Targeting glucagon receptor signalling in treating metabolic syndrome and renal injury in Type 2 diabetes: theory versus promise

Pancreatic bi-hormones insulin and glucagon are the Yin and Yang in the regulation of glucose metabolism and homoeostasis. Insulin is synthesized primarily by pancreatic β-cells and is released in response to an increase in blood glucose levels (hyperglycaemia). By contrast, glucagon is synthesized by pancreatic α-cells and is released in response to a decrease in blood glucose (hypoglycaemia). The principal role of glucagon is to counter the actions of insulin on blood glucose homoeostasis, but it also has diverse non-hyperglycaemic actions. Although Type 1 diabetes is caused by insulin deficiency (insulin-dependent) and can be corrected by insulin replacement, Type 2 diabetes is a multifactorial disease and its treatment is not dependent on insulin therapy alone. Type 2 diabetes in humans is characterized by increased insulin resistance, increased fasting blood glucose, impaired glucose tolerance and the development of glomerular hyperfiltration and microalbuminuria, ultimately leading to diabetic nephropathy and end-stage renal disease. Clinical studies have suggested that an inappropriate increase in hyperglycaemic glucagon (hyperglucagonaemia) over hypoglycaemic insulin (not insulin deficiency until advanced stages) plays an important role in the pathogenesis of Type 2 diabetes. However, for decades, research efforts and resources have been devoted overwhelmingly to studying the role of insulin and insulin-replacement therapy. By contrast, the implication of glucagon and its receptor signalling in the development of Type 2 diabetic metabolic syndromes and end-organ injury has received little attention. The aim of this review is to examine the evidence as to whether glucagon and its receptor signalling play any role(s) in the pathogenesis of Type 2 diabetic renal injury, and to explore whether targeting glucagon receptor signalling remains only a theoretical antidiabetic strategy in Type 2 diabetes or may realize its promise in the future.