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

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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