An update on the effect of incretin-based therapies on β-cell function and mass

Diabetes and Metabolism Journal

Volumn 40, Issue 2, 2016, Pages 99-114

  Chon, Suk ^a   Gautier, Jean François ^b,c,d  

^a Kyung Hee University Hospital   (South Korea)

^b HÔPITAL LARIBOISIÈRE   (France)

^c SAINT LOUIS HOSPITAL   (France)

^d CENTRE DE RECHERCHE DES CORDELIERS   (France)

Author keywords

Diabetes mellitus; Dipeptidyl peptidase 4 inhibitor; Glucagon like peptide 1 receptor agonist; Incretins; Insulin secreting cells

Indexed keywords

ALBIGLUTIDE; ALOGLIPTIN; ALPHA GLUCOSIDASE INHIBITOR; ANAGLIPTIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; DULAGLUTIDE; ETANERCEPT; EXENDIN 4; GASTRIC INHIBITORY POLYPEPTIDE; GEMIGLIPTIN; GLIMEPIRIDE; GLITAZONE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INCRETIN; INSULIN; INSULIN GLARGINE; LINAGLIPTIN; LIRAGLUTIDE; LIXISENATIDE; METFORMIN; MK 0626; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; SULFONYLUREA; UNCLASSIFIED DRUG; VILDAGLIPTIN;

ADD ON THERAPY; ANTIDIABETIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; AREA POSTREMA; AREA UNDER THE CURVE; AUTOPHAGY; BLOOD GLUCOSE MONITORING; CALCIUM MOBILIZATION; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL PROTECTION; DISEASE COURSE; DOWN REGULATION; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DOSAGE FORM COMPARISON; DRUG HALF LIFE; DRUG WITHDRAWAL; ENDOPLASMIC RETICULUM STRESS; ENZYME INHIBITION; EXOCYTOSIS; GLUCOSE HOMEOSTASIS; GLUCOSE INFUSION; GLUCOSE TRANSPORT; GLUCOTOXICITY; GLYCEMIC CONTROL; HUMAN; HYPERGLYCEMIA; IMPAIRED GLUCOSE TOLERANCE; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN LIKE ACTIVITY; INSULIN RESISTANCE; MEMBRANE DEPOLARIZATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE STRESS; PANCREAS ISLET BETA CELL; PANCREAS ISLET CELL FUNCTION; PANCREAS ISLET DISEASE; PATHOGENESIS; PROTEIN SYNTHESIS; REVIEW; SOLITARY TRACT NUCLEUS; UPREGULATION; WEIGHT GAIN;

EID: 84964725797     PISSN: 22336079     EISSN: 22336087     Source Type: Journal    
DOI: 10.4093/dmj.2016.40.2.99     Document Type: Review

References (102)

