The elucidation of the mode of glucagon action in regulation of carbohydrate metabolism is directly related to a better understanding of the causes of hyperglycemia in the diabetic state. One of the sites of glucagon action occurs at the fructose 6-phosphate - fructose 1,6-bisphosphate interconversion step, but the molecular mechanism(s) by which glucagon acts on this step remains to be established. To gain an insight into these mechanisms, it is the objective of this proposal to study the enzymes involved in the above metabolic step, namely phosphofructokinase and fructose 1,6-bisphosphatase. In this general context, this research will cover: (a) Studies on liver phosphofructokinase from C57BL/KsJ normal and diabetic mice; (b) Studies of in vitro proteolysis of fructose 1,6-bisphosphatase by proteases from C57BL/KsJ normal and diabetic mice; (c) Studies on the identification of amino acid residues and/or regions involved in the function and regulation of fructose 1,6-bisphosphatase. The genetically diabetic mouse to be used in these studies (C57BL/KsJ-db) is characterized by prevailing hyperglucagonemia accompanied by a lack of effective circulating insulin, and is considered to be a model system of human maturity onset diabetes.
