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

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14 transcription factors regulating beta-cell differentiation and function. Markers of oxidative stress, such as nitrotyrosine and 8-hydroxy-2’-deoxyguanosine concentrations, were significantly higher in DM2 than control islets and correlated with the degree of glucose- stimulated insulin release impairement. The addition of glutathione in the incubation medium determined reduction of oxidative stress (as suggested by diminished levels of nitrotyrosine) improved glucose-stimulated insulin secretion and increased insulin mRNA expression. Thus, the AA concluded that the functional impairment of DM2 islets could be, at least in part, reversible by reducing islet cell oxidative stress.It is important to emphasize that in this study the percentage of beta-cells was only slightly (~10%), although significantly, reduced in diabetic islets compared with control islets. As reasoned by Robertson et al. (47), if the steady decline in beta-cell function in DM2 is attributable to any significant extent to ongoing apoptosis via chronic oxidative stress with no deterioration in beta-cell replication, then interference with apoptosis by antioxidants or any other therapy, might provide a much needed new approach to conventional treatment that could stabilize beta-cell mass. B. Lipotoxicity Diabetes is associated with dyslipidemia characterized by an increase in circulating free fatty acid (FFAs) and changes in lipoprotein profile. In healthy humans besides the hyperinsulinemia induced by an acute elevation of FFAs there is also an increase in glucose-stimulated insulin secretion following prolonged FFA infusion (48 and 96 hours) (54, 55) but not in non-diabetic individuals genetically predisposed to developing DM2 (55). In healthy control subjects the FFA-induced insulin resistance was compensated by the enhanced insulin secretion while persistently elevated FFAs may contribute to progressive beta-cell failure (beta cell lipotoxicity) in individuals genetically predisposed to DM 2. Santomauro et al. (56) have demonstrated that overnight administration of the nicotinic acid analogue Acipimox lowered plasma FFA as well as fasting insulin and glucose levels, reduced insulin resistance and improved oral glucose tolerance with decreased insulin levels in lean and obese nondiabetic subjects and in subjects with impaired glucose tolerance and DM2. The significant decrease in insulin levels suggested
15 that plasma FFA support between 30-50% of basal insulin levels. A sustained (7-day) reduction in plasma FFA concentrations in DM 2, with Acipimox, was also associated with enhanced insulin-stimulated glucose disposal (reduced insulin resistance) associated with a decreased content of intramyocellular long-chain fatty acids and improvement in oral glucose tolerance test with a slight decrease in mean plasma insulin levels (57). These data suggest that physiological increases in plasma FFA concentrations in humans potentiate glucose-stimulated insulin secretion and are unlikely to be “lipotoxic” to beta-cells (58) but may contribute to progressive beta-cell failure in at least some individuals who are genetically predisposed to developing DM 2 (55). For all studies reported in relation to the FFA-beta-cell interaction it is important to emphasize that the stimulatory effects on glucose-stimulated insulin secretion are physiological in nature, particularly during the fasted to fed transition. Circulating FFAs help maintain a basal rate of insulin secretion, keeping adipose tissue lipolysis in check. In rodent islets, increased FFAs have been shown to be pro-apoptotic in beta-cell (59). Exposure of cultured human islets to saturated fatty acids such as palmitate are highly toxic to the beta cell inducing beta-cell apoptosis, decreased beta-cell proliferation and impaired beta-cell function. In contrast the mono-unsaturated fatty acids such as oleate are protective against both palmitate and glucose-induced apoptosis and increase in proliferation. The deleterious effect of palmitic acid was mediated via ceramide- mitochondrial apoptotic pathways whereas induction of the mitochondrial protein Bcl-2 by oleic acid may contribute to the protective effect of monounsaturated fatty acids, such as palmitoleic or oleic acids (60). A similar balance between pro- and anti-apoptotic effects is found for lipoprotein action on insulin-secreting cells from mouse pancreatic islets. The sole available study testing the hypothesis that lipoproteins modulate the function and survival of the cells, has demonstrated that purified human VLDL and LDL particles reduced insulin mRNA levels and beta-cell proliferation and were pro-apoptotic whilst HDL protected beta-cells against these pro-apoptotic effects. The protective effects of HDL were mediated, partially at least, by inhibition of caspase-3 cleavage and activation of Akt/ protein kinase B while pro- apoptotic lipoproteins seem to act via c-Jun N-terminal kinase (JNK) (61). These results are
Page 1 and 2: Endocrine Reviews. First published
Page 3 and 4: 3 Sitagliptin (MK-0431) Vildaglipti
Page 5 and 6: 5 associated with impairment of bet
Page 7 and 8: 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: 13 time-dependent establishment of
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
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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
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Page 61 and 62: 61 mathematical model. In a similar
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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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