Involvement of steatosis-induced glucagon resistance in hyperglucagonaemia

For more than a century type 2 diabetes has been looked upon mainly as an insulin-related disease and it is well-acknowledged that insulin resistance and beta cell dysfunction play important roles in the pathophysiology of the disease. During the last couple of decades, glucagon has also been recognised to play a significant role in type 2 diabetic pathophysiology. However, the mechanisms underlying disturbances in the regulation of glucagon remain unclear. Glucagon constitutes the primary stimulus for hepatic glucose production and, thus, upholds adequate blood glucose levels during fasting conditions. Many - but not all - patients with type 2 diabetes are characterised by inappropriately elevated plasma levels of glucagon contributing to their hyperglycaemic state. We believe that phenotypical dissimilarities within this group of patients may determine the presence and degree of hyperglucagonaemia. Results from our group show that both normoglycaemic individuals and patients with type 2 diabetes with non-alcoholic fatty liver disease (NAFLD) exhibit fasting hyperglucagonaemia compared to similarly grouped individuals without NAFLD. Therefore, we speculate that NAFLD - and not type 2 diabetes per se - is the main driver behind fasting hyperglucagonaemia. We hypothesise that in the majority of type 2 diabetic individuals hepatic sensitivity to glucagon is compromised due to hepatic steatosis, and that this provides a feedback mechanism acting at the level of pancreatic alpha cells, leading to elevated levels of glucagon. Here we present our hypothesis and propose a way to test it. If our hypothesis holds true, hepatic glucagon resistance would constitute a parallel to the obesity-induced insulin resistance in muscle and liver tissue, and underpin a central role for glucagon in the pathogenesis of type 2 diabetes. This would provide a crucial step forward in understanding the interaction between NAFLD and the alpha cell in the pathophysiology underlying type 2 diabetes.