Incretin Mimetics and Dipeptidyl Peptidase-IV Inhibitors
Incretin Mimetics and Dipeptidyl Peptidase-IV Inhibitors
The emergence of the glucoregulatory hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide has expanded our understanding of glucose homeostasis. In particular, the glucoregulatory actions of the incretin hormone GLP-1 include enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to overcome rapid degradation of GLP-1. One is the use of agents that mimic the enhancement of glucose-dependent insulin secretion, and potentially other antihyperglycemic actions of incretins, and the other is the use of dipeptidyl peptidase-IV inhibitors, which reduce the inactivation of GLP-1, increasing the concentration of endogenous GLP-1. The development of incretin mimetics and dipeptidyl peptidase-IV inhibitors opens the door to a new generation of antihyperglycemic agents to treat several otherwise unaddressed pathophysiologic defects of type 2 diabetes mellitus. We review the physiology of glucose homeostasis, emphasizing the role of GLP-1, the pathophysiology of type 2 diabetes mellitus, the clinical shortcomings of current therapies, and the potential of new therapies—including the newly approved incretin mimetic exenatide—that elicit actions similar to those of GLP-1.
Type 2 diabetes mellitus is a costly and increasingly common chronic disease that currently affects nearly 16 million Americans and is estimated to affect 20 million by 2025. Alarming increases in the rates of obesity fuel this epidemic, and, despite current efforts, type 2 diabetes remains a chronic, progressive metabolic disease leading to clinically significant morbidity and decreased survival. Much of the increase in morbidity can be directly linked to poor glycemic control, which has been associated with an increased risk of microvascular and macrovascular complications.
Despite intensive therapy, investigators from the United Kingdom Prospective Diabetes Study (UKPDS) reported that glycemic control deteriorates over time. Because glycemic control progressively worsens, lifestyle interventions combined with one, then multiple, therapeutic agents are needed. Despite current therapies, more than 60% of Americans with diabetes have poor diabetic control, as reflected by hemoglobin A1c (A1C) values above 7%. The ongoing need for new therapies to address the growing burden of type 2 diabetes is clear.
The emergence of the glucoregulatory hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide has expanded our understanding of glucose homeostasis. In particular, the glucoregulatory actions of the incretin hormone GLP-1 include enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to overcome rapid degradation of GLP-1. One is the use of agents that mimic the enhancement of glucose-dependent insulin secretion, and potentially other antihyperglycemic actions of incretins, and the other is the use of dipeptidyl peptidase-IV inhibitors, which reduce the inactivation of GLP-1, increasing the concentration of endogenous GLP-1. The development of incretin mimetics and dipeptidyl peptidase-IV inhibitors opens the door to a new generation of antihyperglycemic agents to treat several otherwise unaddressed pathophysiologic defects of type 2 diabetes mellitus. We review the physiology of glucose homeostasis, emphasizing the role of GLP-1, the pathophysiology of type 2 diabetes mellitus, the clinical shortcomings of current therapies, and the potential of new therapies—including the newly approved incretin mimetic exenatide—that elicit actions similar to those of GLP-1.
Type 2 diabetes mellitus is a costly and increasingly common chronic disease that currently affects nearly 16 million Americans and is estimated to affect 20 million by 2025. Alarming increases in the rates of obesity fuel this epidemic, and, despite current efforts, type 2 diabetes remains a chronic, progressive metabolic disease leading to clinically significant morbidity and decreased survival. Much of the increase in morbidity can be directly linked to poor glycemic control, which has been associated with an increased risk of microvascular and macrovascular complications.
Despite intensive therapy, investigators from the United Kingdom Prospective Diabetes Study (UKPDS) reported that glycemic control deteriorates over time. Because glycemic control progressively worsens, lifestyle interventions combined with one, then multiple, therapeutic agents are needed. Despite current therapies, more than 60% of Americans with diabetes have poor diabetic control, as reflected by hemoglobin A1c (A1C) values above 7%. The ongoing need for new therapies to address the growing burden of type 2 diabetes is clear.
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