| Abstract: | We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8–induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.Pancreatic islets secrete both insulin and glucagon in a manner which is tightly juxtaposed. Aberrant glucagon production correlates with diabetes and suppression of glucagon corrects the hyperglycemia of diabetes; however, glucagon’s role in the metabolic manifestations of diabetes remains a subject of debate. More recently, targeted disruption of glucagon action has gained traction as a potential treatment for diabetes. Glucagon receptor (GcgR) antagonists include small-molecule inhibitors and humanized antibodies which antagonize glucagon receptor activation. Both antisense oligonucleotides and human antibodies against GcgR show promise to promote glycemic control in patients while minimizing the side effects seen with small molecules (1). GcgR-antagonizing antibodies provide effective glucose control in rodents and primate models of type 2 diabetes (2–4). Hyperglucagonemia and excess proliferation of α-cells also result following these treatments, which phenocopy global or liver-specific GcgR−/− mice (5, 6).More recently, our work demonstrated evidence that the blockage of glucagon action improves glycemia in type 1 diabetic rodents (7). Our observations in type 1 diabetic rodents have been replicated by others who have met these results with skepticism (8, 9). In humans, GcgR antagonism diminishes insulin requirements (10, 11). Initial clinical trials in patients with type 1 diabetes showed no serious adverse effects while improving glucose control (10).During the severe insulin resistance promoted by insulin receptor-antagonizing peptide S961, GcgR antagonism can improve insulin production and β-cell mass over S961 alone, suggesting that GcgR antagonism may be beneficial in promoting functional β-cell mass under conditions of severe insulin resistance (12). We hypothesize that such conditions may also exist during insulin deficiency. While testing the efficacy of a similar GcgR-antagonizing antibody (Ab-4) in models of type 1 diabetes (13), we were struck by the remarkable finding that stable normoglycemia can remain following cessation of the treatment. Here, we assess the efficacy of the GcgR antagonist Ab-4 to enhance functional β-cell mass and restore stable glucose control. |
