The Facts
Glucagon plasma levels are usually grossly elevated in diabetic ketoacidosis, hyper-osmolar non-ketotic coma and poorly controlled diabetes mellitus. In nonobese and obese patients with type 2 diabetes mellitus, plasma glucagon levels are slightly but consistently elevated. These values, however, are usually higher than those found in normal subjects made similarly hyperglycemic by glucose ingestion or infusion. This situation has been termed ‘relative hyperglucagonemia’. There is strong evidence that the lack of postprandial suppression of glucagon can cause postprandial hyperglycemia in the presence of late-peaking postprandial insulin levels in type 2 diabetes.^1,2

The Glucagon Logic
If we accept, as established in many studies, that: glucagon circulating levels are higher in subjects with type 2 diabetes mellitus than in healthy subjects (see above); glucagon is a major determinant of hepatic glucose output; liver glucose output is increased in type 2 diabetes mellitus; and a high liver glucose output is a major factor contributing to fasting and postprandial hyperglycemia in this form of diabetes, the logical conclusion is that glucagon is likely to be involved in the hyperglycemia of non-insulindependent (type 2) diabetes mellitus.

Why Hyperglucagonemia in Type 2 Diabetes?
There is some consensus that the hyperglucagonemia observed in type 1 diabetes is secondary to insulin deficiency. Such an explanation is unlikely in type 2 diabetes since most patients with this condition appear hyperinsuliaemic. Furthermore, insulin treatment or administration does not usually correct the hyperglucagonaemia of type 2 diabetes. An attractive hypothesis, defended by Gerich, is that the alpha cell participates in the insulin resistance characteristic of type 2 diabetes. Indeed, this author has used the euglycemic–hyperinsulinemic glucose-clamp technique to compare the ability of insulin to inhibit glucagon secretion in healthy volunteers and in patients with type 2 diabetes. In non-diabetic subjects, plasma glucagon decreased significantly when plasma insulin was increased to 50mU/litre, whereas no significant change occurred in type 2 diabetic patients until plasma insulin was increased above 100mU/litre, and even at this plateau the decrease was significantly less than that of the control subjects. Only at 1,000mU/litre insulin did the glucagon suppression approach, but not equal, that seen in nondiabetic subjects. An alternative hypothesis is that prolonged hyperglycemia might in some way desensitise the alpha cell to the suppressive effect of glucose on glucagon secretion in a manner similar to the desensitisation reported at the alpha-cell level and likely to be involved in the reduced insulin response to glucose.