Improving glycaemic control in type 2 diabetes: Stimulate insulin secretion or provide beta-cell rest?

Diabetes, Obesity and Metabolism

Volumn 19, Issue 9, 2017, Pages 1205-1213

  van Raalte, Daniël H ^a,b   Verchere, C Bruce ^b  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^b UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

beta cell; clinical trial; glycaemic control; islets; type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; INCRETIN; INSULIN; METFORMIN; SODIUM GLUCOSE COTRANSPORTER 2; SULFONYLUREA; ANTIDIABETIC AGENT;

BARIATRIC SURGERY; CELL FUNCTION; DRUG EFFICACY; EARLY INTERVENTION; FOOD INTAKE; GLUCOSE BLOOD LEVEL; GLYCEMIC CONTROL; HEART DEATH; HUMAN; INSULIN RELEASE; INSULIN TREATMENT; LIFESTYLE; NON INSULIN DEPENDENT DIABETES MELLITUS; PANCREAS ISLET BETA CELL; PANCREAS ISLET CELL FUNCTION; POSTPRANDIAL STATE; PROTEIN SYNTHESIS INHIBITION; REVIEW; COMBINATION DRUG THERAPY; COMPLICATION; DIABETIC COMPLICATION; DIABETIC DIET; DRUG EFFECTS; EVIDENCE BASED MEDICINE; EXERCISE; HEALTHY LIFESTYLE; HYPERGLYCEMIA; HYPOGLYCEMIA; METABOLISM; MULTIMODALITY CANCER THERAPY; SECRETION (PROCESS); TRENDS;

COMBINED MODALITY THERAPY; DIABETES COMPLICATIONS; DIABETES MELLITUS, TYPE 2; DIET, DIABETIC; DRUG THERAPY, COMBINATION; EVIDENCE-BASED MEDICINE; EXERCISE; HEALTHY LIFESTYLE; HUMANS; HYPERGLYCEMIA; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS; INSULIN; INSULIN-SECRETING CELLS;

EID: 85020562001     PISSN: 14628902     EISSN: 14631326     Source Type: Journal    
DOI: 10.1111/dom.12935     Document Type: Review

References (99)

