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Abstract
Insulin and glucagon are potent regulators of glucose metabolism. For decades, we have viewed diabetes from a bi-hormonal perspective of glucose regulation. This perspective is incomplete and inadequate in explaining some of the difficulties that patients and practitioners face when attempting to tightly control blood glucose concentrations. Intensively managing diabetes with insulin is fraught with frustration and risk. Despite our best efforts, glucose fluctuations are unpredictable, and hypoglycemia and weight gain are common. These challenges may be a result of deficiencies or abnormalities in other glucoregulatory hormones. New understanding of the roles of other pancreatic and incretin hormones has led to a multi-hormonal view of glucose homeostasis.
HISTORICAL PERSPECTIVE
Our understanding of diabetes as a metabolic disease has evolved significantly since the discovery of insulin in the 1920s. Insulin was identified as a potent hormonal regulator of both glucose appearance and disappearance in the circulation. Subsequently, diabetes was viewed as a mono-hormonal disorder characterized by absolute or relative insulin deficiency. Since its discovery, insulin has been the only available pharmacological treatment for patients with type 1 diabetes and a mainstay of therapy for patients with insulin-deficient type 2 diabetes.1-7
The recent discovery of additional hormones with glucoregulatory actions has expanded our understanding of how a variety of different hormones contribute to glucose homeostasis. In the 1950s, glucagon was characterized as a major stimulus of hepatic glucose production. This discovery led to a better understanding of the interplay between insulin and glucagon, thus leading to a bi-hormonal definition of diabetes. Subsequently, the discovery of a second [beta]-cell hormone, amylin, was first reported in 1987. Amylin was determined to have a role that complemented that of insulin, and, like insulin, was found to be deficient in people with diabetes. This more recent development led to a view of glucose homeostasis involving multiple pancreatic hormones.8
In the mid 1970s, several gut hormones were identified. One of these, an incretin hormone, glucagon-like peptide-1 (GLP-1), was recognized as another important contributor to the maintenance of glucose homeostasis. 9,10 Based on current understanding, glucose homeostasis is governed by the interplay of insulin, glucagon, amylin, and incretin hormones.
This enhanced understanding of glucose homeostasis will be central to the design of new pharmacological agents to promote better clinical outcomes and...