1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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60 In contrast with GLP-1R agonists, which are administered via injection, the DPP-IV inhibitors, sitagliptin and vildagliptin, accepted for review by the FDA, are administered orally and are well tolerated. Major adverse effects have not been reported in clinical trials examining the efficacy of DPP-IV inhibitors for the treatment of DM2. In healthy subjects a single dose of 100mg or higher of sitagliptin resulted in inhibition of plasma DDP-IV activity over 24 hours by at least 80%, increasing meal- associated rise in active plasma GLP-1 levels two fold without hypoglycemia. Phase III studies with sitagliptin + ongoing metformin and sitagliptin + ongoing pioglitazone, has indicated an improvement in HbA1c and glycemic control as well post-meal indices of β-cell function. The effect of sitagliptin on beta-cell function, assessed by frequently sampled meal tolerance tests in 3 sub-studies from phase III using the C-peptide minimal model, showed improvement in beta-cell responsiveness to basal and above-basal glucose concentrations components following the meals. The dynamic component (beta-cell responsiveness to the rate of increase in above-basal glucose levels following a meal) showed numerical but not significant improvements with sitagliptin. Disposition indices were also improved. Preclinical studies have demonstrated that vildagliptin increased beta-cell mass by increasing the number of replicating islet cells and reducing the number of apoptotic islet cells as assessed in neonatal rats, a model for rapid beta-cell turnover and growth.The head-to-head comparison of vildagliptin with exenatide in a mouse model of streptozotocin-induced beta-cell injury showed that both had a protective effect against beta-cell injury, promoted early differentiation of pancreatic progenitor cells and increased formation of ductal beta-cells, improving glucose tolerance with the effect being maintained after the treatment washout. Although vildagliptin reduced postprandial glucose in DM2 it did not increase post- meal insulin levels during 4-12 week treatment. In diet-treated DM2 oral glucoseload (75g) provided an intense glucose stimulus for insulin secretion when compared to a standard breakfast meal test. In drug naïve patients, 4-week treatment with vildagliptin (100mg bid) improved β-cell function by increasing insulin secretion at any glucose level while the slope of β-cell dose response and the potentiation factor were not affected using a
61 mathematical model. In a similar study over 52 weeks of vildagliptin added to metformin treated DM2, an improvement was demonstrated in beta-cell function, with enhanced postprandial insulin secretion, increased insulin sensitivity and “dispostion index”. Twelve week treatment of drug-naïve DM2 with vildagliptin (50 mg bid) restored the acute insulin response to glucose (AIRg) and sensitivity index(Si) determined by FSIVGTT. The disposition index (AIRg x Si) increased >4-fold and part of its effect remained after 2-4 week washout, suggesting that vildagliptin may exert some disease-modifying effect. Three recent studies have been carried out in the same line as for sitagliptin. One study compared vildagliptin (50mg bid) monotherapy with metformin over 52 weeks, with better sustained control with the DPP-IV inhibitor. In the second study, vildagliptin (50 mg qd or bid) was added to metformin with improvement of glycemic control slightly better with the larger dose. The third study compared vildagliptin (100 mg qd) with placebo in insulin-requiring DM2. After 24 weeks, there was a reduction in HbA1c and in the mean insulin doses. Single-dose studies indicate that sitagliptin and vildagliptin have similar clinical efficiency in reducing the glucose excursion after oral glucose.Data are not yet available to enable comparison of the efficacies of both products in chronic use. Potential effects on preservation and augmentation of β-cell mass Regarding the most important question concerning both GLP-1 analogs, GLP-1R activators and DPP-IV inhibitors(incretin enhancers) – incretin mimetics - is whether they will be able to slow or prevent the apparently inevitable progress of the DM2,considering their trophic effects on beta-cells (249), not only stimulating their proliferation (185, 250) but also enhancing the differentiation of new beta-cells from progenitor cells in the pancreatic duct epithelium (251) and, perhaps most importantly, being capable of inhibiting apoptosis of the beta cells including human beta cells (195). Since the normal number of beta-cells is maintained in a balace between apoptosis and proliferation, the protective effects of incretin mimetics could be relevant under conditions in which beta-cell apoptosis is increased, such as in DM2 (4). Since, for obvious reasons, it is difficult to estimate the protective effects of incretin mimetics on beta-cells in humans there is no clinical evidences that these drugs really have protective effects on beta cells
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Endocrine Reviews. First published
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3 Sitagliptin (MK-0431) Vildaglipti
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5 associated with impairment of bet
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7 kindreds (but not similar obese c
Page 9 and 10: 9 It is well recognized that the re
Page 11 and 12: 11 Opinions diverge regarding the r
Page 13 and 14: 13 time-dependent establishment of
Page 15 and 16: 15 that plasma FFA support between
Page 17 and 18: 17 generation of reactive oxygen sp
Page 19 and 20: 19 D. Islet-cell amyloid The releva
Page 21 and 22: 21 reduced beta-cell mass can lead
Page 23 and 24: 23 Numbering among the factors for
Page 25 and 26: 25 greater recovery of beta-cell fu
Page 27 and 28: 27 These effects could be dissociat
Page 29 and 30: 29 in in vitro studies in rodent an
Page 31 and 32: 31 suppression of TNF-α expression
Page 33 and 34: 33 Zeender et al. (127) were able t
Page 35 and 36: 35 comparison with both placebo and
Page 37 and 38: 37 Diabetes Prevention Program (DPP
Page 39 and 40: 39 with significant improvement in
Page 41 and 42: 41 mediated by inhibition of glucag
Page 43 and 44: 43 with DM2 (81, 180, 170). Its sub
Page 45 and 46: 45 Table 2. Effects of incretin (GL
Page 47 and 48: 47 Three similarly designed 6-month
Page 49 and 50: 49 function:early (first-phase) ins
Page 51 and 52: 51 whereas the sub-acute effect is
Page 53 and 54: 53 Concerning the potential mediato
Page 55 and 56: 55 in 741 patients with DM2, random
Page 57 and 58: 57 cell function was examined in dr
Page 59: 59 available to enable comparison o
Page 63 and 64: 63 to an excessive glucose producti
Page 65 and 66: 2 14. Weyer C,Bogardus C,Mott DM,Pr
Page 67 and 68: 4 39. Clark A,Wells CA,Buley ID Cru
Page 69 and 70: 6 63. Yaney GC,Corkey BE 2003 Fatty
Page 71 and 72: 8 89. Bell DSH 2004 Management of t
Page 73 and 74: 10 113. Dubois M,Pattou F,Carr-Cont
Page 75 and 76: 12 135. Li J,Tian H,Ren Y,Yu H,Wang
Page 77 and 78: 14 158 Hansen L, Holst JJ 2005 The
Page 79 and 80: 16 183. Farilla L,Hui H,Bertolloto
Page 81 and 82: 18 206. Visboll T,Agerso H,Krarup T
Page 83 and 84: 20 229. Herman GA,Zhao P-L,Dietrich
Page 85: 22 250. Stoffers DA,Kieffer TJ,Huss
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