sugg J, Langkilde A, Parikh S (2014) Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss Over 48-weeks: a randomized, double-blind, parallel-group, placebo-controlled trial. Diabetes Ther 5:267–283

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  212. Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S (2014) Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract 103:373–381

    Article  CAS  PubMed  Google Scholar 

  213. Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I (2016) Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol 15:37

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  214. MacIsaac RJ, Jerums G, Ekinci EI (2016) Cardio-renal protection with empagliflozin. Ann Transl Med 4:409–412

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  215. Liakos A, Karagiannis T, Bekiari E, Boura P, Tsapas A (2014) Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab 6:61–67

    Article  CAS  Google Scholar 

  216. Sosale B, Sosale A, Bhattacharyya A (2016) Clinical effectiveness and impact on insulin therapy cost after addition of dapagliflozin to patients with uncontrolled type 2 diabetes. Diabetes Ther 7:765–776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  217. Issandou M, Bouillot A, Brusq J, Forest M, Grillot D, Guillard R, Martin S, Michiels C, Sulpice T, Daugan A (2009) Pharmacological inhibition of Stearoyl-CoA Desaturase 1 improves insulin sensitivity in insulin-resistant rat models. Eur J Pharmacol 618:28–36

    Article  CAS  PubMed  Google Scholar 

  218. Lepifre F, Christmann-Franck S, Roche D, Leriche C, Carniato D, Charon C, Bozec S, Doare L, Schmidlin F, Lecomte M, Valeur E (2009) Discovery and structure-guided drug design of inhibitors of 11b-hydroxysteroid-dehydrogenase type I based on a spiro-carboxamide scaffold. Bioorg Med Chem Lett 19:3682

    Article  CAS  PubMed  Google Scholar 

  219. Birch AM, Buckett LK, Turnbull AV (2010) DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Devel 13:489–496

    CAS  PubMed  Google Scholar 

  220. Kaiser D, Oetjen E (2014) Something old, something new and something very old: drugs for treating type 2 diabetes. Br J Pharmacol 171:2940–2950

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  221. Ichimura A, Hasegawa S, Kasubuchi M, Kimura I (2014) Free fatty acid receptors as therapeutic targets for the treatment of diabetes. Front Pharmacol 5:236

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  222. Miller BR, Nguyen H, Hu CJH, Lin C, Nguyen QT (2014) New and emerging drugs and targets for type 2 diabetes: reviewing the evidence. Am Health Drug Benefits 7:452–463

    CAS  PubMed Central  PubMed  Google Scholar 

  223. Cornell S (2015) Continual evolution of type 2 diabetes: an update on pathophysiology and emerging treatment options. Ther Clin Risk Manag 11:621–632

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  224. Morgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D (2011) The cost of drug development: a systematic review. Health Policy 100:4–17

    Article  PubMed  Google Scholar 

  225. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL (2010) How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 9:203–214

    Article  CAS  PubMed  Google Scholar 

  226. Herper M (2012) The truly staggering cost of inventing new drugs. Forbes. https://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/

Download references

Author information

Authors and Affiliations

  1. Medical School, University of Buckingham, Buckingham, UK

    John C. Clapham

Authors
  1. John C. Clapham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John C. Clapham .

Editor information

Editors and Affiliations

  1. Medical School, University of Buckingham, Buckingham, Buckinghamshire, UK

    Claire J. Stocker

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Clapham, J.C. (2020). Sixty Years of Drug Discovery for Type 2 Diabetes: Where Are We Now?. In: Stocker, C. (eds) Type 2 Diabetes. Methods in Molecular Biology, vol 2076. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9882-1_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9882-1_1

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9880-7

  • Online ISBN: 978-1-4939-9882-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation