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

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16 highly suggestive that the changes in lipoprotein profile observed in DM2 could contribute to the pathogenesis and progression of beta-cell failure. Regarding the mechanism(s) by which lipotoxicity can impair beta-cell function, the emerging evidence has suggested that long-chain fattyAcylCoAs might be involved in the beta-cell dysfunction that occurs after prolonged exposure to FFAs, mediating its deleterious effects, at least in rodents, as initially proposed by Prentki and Corkey (62) and recently reviewed by Yaney and Corkey (63). According to these AA, the simultaneous presence of elevated glucose and FA results, from glucose as an oxidative fuel, in accumulation of cytosolic citrate, the precursor of malonyl-CoA,which in turn inhibits carnitine-palmitoyl-transferase-1, the enzyme responsible for transport of FA into the mitochondrium, blocking their oxidation and energy production, resulting in cytosolic accumulation of long-chain fattyAcyl-CoAs . Thus, this model proposes that glucose concentration plays a critical role in the effect of FAs. Whether long-chain AcylCoA accumulation directly affects beta-cell function or whether it serves as a precursor for other active molecules such as diacylglycerols or phospholipids directly activating PKC isoforms somehow synergizing with glucose to enhance insulin secretion was not characterized while the nature of the effectors downstream of lipid metabolite accumulation remains unknown (62, 63, 64). As reported by Poitout and Robertson (64) the “malonyl-CoA/Long chain- AcylCoA” proposed as a biochemical basis for lipotoxicity implies that the effects of FA are greatly influenced by concomitant glucose concentration. Therefore, in the presence of physiological glucose concentrations elevated FA should be readily oxidized in the mitochondrion and should not harm the beta-cell. Under circumstances where both FA and glucose are elevated, accumulation of metabolites derived from FA esterification would inhibit glucose-induction insulin secretion and insulin gene expression. Thus, glucotoxicity and lipotoxicity are closely interrelated, in the sense that lipotoxicity does not exist without chronic hyperglycemia. Furthermore, the effects of glucose on lipid metabolism are so intense that according to these AA (64) lipotoxicity can be viewed as one mechanism of glucotoxicity. Hence, generation of reactive oxygen species may be an alternative mechanism of both gluco- and lipotoxicity. In effect, exposure of islets to palmitate induces
17 generation of reactive oxygen species (65) and treatment of islets with metformin, which has antioxidant properties protecting from deleterious effects of FAs (66). C. Pro-inflammatory cytokines and leptin The chronic increase in inflammatory mediators observed in DM2 might affect not only insulin-sensitive tissues and blood vessel walls but could also affect pancreatic beta- cells. In addition to genetic factors, developmentof DM2, with a central role for the functional beta-cell mass, is strongly influenced by environmental factors, including decreased physical activity, nutrition and obesity, as well known. This promotes the following factors, which are possible mediators of an inflammatory process (67). 1. Adipocyte-secreted factors Locally produced hormones and cytokines possess important auto/paracrine properties. Some are also released into circulation and have endocrine effects. In particular, leptin, tumor necrosis factor-α (TNF-α), interleukin (IL)6 and IL-1 receptor antagonist (IL-1Ra) are produced and secreted by fat tissue, being increased in obesity and have been causally linked to insulin resistance (18, 68). Leptin is expressed primarily in adipose tissue representing the most obvious exponent of the adipocyte. Recently, leptin has also been considered as a pro-inflammatory cytokine because of its structural similarity with other cytokines and its receptor induced signaling pathways (69). In rodent islets leptin induces beta-cell proliferation and protects from FFA-induced beta-cell apoptosis. In contrast, chronic exposure of human islets to leptin leads to beta-cell apoptosis via increasing release of interleukin-1 β(IL-1β) and decreasing release of IL-1Ra in the islets (70). Other cytokines released by adipocytes, including TNF-α and IL-6, may also modulate beta-cell survival, although it is unclear if the amount released into the circulation is sufficient to affect beta-cells (70). Furthermore, it may well be that these cytokines are only effective in the presence of other cytokines. 2. Increased cell nutrients Elevated glucose concentrations and FFAs,in addition to their role of cell nutrients, also have a dual effect on beta-cell turnover. Depending on duration of exposure to glucose or FFA and on the genetic background of the islets, glucose and FFAs may induce beta-cell
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 and 14: 13 time-dependent establishment of
Page 15: 15 that plasma FFA support between
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 and 60: 59 available to enable comparison o
Page 61 and 62: 61 mathematical model. In a similar
Page 63 and 64: 63 to an excessive glucose producti
Page 65 and 66: 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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