Biochemical mechanisms linking liver disease in diabetes

S Andrikopoulos

University of Melbourne Department of Medicine

Increased hepatic glucose production is a cardinal defect contributing to fasting hyperglycaemia in type 2 diabetes. Despite much effort the exact mechanisms causing increased hepatic glucose output are not known. We and others have previously shown that obesity/high fat diets can contribute to excess glucose production by providing substrates as well as dampening the suppressive effects of insulin (hepatic insulin resistance) on the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase) and glucose-6-phosphatase (G6Pase). To further understand the role of increased hepatic glucose production on dysglycaemia we have generated a number of genetically-modified animal models including a liver specific transgenic FBPase mouse and PEPCK rat. FBPase transgenic mice displayed increased gluconeogenic capacity and hepatic glucose output associated with glucose intolerance, despite lower food intake and body weight. That a specific upregulation of a liver gluconeogenic enzyme would reduce appetite was surprising and was associated with increased fatty acid oxidation and plasma ketone levels and reduced neuropeptide-Y and agouti-related peptide in the hypothalamus. PEPCK transgenic rats displayed increased weight gain, hepatic glucose production as well as muscle/fat insulin resistance and impaired insulin secretion – that is, a primary increase in glucose production was capable of causing defects in other tissues. In addition increased hepatic glucose production alone was not enough to result in hyperglycaemia and glucose intolerance without the concomitant presence of muscle/fat insulin resistance and reduced insulin secretion. Correcting the body weight of PEPCK transgenic rats in pair-feeding experiments improved glucose tolerance associated with enhanced glucose disposal and increased muscle/fat glucose uptake. Our body of work highlights the importance of increased liver glucose production in causing defects in other sites affecting glucose metabolism and indeed contributing to hyperglycaemia and glucose intolerance. Furthermore, we provide support that the liver can also regulate appetite and lead to changes in body weight that can further adversely affect glucose homeostasis. Thus the liver plays a complex role in glucose and body weight homeostasis that a therapeutic strategy needs to consider for the effective management of type 2 diabetes.