title: Chronic effects of fatty acids on pancreatic beta-cell function: new insights from functional genomics.
abstract: Type 2 diabetes can be viewed as a failure of the pancreatic beta-cell to compensate for peripheral insulin resistance with enhanced insulin secretion. This failure is explained by both a relative loss of beta-cell mass as well as secretory defects that include enhanced basal secretion and a selective loss of sensitivity to glucose. These features are reproduced by chronic exposure of beta-cells to fatty acids (FAs), suggesting that hyperlipidemia might contribute to decompensation. Using MIN6 cells pretreated for 48 h with oleate or palmitate, we have previously defined alterations in global gene expression by transcript profiling and described additional secretory changes to those already established (Busch A-K, Cordery D, Denyer G, Biden TJ: Diabetes 51:977-987, 2002). In contrast to a modest decoupling of glucose-stimulated insulin secretion, FA pretreatment markedly enhanced the secretory response to an acute subsequent challenge with FAs. We propose that this apparent switch in sensitivity from glucose to FAs would be an appropriate response to hyperlipidemia in vivo and thus plays a positive role in beta-cell compensation for insulin resistance. Altered expression of dozens of genes could contribute to this switch, and allelic variations in any of these genes could (to varying degrees) impair beta-cell compensation and thus contribute to conditions ranging from impaired glucose tolerance to frank diabetes.
authors.affiliation: Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia. t.biden@garvan.org.au
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Biden
authors.forename: Darren
authors.initials: D
authors.lastname: Robinson
authors.forename: Damien
authors.initials: D
authors.lastname: Cordery
authors.forename: William E
authors.initials: WE
authors.lastname: Hughes
authors.forename: Anna K
authors.initials: AK
authors.lastname: Busch
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology; D005227:Fatty Acids / Q000494:pharmacology*; D023281:Genomics; D006801:Humans; D006949:Hyperlipidemias / Q000503:physiopathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*
chemical_list: D005227:Fatty Acids