Taking Aim at Islet Hormones With GLP-1: Is Insulin or Glucagon the Better Target?

Abstract

The last decade has seen a shift in the therapeutics of type 2 diabetes from insulin-centric to more multifarious approaches. Whereas previously drug treatment was based almost entirely on increasing insulin action—either by giving drugs to raise plasma insulin levels or to increase tissue responsiveness to insulin—it is now clear that addressing other processes controlling glucose metabolism is also fruitful. To wit, drugs that delay gastric emptying or carbohydrate digestion or promote renal glucose elimination have been shown to be effective for treating hyperglycemia. Compounds that affect hepatic glucose production directly or act through the central nervous system to lower blood glucose are in various phases of development. Moreover, glucagon, long known to contribute to abnormal glucose regulation in diabetes (1,2), is now amenable to therapeutic manipulation using drugs based on the naturally occurring hormones islet amyloid polypeptide (IAPP, also known as amylin) and glucagon-like peptide 1 (GLP-1). GLP-1 is an essential component of the system regulating blood glucose and has been the basis for two new classes of drugs to treat diabetes, GLP-1 receptor (GLP-1r) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (3,4). GLP-1r activation has a broad reach that affects islet hormone secretion, gastrointestinal motility, food intake, and glucose production, all in a manner that lowers blood glucose (5). While enhanced β-cell function is generally accepted to be central in the glycemic response to GLP-1, it is noteworthy that plasma levels of insulin and C-peptide in patients treated with GLP-1r agonists and DPP-4 inhibitors are not dramatically increased (6–8). This is due in part to the overall effect of GLP-1 signaling to lower blood glucose, reducing the glycemic stimulus to the β-cells. With sophisticated modeling of plasma C-peptide levels, the insulinotropic effects of GLP-1–based drugs are clear (6,7), but the subtlety …