Diabetes 50:69-76, 2001
C 2001 by the American Diabetes Association, Inc.

Distinct Effects of Saturated and Monounsaturated Fatty Acids on ß-Cell
Turnover and Function
K. Maedler, G.A. Spinas, D. Dyntar, W. Moritz, N. Kaiser, and Marc Y. Donath
From the Division of Endocrinology and Diabetes (K.M., G.A.S., D.D., W.M.,
M.Y.D.), University Hospital, Zurich, Switzerland; and the Department of
Endocrinology and Metabolism (N.K.), Hebrew University-Hadassah Medical
Center, Jerusalem, Israel.

Correspondence: Address correspondence and reprint requests to Marc Donath,
MD, Division of Endocrinology and Diabetes, Department of Medicine,
University Hospital, CH-8091 Zurich, Switzerland. E-mail:
m...@d...usz.ch .


Glucotoxicity and lipotoxicity contribute to the impaired ß-cell function
observed in type 2 diabetes. Here we examine the effect of saturated and
unsaturated fatty acids at different glucose concentrations on ß-cell
proliferation and apoptosis. Adult rat pancreatic islets were cultured onto
plates coated with extracellular matrix derived from bovine corneal
endothelial cells. Exposure of islets to saturated fatty acid (0.5 mmol/l
palmitic acid) in medium containing 5.5, 11.1, or 33.3 mmol/l glucose for 4
days resulted in a five- to ninefold increase of ß-cell DNA fragmentation.
In contrast, monounsaturated palmitoleic acid alone (0.5 mmol/l) or in
combination with palmitic acid (0.25 or 0.5 mmol/l each) did not affect DNA
fragmentation. Increasing concentrations of glucose promoted ß-cell
proliferation that was dramatically reduced by palmitic acid. Palmitoleic
acid enhanced the proliferation activity in medium containing 5.5 mmol/l
glucose but had no additional effect at higher glucose concentrations (11.1
and 33.3 mmol/l). The cell-permeable ceramide analog C2-ceramide mimicked
both the palmitic acid-induced ß-cell apoptosis and decrease in
proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1
blocked the deleterious effects of palmitic acid on ß-cell viability.
Additionally, palmitic acid but not palmitoleic acid decreased the
expression of the mitochondrial adenine nucleotide translocator and induced
release of cytochrome c from the mitochondria into the cytosol. Finally,
palmitoleic acid improved ß-cell-secretory function that was reduced by
palmitic acid. Taken together, these results suggest that the lipotoxic
effect of the saturated palmitic acid involves an increased apoptosis rate
coupled with reduced proliferation capacity of ß-cells and impaired insulin
secretion. The deleterious effect of palmitate on ß-cell turnover is
mediated via formation of ceramide and activation of the apoptotic
mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid
does not affect ß-cell apoptosis, yet it promotes ß-cell proliferation at
low glucose concentrations, counteracting the negative effects of palmitic
acid as well as improving ß-cell function.