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;58:773-95.
2. 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;44:1249-58.
3. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-43.
4. Chon S, Riveline JP, Blondeau B, Gautier JF. Incretin-based therapy and pancreatic beta cells. Diabetes Metab 2014;40: 411-22.
5. Zunz E, La Barre J. Contributiona a l'etude des variations physiologiques de la secretion interne du pancreas: relations entre les secretions externe et interne du pancreas. Arch Int Physiol Biochim 1929;31:20-44.
6. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964;24:1076-82.
7. Yabe D, Seino Y. Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Prog Biophys Mol Biol 2011;107:248-56.
8. Rorsman P, Renstrom E. Insulin granule dynamics in pancreatic beta cells. Diabetologia 2003;46:1029-45.
9. Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol 1989;257(2 Pt 1):E241-6.
10. Steiner KE, Mouton SM, Bowles CR, Williams PE, Cherrington AD. The relative importance of first-and secondphase insulin secretion in countering the action of glucagon on glucose turnover in the conscious dog. Diabetes 1982; 31:964-72.
11. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153-65.
12. Meloni AR, DeYoung MB, Lowe C, Parkes DG. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obes Metab 2013; 15:15-27.
13. Fehmann HC, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucosedependent insulin releasing polypeptide. Endocr Rev 1995; 16:390-410.
14. Holz GG. Epac: a new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. Diabetes 2004;53:5-13.
15. Phillips LK, Prins JB. Update on incretin hormones. Ann N Y Acad Sci 2011;1243:E55-74.
16. Burcelin R, Da Costa A, Drucker D, Thorens B. Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes 2001;50:1720-8.
17. Cabou C, Burcelin R. GLP-1, the gut-brain, and brain-periphery axes. Rev Diabet Stud 2011;8:418-31.
18. Ahren B. Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice. Am J Physiol Regul Integr Comp Physiol 2004;286:R269-72.
19. Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Gremeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF, Delzenne NM, Postic C, Burcelin R. Brain glucagonlike peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest 2005;115:3554-63.
20. Dalle S, Burcelin R, Gourdy P. Specific actions of GLP-1 receptor agonists and DPP4 inhibitors for the treatment of pancreatic β-cell impairments in type 2 diabetes mellitus. Cell Signal 2013;25:570-9.
21. Widenmaier SB, Ao Z, Kim SJ, Warnock G, McIntosh CH. Suppression of p38 MAPK and JNK via Akt-mediated inhibition of apoptosis signal-regulating kinase 1 constitutes a core component of the beta-cell pro-survival effects of glucose-dependent insulinotropic polypeptide. J Biol Chem 2009;284: 30372-82.
22. Klinger S, Poussin C, Debril MB, Dolci W, Halban PA, Thorens B. Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response element modulator-alpha and DUSP14. Diabetes 2008;57: 584-93.
23. Porte D Jr. Clinical importance of insulin secretion and its interaction with insulin resistance in the treatment of type 2 diabetes mellitus and its complications. Diabetes Metab Res Rev 2001;17:181-8.
24. Ferner RE, Ashworth L, Tronier B, Alberti KG. Effects of short-term hyperglycemia on insulin secretion in normal humans. Am J Physiol 1986;250(6 Pt 1):E655-61.
25. Guillausseau PJ, Meas T, Virally M, Laloi-Michelin M, Medeau V, Kevorkian JP. Abnormalities in insulin secretion in type 2 diabetes mellitus. Diabetes Metab 2008;34 Suppl 2:S43-8.
26. 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;104:787-94.
27. 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;52:102-10.
28. Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 2003;88:2300-8.
29. 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.
30. Meier JJ, Breuer TG, Bonadonna RC, Tannapfel A, Uhl W, Schmidt WE, Schrader H, Menge BA. Pancreatic diabetes manifests when beta cell area declines by approximately 65% in humans. Diabetologia 2012;55:1346-54.
31. Ward WK, Bolgiano DC, McKnight B, Halter JB, Porte D Jr. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest 1984;74:1318-28.
32. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 2003;52: 581-7.
33. Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 1995;44:863-70.
34. Prentki M, Joly E, El-Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in betacell adaptation and failure in the etiology of diabetes. Diabetes 2002;51 Suppl 3:S405-13.
35. Ahren B. Incretin dysfunction in type 2 diabetes: clinical impact and future perspectives. Diabetes Metab 2013;39:195-201.
36. Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med 2011;124(1 Suppl):S3-18.
37. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 2011;54:10-8.
38. Hansen KB, Vilsboll T, Bagger JI, Holst JJ, Knop FK. Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects. J Clin Endocrinol Metab 2012;97:1363-70.
39. Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context 2015;4:212283.
40. Barnett AH. Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes. Core Evid 2011;6:67-79.
41. Wang C, Chen X, Ding X, He Y, Gu C, Zhou L. Exendin-4 promotes beta cell proliferation via PI3k/Akt signalling pathway. Cell Physiol Biochem 2015;35:2223-32.
42. Zhao Q, Yang Y, Hu J, Shan Z, Wu Y, Lei L. Exendin-4 enhances expression of Neurod1 and Glut2 in insulin-producing cells derived from mouse embryonic stem cells. Arch Med Sci 2016;12:199-207.
43. Abe H, Uchida T, Hara A, Mizukami H, Komiya K, Koike M, Shigihara N, Toyofuku Y, Ogihara T, Uchiyama Y, Yagihashi S, Fujitani Y, Watada H. Exendin-4 improves β-cell function in autophagy-deficient β-cells. Endocrinology 2013;154:4512-24.
44. Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M, Knudsen LB. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab 2002;283: E745-52.
45. Bregenholt S, Moldrup A, Blume N, Karlsen AE, Nissen Friedrichsen B, Tornhave D, Knudsen LB, Petersen JS. The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro. Biochem Biophys Res Commun 2005;330:577-84.
46. Shimoda M, Kanda Y, Hamamoto S, Tawaramoto K, Hashiramoto M, Matsuki M, Kaku K. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia 2011;54:1098-108.
47. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17:819-37.
48. Ellenbroek JH, Tons HA, Westerouen van Meeteren MJ, de Graaf N, Hanegraaf MA, Rabelink TJ, Carlotti F, de Koning EJ. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice. Diabetologia 2013;56:1980-6.
49. Zheng J, Chen T, Zhu Y, Li HQ, Deng XL, Wang QH, Zhang JY, Chen LL. Liraglutide prevents fast weight gain and β-cell dysfunction in male catch-up growth rats. Exp Biol Med (Maywood) 2015;240:1165-76.
50. Koehler JA, Baggio LL, Cao X, Abdulla T, Campbell JE, Secher T, Jelsing J, Larsen B, Drucker DJ. Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis. Diabetes 2015;64:1046-56.
51. Yang C, Loehn M, Jurczyk A, Przewozniak N, Leehy L, Herrera PL, Shultz LD, Greiner DL, Harlan DM, Bortell R. Lixisenatide accelerates restoration of normoglycemia and improves human beta-cell function and survival in diabetic immunodeficient NOD-scid IL-2rg(null) RIP-DTR mice engrafted with human islets. Diabetes Metab Syndr Obes 2015; 8:387-98.
52. Tian L, Gao J, Weng G, Yi H, Tian B, O'Brien TD, Guo Z. Comparison of exendin-4 on beta-cell replication in mouse and human islet grafts. Transpl Int 2011;24:856-64.
53. He ZX, Zhou ZW, Yang Y, Yang T, Pan SY, Qiu JX, Zhou SF. Overview of clinically approved oral antidiabetic agents for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2015;42:125-38.
54. van Genugten RE, van Raalte DH, Diamant M. Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence. Diabetes Obes Metab 2012;14:101-11.
55. Flock G, Baggio LL, Longuet C, Drucker DJ. Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes 2007;56:3006-13.
56. Hamamoto S, Kanda Y, Shimoda M, Tatsumi F, Kohara K, Tawaramoto K, Hashiramoto M, Kaku K. Vildagliptin preserves the mass and function of pancreatic β cells via the developmental regulation and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetes Obes Metab 2013;15:153-63.
