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

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2 3. Thiazolidinediones (TZDs) a) Effect of TZDs on beta-cells 1) Animal data 2)In vitro data in human beta-cells 3) Mechanism of action of TZDs on the beta-cell Indirect effects by amelioration of insulin sensitivity Direct effects via PPARγ activation in pancreatic islets 4) Further clinical evidences of TZDs effects on human beta-cell function 5)TZDs in the prevention of diabetes Troglitazone in prevention of diabetes (TRIPOD) Pioglitazone in prevention of diabetes (PIPOD) 4. Incretin mimetics and enhancers Diabetes Prevention Program (DPP) TZD therapy in the prevention/delay of type 2 diabetes in patients with IFG+IGT. a) Effect of incretin (GLP-1, incretin mimetics and enhancers on β-cells 1) Animal data 2) In vitro data in human beta-cells 3) Clinical evidences of incretin mimetics effects on human beta-cell function GLP-1 receptor agonists: Exenatide Liraglutide Dipeptidyl peptidase-IV(DPP-IV) inhibitors (enhancers)
3 Sitagliptin (MK-0431) Vildagliptin (LAF-237) 4) Potential effects on preservation and augmentation of beta-cell mass Disclosure statement: The author has nothing to disclose. Abbreviations : AIR g , Acute insulin response to IV glucose; AGEs, advanced glycation end-products; AUC, area under a curve; CSII, continuous subcutaneous insulin infusion; DM 2, type 2 diabetes mellitus; DPP-IV, dipeptidyl peptidase –IV; ER, endoplasmic reticulum; FA, fatty acid; FFAs, free fatty acids; FSIVGTT, frequently sampled intravenous glucose tolerance test; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon like peptide-1; GLP-1R, GLP-1 receptor; HOMA, homeostasis model assessment; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment of beta-cell function; IAPP, islet amyloid polypeptide; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IL, interleukin; M, insulin-stimulated glucose disposal; ROS, reactive oxygen species; TZDs, thiazolidinediones; TNF-α, tumor necrosis factor-α; UKPDS, United Kingdom Prospective Diabetes Study. I. Introduction It is well known that there is a progressive deterioration in beta-cell function over time in type 2 diabetes (DM2), as indicated by the UKPDS (United Kingdom Prospective Diabetes Study) (1,2), regardless of therapy allocation, albeit conventional (mainly diet), insulin, chlorpropamide, glibenclamide or metformin treatment. Moreover, the pancreatic islet function was found to be about 50% of normal at the time of diagnosis, independent of the degree of insulin resistance, with the reduction in function probably commencing 10-12 years prior to diagnosis and aggravated by increasing fasting plasma glucose levels (3). The
Page 1: Endocrine Reviews. First published
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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
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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
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Page 51 and 52: 51 whereas the sub-acute effect is
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53 Concerning the potential mediato
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55 in 741 patients with DM2, random
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57 cell function was examined in dr
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59 available to enable comparison o
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2 14. Weyer C,Bogardus C,Mott DM,Pr
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4 39. Clark A,Wells CA,Buley ID Cru
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6 63. Yaney GC,Corkey BE 2003 Fatty
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8 89. Bell DSH 2004 Management of t
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10 113. Dubois M,Pattou F,Carr-Cont
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12 135. Li J,Tian H,Ren Y,Yu H,Wang
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14 158 Hansen L, Holst JJ 2005 The
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16 183. Farilla L,Hui H,Bertolloto
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18 206. Visboll T,Agerso H,Krarup T
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20 229. Herman GA,Zhao P-L,Dietrich
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22 250. Stoffers DA,Kieffer TJ,Huss
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