Sofie Hædersdal - Elucidation of the pathophysiological consequences of hyperglucagonaemia in patients with type 2 diabetes using a glucagon receptor antagonist

In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and glucagon concentrations fail to decrease appropriately and may even increase in response to ingestion of glucose and after ingestion of a mixed meal.

This diabetic hyperglucagonaemia may therefore contribute importantly to the hyperglycaemia of the patients. Interestingly, in 2007 we showed that differences in glucagon secretion during oral and iv glucose may contribute to the reduced incretin effect observed in type 2 diabetes. However, the precise consequence of this difference on the incretin effect has not been teased out; primarily due to the lack of an applicable glucagon receptor antagonist.

Several glucose-lowering treatment modalities have been shown to affect glucagon levels in patients with type 2 diabetes, but again the role of glucagon in the glucose-lowering effects of these treatment modalities has been difficult to discern. By using a glucagon receptor antagonist (GRA) the present PhD project will elucidate how the paradoxical hyperglucagonaemia in diabetes affects overall glucose disposal and postprandial glucose excursions in patients with type 2 diabetes. Ten patients with type 2 diabetes and 10 matched healthy controls will be included in a blinded, placebo-controlled protocol.

Furthermore, we will exploit glucagon receptor antagonism to delineate the role of glucagon during treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors, which have been shown to increase and decrease plasma glucagon levels, respectively.