57. Omar BA, Vikman J, Winzell MS, Voss U, Ekblad E, Foley JE, Ahren B. Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model. Diabetologia 2013;56:1752-60.
58. Wu YJ, Guo X, Li CJ, Li DQ, Zhang J, Yang Y, Kong Y, Guo H, Liu DM, Chen LM. Dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits pancreatic beta cell apoptosis in association with its effects suppressing endoplasmic reticulum stress in db/db mice. Metabolism 2015;64:226-35.
59. Shah P, Ardestani A, Dharmadhikari G, Laue S, Schumann DM, Kerr-Conte J, Pattou F, Klein T, Maedler K. The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization. J Clin Endocrinol Metab 2013;98:E1163-72.
60. Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, Butler AE, Butler PC. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes 2009;58:1604-15.
61. Morita A, Mukai E, Hiratsuka A, Takatani T, Iwanaga T, Lee EY, Miki T. Distinct effects of dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 receptor agonist on islet morphology and function. Endocrine 2016;51:429-39.
62. Campbell RK. Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus. Clin Ther 2011; 33:511-27.
63. Bunck MC, Diamant M, Corner A, Eliasson B, Malloy JL, Shaginian RM, Deng W, Kendall DM, Taskinen MR, Smith U, Yki-Jarvinen H, Heine RJ. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care 2009;32:762-8.
64. Chang AM, Jakobsen G, Sturis J, Smith MJ, Bloem CJ, An B, Galecki A, Halter JB. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2003;52:1786-91.
65. Vilsboll T, Brock B, Perrild H, Levin K, Lervang HH, Kolendorf K, Krarup T, Schmitz O, Zdravkovic M, Le-Thi T, Madsbad S. Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with type 2 diabetes mellitus. Diabet Med 2008;25:152-6.
66. Madsbad S. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics). Preclinical and clinical results. Best Pract Res Clin Endocrinol Metab 2009;23:463-77.
67. Bolli GB, Munteanu M, Dotsenko S, Niemoeller E, Boka G, Wu Y, Hanefeld M. Efficacy and safety of lixisenatide once daily vs. placebo in people with type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet Med 2014;31: 176-84.
68. Kapitza C, Forst T, Coester HV, Poitiers F, Ruus P, Hincelin Mery A. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab 2013;15:642-9.
69. Edwards KL, Minze MG. Dulaglutide: an evidence-based review of its potential in the treatment of type 2 diabetes. Core Evid 2015;10:11-21.
70. Bunck MC, Corner A, Eliasson B, Heine RJ, Shaginian RM, Taskinen MR, Smith U, Yki-Jarvinen H, Diamant M. Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 2011;34:2041-7.
71. Gallwitz B, Guzman J, Dotta F, Guerci B, Simo R, Basson BR, Festa A, Kiljanski J, Sapin H, Trautmann M, Schernthaner G. 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;379:2270-8.
72. Garber A, Henry RR, Ratner R, Hale P, Chang CT, Bode B; LEAD-3 (Mono) Study Group. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab 2011;13:348-56.
73. Mari A, Scherbaum WA, Nilsson PM, Lalanne G, Schweizer A, Dunning BE, Jauffret S, Foley JE. 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;93:103-9.
74. Aaboe K, Knop FK, Vilsboll T, Deacon CF, Holst JJ, Madsbad S, Krarup T. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2010;12:323-33.
75. Scherbaum WA, Schweizer A, Mari A, Nilsson PM, Lalanne G, Jauffret S, Foley JE. Efficacy and tolerability of vildagliptin in drug-naive patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab 2008;10:675-82.
76. Ahren B, Pacini G, Foley JE, Schweizer A. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care 2005; 28:1936-40.
77. Foley JE, Bunck MC, Moller-Goede DL, Poelma M, Nijpels G, EekhoffEM, Schweizer A, Heine RJ, Diamant M. Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naïve patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial. Diabetologia 2011;54:1985-91.
78. Esposito K, Chiodini P, Maiorino MI, Bellastella G, Capuano A, Giugliano D. Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials. BMJ Open 2014;4:e005442.
79. Leibowitz G, Cahn A, Bhatt DL, Hirshberg B, Mosenzon O, Wei C, Jermendy G, Sheu WH, Sendon JL, Im K, Braunwald E, Scirica BM, Raz I. Impact of treatment with saxagliptin on glycaemic stability and β-cell function in the SAVOR-TIMI 53 study. Diabetes Obes Metab 2015;17:487-94.
80. Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev 2016;32:289-96.
81. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Response to comments on: Butler et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62:2595-604.
82. Kahn SE. Incretin therapy and islet pathology: a time for caution. Diabetes 2013;62:2178-80.
83. Harja E, Lord J, Skyler JS. An analysis of characteristics of subjects examined for incretin effects on pancreatic pathology. Diabetes Technol Ther 2013;15:609-18.
84. Bonner-Weir S, In't Veld PA, Weir GC. Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies. Diabetes Obes Metab 2014;16:661-6.
85. Egan AG, Blind E, Dunder K, de GraeffPA, Hummer BT, Bourcier T, Rosebraugh C. Pancreatic safety of incretin-based drugs: FDA and EMA assessment. N Engl J Med 2014;370: 794-7.
86. Sheffield CA, Kane MP, Busch RS. Off-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection. Pharmacotherapy 2007;27:1449-55.
87. Dupre J, Behme MT, McDonald TJ. Exendin-4 normalized postcibal glycemic excursions in type 1 diabetes. J Clin Endocrinol Metab 2004;89:3469-73.
88. Rother KI, Spain LM, Wesley RA, Digon BJ 3rd, Baron A, Chen K, Nelson P, Dosch HM, Palmer JP, Brooks-Worrell B, Ring M, Harlan DM. Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care 2009;32:2251-7.
89. Dejgaard TF, Frandsen CS, Hansen TS, Almdal T, Urhammer S, Pedersen-Bjergaard U, Jensen T, Jensen AK, Holst JJ, Tarnow L, Knop FK, Madsbad S, Andersen HU. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2016;4:221-32.
90. Hari Kumar KV, Shaikh A, Prusty P. Addition of exenatide or sitagliptin to insulin in new onset type 1 diabetes: a randomized, open label study. Diabetes Res Clin Pract 2013;100:e55-8.
91. Ghofaili KA, Fung M, Ao Z, Meloche M, Shapiro RJ, Warnock GL, Elahi D, Meneilly GS, Thompson DM. Effect of exenatide on beta cell function after islet transplantation in type 1 diabetes. Transplantation 2007;83:24-8.
92. Faradji RN, Froud T, Messinger S, Monroy K, Pileggi A, Mineo D, Tharavanij T, Mendez AJ, Ricordi C, Alejandro R. Long-term metabolic and hormonal effects of exenatide on islet transplant recipients with allograft dysfunction. Cell Transplant 2009;18:1247-59.
93. Gangemi A, Salehi P, Hatipoglu B, Martellotto J, Barbaro B, Kuechle JB, Qi M, Wang Y, Pallan P, Owens C, Bui J, West D, Kaplan B, Benedetti E, Oberholzer J. Islet transplantation for brittle type 1 diabetes: the UIC protocol. Am J Transplant 2008; 8:1250-61.
94. Cechin SR, Perez-Alvarez I, Fenjves E, Molano RD, Pileggi A, Berggren PO, Ricordi C, Pastori RL. Anti-inflammatory properties of exenatide in human pancreatic islets. Cell Transplant 2012;21:633-48.
95. Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simoes BP, Martinez EZ, Foss MC, Burt RK, Voltarelli JC. Cpeptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009;301: 1573-9.
96. Kim SJ, Nian C, Doudet DJ, McIntosh CH. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes 2009;58:641-51.
97. Levine F, Itkin-Ansari P. Beta-cell regeneration: neogenesis, replication or both? J Mol Med (Berl) 2008;86:247-58.
98. Parnaud G, Bosco D, Berney T, Pattou F, Kerr-Conte J, Donath MY, Bruun C, Mandrup-Poulsen T, Billestrup N, Halban PA. Proliferation of sorted human and rat beta cells. Diabetologia 2008;51:91-100.
99. Tiedge M. Inside the pancreas: progress and challenges of human beta cell mass quantification. Diabetologia 2014;57:856-9.
100. Nakashima R, Yano T, Ogawa J, Tanaka N, Toda N, Yoshida M, Takano R, Inoue M, Honda T, Kume S, Matsumoto K. 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.
101. Dalboge LS, Almholt DL, Neerup TS, Vrang N, Jelsing J, Fosgerau K. The novel GLP-1-gastrin dual agonist ZP3022 improves glucose homeostasis and increases β-cell mass without affecting islet number in db/db mice. J Pharmacol Exp Ther 2014; 350:353-60.
102. Ansarullah, Lu Y, Holstein M, DeRuyter B, Rabinovitch A, Guo Z. Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor. PLoS One 2013;8: e53345.