Effects of Glucose and Free Fatty Acids on ERK1/2 in Pancreatic B-Cells
Arnette, Donald Ervin, Jr.
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Diabetes is a growing problem in the United States. There is a growing occurrence of obesity in the United States, which directly adds to the incidence and occurrence of diabetes. Our lab has previously showed that the extracellular signal-regulated protein kinases (ERKs) 1 and 2 are activated by elevated concentrations of glucose and are involved in insulin transcription. In this study we examine the mechanism by which glucose induces ERK1/2 activity. The effects of free fatty acids on ERK1/2 activity were also examined. In this study a rat insulinoma cell line was used. The rat insulinoma cell line INS-1 is a model system which is commonly used to represent pancreatic ᭣ells. Elevated glucose activates ERK1/2 in INS-1 cells. With the use of several pharmacological agents which interrupt calcium signaling, it was concluded that calcium signaling is involved in glucose-induced ERK1/2 activation. Calmodulin and the calmodulin-dependent phosphatase calcineurin were determined to be required for glucose-induced ERK1/2 activity as well as glucagons-like peptide induced ERK1/2 activity. This activation was also shown to require the release of calcium from intracellular stores. It has been well documented that free fatty acids (FFAs) have negative effects on pancreatic ᭣ells. FFAs have been shown to decrease insulin secretion. The effects ofFFAs on ERK1/2 activity were also examined. Chronic exposure of FFAs causes constitutive activation of ERK1/2 in INS-1 cells. This constitutive activity of ERK1/2 was determined to be protein kinase C (PKC) independent. The FFA-induced ERK1/2 activity resulted in a ERK1/2 nuclear localization pattern that is dramatically different from the usual pattern of ERK1/2 nuclear localization. It has been previously shown that ERK1/2 phosphorylate insulin transcription factors that are required for maximal glucose-induced insulin transcription. This altered ERK1/2 nuclear localization may affect the phosphorylation of these transcription factors, which might explain how chronic exposure to FFAs inhibits insulin transcription.