1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
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14<br />
transcription factors regulating beta-cell differentiation and function. Markers of oxidative<br />
stress, such as nitrotyrosine and 8-hydroxy-2’-deoxyguanosine concentrations, were<br />
significantly higher in DM2 than control islets and correlated with the degree of glucose-<br />
stimulated insulin release impairement. The addition of glutathione in the incubation<br />
medium determined reduction of oxidative stress (as suggested by diminished levels of<br />
nitrotyrosine) improved glucose-stimulated insulin secretion and increased insulin mRNA<br />
expression. Thus, the AA concluded that the functional impairment of DM2 islets could be,<br />
at least in part, reversible by reducing islet cell oxidative stress.It is important to emphasize<br />
that in this study the percentage of beta-cells was only slightly (~10%), although<br />
significantly, reduced in diabetic islets compared with control islets. As reasoned by<br />
Robertson et al. (47), if the steady decline in beta-cell function in DM2 is attributable to<br />
any significant extent to ongoing apoptosis via chronic oxidative stress with no<br />
deterioration in beta-cell replication, then interference with apoptosis by antioxidants or any<br />
other therapy, might provide a much needed new approach to conventional treatment that<br />
could stabilize beta-cell mass.<br />
B. Lipotoxicity<br />
Diabetes is associated with dyslipidemia characterized by an increase in circulating<br />
free fatty acid (FFAs) and changes in lipoprotein profile. In healthy humans besides the<br />
hyperinsulinemia induced by an acute elevation of FFAs there is also an increase in<br />
glucose-stimulated insulin secretion following prolonged FFA infusion (48 and 96 hours)<br />
(54, 55) but not in non-diabetic individuals genetically predisposed to developing DM2<br />
(55). In healthy control subjects the FFA-induced insulin resistance was compensated by<br />
the enhanced insulin secretion while persistently elevated FFAs may contribute to<br />
progressive beta-cell failure (beta cell lipotoxicity) in individuals genetically predisposed to<br />
DM 2. Santomauro et al. (56) have demonstrated that overnight administration of the<br />
nicotinic acid analogue Acipimox lowered plasma FFA as well as fasting insulin and<br />
glucose levels, reduced insulin resistance and improved oral glucose tolerance with<br />
decreased insulin levels in lean and obese nondiabetic subjects and in subjects with<br />
impaired glucose tolerance and DM2. The significant decrease in insulin levels suggested