Abstract
BackgroundSustained exposure of pancreatic β cells to an increase in saturated fatty acids induces pleiotropic effects on β-cell function, including a reduction in stimulus-induced insulin secretion. The objective of this study was to investigate the effects of chronic over supply of palmitate upon glucose- and amino acid-stimulated insulin secretion (GSIS and AASIS, respectively) and autocrine-dependent insulin signalling with particular focus on the importance of ceramide, ERK and CaMKII signalling.Principal FindingsGSIS and AASIS were both stimulated by >7-fold resulting in autocrine-dependent activation of protein kinase B (PKB, also known as Akt). Insulin release was dependent upon nutrient-induced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) as their pharmacological inhibition suppressed GSIS/AASIS significantly. Chronic (48 h, 0.4 mM) palmitate treatment blunted glucose/AA-induced activation of CaMKII and ERK and caused a concomitant reduction (∼75%) in GSIS/AASIS and autocrine-dependent activation of PKB. This inhibition could not be attributed to enhanced mitochondrial fatty acid uptake/oxidation or ceramide synthesis, which were unaffected by palmitate. In contrast, diacylglycerol synthesis was elevated suggesting increased palmitate esterification rather than oxidation may contribute to impaired stimulus-secretion coupling. Consistent with this, 2-bromopalmitate, a non-oxidisable palmitate analogue, inhibited GSIS as effectively as palmitate.ConclusionsOur results exclude changes in ceramide content or mitochondrial fatty acid handling as factors initiating palmitate-induced defects in insulin release from MIN6 β cells, but suggest that reduced CaMKII and ERK activation associated with palmitate overload may contribute to impaired stimulus-induced insulin secretion.
Highlights
Hyperlipidemia is one of a cluster of abnormalities associated with the metabolic syndrome, which promotes insulin resistance, but results in the dysfunction of numerous cellular responses in tissues such as skeletal muscle [1], heart [2], liver [3], adipose [4] and the pancreas [5]
Our results exclude changes in ceramide content or mitochondrial fatty acid handling as factors initiating palmitate-induced defects in insulin release from MIN6 b cells, but suggest that reduced calmodulindependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) activation associated with palmitate overload may contribute to impaired stimulus-induced insulin secretion
Palmitate induces a loss in glucose- and amino acidstimulated insulin secretion and induces apoptosis in MIN6 b cells
Summary
Hyperlipidemia is one of a cluster of abnormalities associated with the metabolic syndrome, which promotes insulin resistance, but results in the dysfunction of numerous cellular responses in tissues such as skeletal muscle [1], heart [2], liver [3], adipose [4] and the pancreas [5]. Fatty acids are thought to play an essential role in GSIS augmenting the glucose-induced secretion of insulin [8,9]. Fatty acids are free in the cytosol of beta cells, and, under these circumstances, are channelled into mitochondria for b-oxidation and generation of ATP [10] and do not promote any detectable increase in insulin secretion. Upon feeding, the rise in blood glucose promotes insulin release from beta cells by a mechanism involving the inactivation (closure) of plasma membrane K+ATP channels, but glucose will contribute to metabolic anaplerosis. Citrate produced in the mitochondria from glucose metabolism will form malonyl-CoA in the cytosol [11,12], which prevents b-oxidation by inhibiting carnitine palmitoyltransferase (CPT-1), thereby allowing an increase in long chain fatty acids which can stimulate insulin secretion. The objective of this study was to investigate the effects of chronic over supply of palmitate upon glucose- and amino acid-stimulated insulin secretion (GSIS and AASIS, respectively) and autocrine-dependent insulin signalling with particular focus on the importance of ceramide, ERK and CaMKII signalling
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