Glucagon is produced by alpha cells in the pancreas and secreted into the blood stream during episodes of hypoglycemia. Glucagon primarily acts via the glucagon receptor on the surface of hepatocytes, triggering release of glucose from the liver. Patients with type 2 diabetes are often characterized by fasting hyperglucagonemia and a failure to suppress postprandial glucagon levels adequately, creating an unwanted effect on already inappropriately high plasma glucose levels. The effect of hyperglucagonemia has been attributed to contribute up to 50% of the aberrant hyperglycemia observed in type 2 diabetes. Hyperglucagonemia is also observed in obese, otherwise normoglycemic people, possibly constituting an early pathogenetic component in the development of diabetes. Importantly, recent clinical studies show that antagonism of the glucagon receptor reduces glucose levels in patients with type 2 diabetes demonstrating that hyperglucagonemia plays an important role in type 2 diabetes. While the cause of hyperglucagonemia in type 2 diabetes is not yet completely understood, the general understanding is that the diabetic alpha cells are less sensitive to glucose and/or insulin and therefore less likely to be inhibited by hyperglycemia and the ensuing insulin secretion. However, this notion has recently been challenged by a number of studies showing that oral glucose, in contrast to intravenous glucose (which results in abrupt and intact suppression of plasma glucagon in patients with type 2 diabetes), elicits transient hyperglucagonemia and delayed suppression of plasma glucagon concentrations, suggesting that gut-derived factors and/or gut-derived glucagon may play a hitherto underestimated role in type 2 diabetic hyperglucagonemia.