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. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104:787-794.
3. U.K. Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258.
4. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.
5. Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med. 1998;15:290-296.
6. Kahn SE, Lachin JM, Zinman B, et al. Effects of rosiglitazone, glyburide, and metformin on beta-cell function and insulin sensitivity in ADOPT. Diabetes. 2011;60:1552-1560.
7. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728-742.
8. Halban PA, Polonsky KS, Bowden DW, et al. Beta-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014;37:1751-1758.
9. Hull RL, Westermark GT, Westermark P, Kahn SE. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab. 2004;89:3629-3643.
10. Montane J, Klimek-Abercrombie A, Potter KJ, Westwell-Roper C, Bruce Verchere C. Metabolic stress, IAPP and islet amyloid. Diabetes Obes Metab. 2012;14(suppl 3):68-77.
11. Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci U S A. 1987;84:8628-8632.
12. Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab. 2013;17:860-872.
13. Ehses JA, Perren A, Eppler E, et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes. 2007;56:2356-2370.
14. Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic beta-cell death. Trends Endocrinol Metab. 2011;22:266-274.
15. Dai C, Kayton NS, Shostak A, et al. Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest. 2016;126:1857-1870.
16. Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, Garcia-Ocana A, Stewart AF. Diabetes mellitus--advances and challenges in human beta-cell proliferation. Nat Rev Endocrinol. 2015;11:201-212.
17. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102-110.
18. Hostens K, Ling Z, Van Schravendijk C, Pipeleers D. Prolonged exposure of human beta-cells to high glucose increases their release of proinsulin during acute stimulation with glucose or arginine. J Clin Endocrinol Metab. 1999;84:1386-1390.
19. Henquin JC, Dufrane D, Kerr-Conte J, Nenquin M. Dynamics of glucose-induced insulin secretion in normal human islets. Am J Physiol Endocrinol Metab. 2015;309:E640-650.
20. Eizirik DL, Jansson L, Flodstrom M, Hellerstrom C, Andersson A. Mechanisms of defective glucose-induced insulin release in human pancreatic islets transplanted to diabetic nude mice. J Clin Endocrinol Metab. 1997;82:2660-2663.
21. Jansson L, Eizirik DL, Pipeleers DG, Borg LA, Hellerstrom C, Andersson A. Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice. J Clin Invest. 1995;96:721-726.
22. Qvigstad E, Kollind M, Grill V. Nine weeks of bedtime diazoxide is well tolerated and improves beta-cell function in subjects with Type 2 diabetes. Diabet Med. 2004;21:73-76.
23. Song SH, Rhodes CJ, Veldhuis JD, Butler PC. Diazoxide attenuates glucose-induced defects in first-phase insulin release and pulsatile insulin secretion in human islets. Endocrinology. 2003;144:3399-3405.
24. Aston-Mourney K, Proietto J, Morahan G, Andrikopoulos S. Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin. Diabetologia. 2008;51:540-545.
25. Rustenbeck I, Baltrusch S, Tiedge M. Do insulinotropic glucose-lowering drugs do more harm than good? The hypersecretion hypothesis revisited. Diabetologia. 2010;53:2105-2111.
26. Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab. 2008;10(suppl 4):32-42.
27. Abdulreda MH, Rodriguez-Diaz R, Caicedo A, Berggren PO. Liraglutide compromises pancreatic beta cell function in a humanized mouse model. Cell Metab. 2016;23:541-546.
28. Retnakaran R, Zinman B. Short-term intensified insulin treatment in type 2 diabetes: long-term effects on beta-cell function. Diabetes Obes Metab. 2012;14(suppl 3):161-166.
29. van Raalte DH, Bunck MC, Smits MM, et al. Exenatide improves beta-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial. Eur J Endocrinol. 2016;175:345-352.
30. Gallwitz B, Guzman J, Dotta F, et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet. 2012;379:2270-2278.
31. Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY. Sulfonylurea induced beta-cell apoptosis in cultured human islets. J Clin Endocrinol Metab. 2005;90:501-506.
32. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-2157.
33. Plamboeck A, Veedfald S, Deacon CF, et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol. 2013;304:G1117-1127.
34. Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:2719-2725.
35. Buse JB; the Leader Steering Committee. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:1798-1799.
36. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.
37. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-2257.
38. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-242.
39. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335.
40. Shah P, Ardestani A, Dharmadhikari G, et al. The DPP-4 inhibitor linagliptin restores beta-cell function and survival in human isolated islets through GLP-1 stabilization. J Clin Endocrinol Metab. 2013;98:E1163-1172.
41. Cunha DA, Ladriere L, Ortis F, et al. Glucagon-like peptide-1 agonists protect pancreatic beta-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB. Diabetes. 2009;58:2851-2862.
42. Park YJ, Ao Z, Kieffer TJ, et al. The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation. Diabetologia. 2013;56:508-519.
43. Pugazhenthi U, Velmurugan K, Tran A, Mahaffey G, Pugazhenthi S. Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients. Diabetologia. 2010;53:2357-2368.
44. Bunck MC, Corner A, Eliasson B, et al. Effects of exenatide on measures of beta-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care. 2011;34:2041-207.
45. Foley JE, Bunck MC, Moller-Goede DL, et al. Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial. Diabetologia. 2011;54:1985-1991.
46. Retnakaran R, Kramer CK, Choi H, Swaminathan B, Zinman B. Liraglutide and the preservation of pancreatic beta-cell function in early type 2 diabetes: the LIBRA trial. Diabetes Care. 2014;37:3270-3278.
47. Mari A, Scherbaum WA, Nilsson PM, et al. Characterization of the influence of vildagliptin on model-assessed -cell function in patients with type 2 diabetes and mild hyperglycemia. J Clin Endocrinol Metab. 2008;93:103-109.
48. van Raalte DH, Verchere CB. Glucagon-like peptide-1 receptor agonists: beta-cell protection or exhaustion? Trends Endocrinol Metab. 2016;27:442-445.
49. Mari A, Del Prato S, Ludvik B, et al. Differential effects of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide and metformin on pancreatic beta-cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18:834-839.
