Steve V. Edelman, MD
Robert R. Henry, MD
The discovery of insulin over 80 years ago is one of the great success stories in the history of modern medicine. Although insulin remains the mainstay of therapy for many patients with diabetes, the greatest deterrents to the use of intensive insulin regimens are hypoglycemia, the fear of hypoglycemia, and the need for…
frequent fine-tuning of insulin doses on a day-to-day basis. Particularly in patients with Type 2 diabetes, who are often overweight, the weight gain associated with intensive insulin therapy is also a significant concern. Additionally, current insulin formulations and methods of delivery fail to duplicate insulin action of healthy individuals, especially during the postprandial period when normally there is a rapid surge of insulin into the portal vein.
Given these concerns, the quest for more physiologic, and thus more effective, approaches to treatment has prompted investigation of other glucoregulatory hormones. These include the beta-cell hormone amylin, the alpha-cell hormone glucagon, and numerous gut-derived hormones, such as the potent incretins glucagon-like polypeptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Because the effects of some, if not all, of these hormones are dysregulated to some extent in people with diabetes, many researchers now believe that replicating glucose homeostasis requires a multipronged effort involving more than replacement of insulin and/or enhancement of peripheral glucose uptake. Along these lines, replacing the function of both pancreatic beta-cell hormones, amylin and insulin, may afford more complete restoration of the physiology of glucose control.
The synthetic human amylin analog, pramlintide acetate (Symlin) injection, which retains the desired biologic activities of human amylin but has superior stability and solubility, was FDA approved as an adjunct treatment for patients with Type 2 diabetes who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent SFU agent and/or MET, and also for patients with Type 1 diabetes who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal insulin therapy.
A New Paradigm: Regulating Glucose Appearance and Disappearance
Given the physiology of glycemic regulation, management of patients with diabetes requires interventions aimed at reestablishing and maintaining glycemic homeostasis by regulating glucose appearance and disappearance. Type 2 diabetes is a progressive disease characterized by ongoing beta-cell failure. The current management paradigm for patients with Type 2 diabetes starts with diet and exercise, followed as needed with sequential oral antidiabetic agents. Ultimately, because of progressive beta-cell failure, these initial steps are not sufficient to maintain adequate glycemic control, and the patient will require insulin.
Insulin controls PPG by two major mechanisms. First, it promotes the uptake of glucose into insulin-sensitive peripheral tissues. Second, it inhibits hepatic glucose output by exerting direct and indirect effects on the liver, including suppression of glucagon secretion. Amylin is packaged together with insulin in the beta-cell granules and is co-secreted with insulin. In healthy individuals, amylin secretion follows the same pattern as insulin, whereby it surges into the bloodstream in response to nutrient uptake (Figure 11.1-A). Like insulin, amylin secretion is abnormal in patients with Type 2 diabetes and is deficient in patients with Type 1 diabetes (Figure 11.1-B).
Whereas insulin primarily stimulates the disappearance of glucose from plasma, amylin inhibits its appearance through three different mechanisms of action, all of which are thought to be mediated via the central nervous system (Figure 11.2):
• Pramlintide slows gastric emptying, i.e., the rate at which food is released from the stomach to the small intestine.
• Pramlintide suppresses glucagon secretion, which leads to suppression of endogenous glucose output from the liver.
• Pramlintide regulates food intake due to centrally mediated modulation of appetite.
FIGURE 11.2 — Proposed Model of Amylin and Insulin Action in Postprandial Glucose Homeostasis
Insulin is the major hormonal regulator of glucose disposal. Preclinical and clinical studies indicate that amylin complements the effects of insulin by regulating the rate of glucose inflow to the bloodstream.
* Reported in rodents.
Edelman SV, Weyer C. Diabetes Technol Ther. 2002;4:180.
Thus amylin is a neuroendocrine hormone that regulates glucose appearance and works in concert with insulin, which primarily promotes glucose disappearance. In patients with diabetes, glucose regulation is disrupted. With the development of pramlintide, a more comprehensive approach to glucose homeostasis is possible.
© Copyright 2010. Steven V. Edelman, MD, Robert R. Henry, MD, Professional Communications, Inc. All rights reserved.
Next Week, Part 2: Mechanisms of Action of Pramlintide
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