Chronic effects of palmitate overload on nutrient-induced insulin secretion and autocrine signalling in pancreatic MIN6 beta cells

• Published in: PloS one Vol. 6; no. 10; p. e25975
• Main Authors: Watson, Maria L, Macrae, Katherine, Marley, Anna E, Hundal, Harinder S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05-10-2011; Public Library of Science (PLoS)
• Subjects: Activation; AKT protein; Amino acids; Amino Acids - pharmacology; Analysis; Animals; Apoptosis - drug effects; Autocrine Communication - drug effects; Autocrine signalling; Beta cells; Biology; Ca2+/calmodulin-dependent protein kinase II; Calcium; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; Cell Line; Ceramide; Chronic effects; Diglycerides; Enzyme Activation - drug effects; Esterification; Extracellular signal-regulated kinase; Fatty acids; Glucose; Glucose - pharmacology; Inhibition; Insulin; Insulin - metabolism; Insulin resistance; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Kinases; Lipids; Medicine; Mitochondria; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Nutrient release; Nutrients; Oxidation; Palmitates - pharmacology; Palmitic acid; Pancreas; Pancreatic beta cells; Pharmacology; Protein folding; Protein kinases; Reduction; Saturated fatty acids; Secretion; Signal Transduction - drug effects; Stimulus-secretion coupling; Synthesis; Time Factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025975

Sustained 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.
GSIS 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.
Our 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.