The role fructose-1,6-bisphosphatase on the regulation of hepatic gluconeogenesis

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Type 2 or adult onset diabetes is a disease characterised by high blood sugar that causes damage to the kidneys, eyes and to the circulation and many patients die from heart attack or stroke. There is an increase in the prevalence of diabetes in Australia and a substantial portion of the health budget is utilised by caring for people with diabetes. Determining what exactly causes the increase in blood sugar levels is critical in the treatment of the disease. It is known that the sugar produced and released by the liver is an important contributor to the high blood sugar levels found in patients with diabetes. The main biochemical pathway responsible for this is called gluconeogenesis, a complex arrangement of enzymes, which convert amino acids and fat into sugar. Although it is known that this pathway is overactive in patients with diabetes, the exact reason for this is not clearly understood. The aim of this proposal is to produce a transgenic mouse that has an increase in liver sugar production as a result of an increase in gluconeogenesis, and to study its effects on blood sugar levels. Furthermore, studies will be performed to understand the regulation of this pathway by infusing the transgenic mice with insulin, the hormone that inhibits gluconeogenesis. The mechanism of action of insulin will be determined by the measurement of key enzymes that regulate gluconeogenesis. The significance of this grant is to identify possible sites for the development of new drugs or gene therapy that will lead to a decrease in the production of sugar by the liver. This will lead to better control of blood sugar levels and slow down or even prevent the onset of diabetes complications.