50. Nauck MA, Petrie JR, Sesti G, et al. A phase 2, randomized, dose-finding 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. Vilsboll T. SUSTAIN – 6 clinical and metabolic outcomes. EASD Oral Presentation # S353; Munich, Germany, September 16th, 2016 EASD conference. Available at: http://www.easdvirtualmeeting.org/contentsessions/2382
52. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
53. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015;3:866-875.
54. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54:2506-2514.
55. Steven S, Hollingsworth KG, Al-Mrabeh A, et al. Very low-calorie diet and 6 months of weight stability in type 2 diabetes: pathophysiological changes in responders and nonresponders. Diabetes Care. 2016;39:808-815.
56. 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.
57. Kitabchi AE, Temprosa M, Knowler WC, et al. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes. 2005;54:2404-2414.
58. Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371:1753-1760.
59. Alvarsson M, Sundkvist G, Lager I, et al. Effects of insulin vs. glibenclamide in recently diagnosed patients with type 2 diabetes: a 4-year follow-up. Diabetes Obes Metab. 2008;10:421-429.
60. Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013;1:28-34.
61. Investigators OT, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319-328.
62. Campbell IW, Mariz S. Beta-cell preservation with thiazolidinediones. Diabetes Res Clin Pract. 2007;76:163-176.
63. Gupta D, Kono T, Evans-Molina C. The role of peroxisome proliferator-activated receptor gamma in pancreatic beta cell function and survival: therapeutic implications for the treatment of type 2 diabetes mellitus. Diabetes Obes Metab. 2010;12:1036-1047.
64. Zeender E, Maedler K, Bosco D, Berney T, Donath MY, Halban PA. Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. J Clin Endocrinol Metab. 2004;89:5059-5066.
65. Lupi R, Del Guerra S, Marselli L, et al. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPARgamma2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab. 2004;286:E560-567.
66. Lin CY, Gurlo T, Haataja L, Hsueh WA, Butler PC. Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3′-kinase-dependent pathway. J Clin Endocrinol Metab. 2005;90:6678-6686.
67. Zhang F, Sjoholm A, Zhang Q. Pioglitazone acutely influences glucose-sensitive insulin secretion in normal and diabetic human islets. Biochem Biophys Res Commun. 2006;351:750-755.
68. Vandewalle B, Moerman E, Lefebvre B, et al. PPARgamma-dependent and -independent effects of rosiglitazone on lipotoxic human pancreatic islets. Biochem Biophys Res Commun. 2008;366:1096-1101.
69. Knowler WC, Hamman RF, Edelstein SL, et al. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes. 2005;54:1150-1156.
70. Xiang AH, Peters RK, Kjos SL, et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes. 2006;55:517-522.
71. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51:2796-2803.
72. DeFronzo RA, Tripathy D, Schwenke DC, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364:1104-1115.
73. Investigators DT, Gerstein HC, Yusuf S, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368:1096-1105.
74. DREAM On (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication Ongoing Follow-up) Investigators, Gerstein HC, Mohan V, Avezum A, et al. Long-term effect of rosiglitazone and/or ramipril on the incidence of diabetes. Diabetologia. 2011;54:487-495.
75. Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care. 2015;38:2344-2353.
76. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
77. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512-517.
78. Muscelli E, Astiarraga B, Barsotti E, et al. Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes. Diabetologia. 2016;59:700-708.
79. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190-1195.
80. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia. 2014;57:891-901.
81. Del Prato S, Nauck M, Duran-Garcia S, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17:581-590.
82. Meier JJ, Rosenstock J, Hincelin-Mery A, et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care. 2015;38:1263-1273.
83. Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3082-3089.
84. Cervera A, Wajcberg E, Sriwijitkamol A, et al. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab. 2008;294:E846-852.
85. van Bloemendaal L, IJzerman RG, Ten Kulve JS, et al. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes. 2014;63:4186-4196.
86. Mari A, Nielsen LL, Nanayakkara N, DeFronzo RA, Ferrannini E, Halseth A. Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea. Horm Metab Res. 2006;38:838-844.
87. Sjostrom L. Review of the key results from the Swedish Obese Subjects (SOS) trial – a prospective controlled intervention study of bariatric surgery. J Intern Med. 2013;273:219-234.
88. Schauer PR, Mingrone G, Ikramuddin S, Wolfe B. Clinical outcomes of metabolic surgery: efficacy of glycemic control, weight loss, and remission of diabetes. Diabetes Care. 2016;39:902-911.
89. Batterham RL, Cummings DE. Mechanisms of diabetes improvement following bariatric/metabolic surgery. Diabetes Care. 2016;39:893-901.
90. Nannipieri M, Baldi S, Mari A, et al. Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. J Clin Endocrinol Metab. 2013;98:4391-4399.
91. Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G. First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes Care. 2009;32:375-380.
92. Manning S, Pucci A, Batterham RL. GLP-1: a mediator of the beneficial metabolic effects of bariatric surgery? Physiology (Bethesda). 2015;30:50-62.
93. Breen DM, Rasmussen BA, Kokorovic A, Wang R, Cheung GW, Lam TK. Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nat Med. 2012;18:950-955.
94. Nathan DM, Buse JB, Kahn SE, et al. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care. 2013;36:2254-2261.
95. Consortium R. Restoring Insulin Secretion (RISE): design of studies of beta-cell preservation in prediabetes and early type 2 diabetes across the life span. Diabetes Care. 2014;37:780-788.
96. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015;17:268-275.
97. DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care. 2010;33:951-957.
98. Panza F, Seripa D, Solfrizzi V, et al. Emerging drugs to reduce abnormal beta-amyloid protein in Alzheimer's disease patients. Expert Opin Emerg Drugs. 2016;21:377-391.
99. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014;13:465-476.