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Ulrika Krus

Coupling mechanisms of insulin secretion - roles of mitochondrial metabolism and cAMP

Type 2 diabetes is a disease that increases tremendously in the western world. It is characterized by insulin resistance and defects in insulin secretion. Insulin resistance is tightly linked to obesity, and usually precedes the onset of type 2 diabetes. When insulin resistance develops, the pancreatic beta-cells compensate by increasing their secretion of insulin, causing hyperinsulinemia. This state may bot be a major risk factor per se; in fact, many people develop severe inuslin resistance and hypoinsulinemia without ever acquiring diabetes.

However, beta-cells in some individuals, perhaps genetically predisposed, are unable to increase their secretion sufficiently to meet the new requirements. This leads to hyperglycemia, the main hallmark of diabetes. To be able to treat diabetes, the defects in the beta-cells causing impaired insulin secretion must be elucidated.

The aim of this theis was to investigate the mechansims of insulin secretion, and especially what couples glucose stimulation of the beta-cell to insulin secretion.
We have found that anaplerosis via pyruvate carboxylase is essential for both phases of glucose-stimulated insulin secretion, presumably via generation of an increased ATP/ADP ratio. Further, we discovered that expression of PDK1 is upregulated in INS-1 832/13 cells cultured at high concentrations of glucose, and that knock-down of PDK1 enhances insulin secretion. both these findings prove that mitochondrial metabolism is important for insulin secretion, and points to the involvement of pyruvate cycling.

We have also showed that PKA signaling is stimulated by glucose, and that inhibition of PKA decreases glucose-stimulated insulin secretion in INS-1 832/13 cells.

More information

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00