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Incretin Hormones in the Treatment of Type 2 Diabetes: Therapeutic Applications of DPP-IV Inhibitors
Posted 04/26/2006
Laurie L. Baggio, PhD; Daniel J. Drucker, MD
Introduction
http://www.medscape.com/viewarticle/530215?src=mp
The pathogenesis of type 2 diabetes is characterized by a combination of factors that ultimately lead to loss of glycemic control, including (1) insulin resistance in liver, muscle, and adipose tissues; (2) a progressive decline in beta-cell mass and function resulting in relative insulin insufficiency; and (3) defective suppression of postprandial glucagon levels leading to increased hepatic glucose production.
Several classes of antidiabetic agents, including insulin and insulin analogs; glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide; sulfonylureas; meglitinides; thiazolidinediones; alpha-glucosidase inhibitors; and biguanides (metformin), are currently in use, either as monotherapies or in combination, to improve glycemic control in patients with diabetes.[1] However, these medications are frequently unable to address all of the underlying pathophysiologic defects in patients with type 2 diabetes, including postprandial hyperglycemia and hyperglucagonemia, defective insulin action, and a progressive decline in beta-cell function. Furthermore, these agents frequently exhibit reduced efficacy over time, leading to inadequate glycemic control. Moreover, several of these agents may be associated with adverse side effects that include weight gain, hypoglycemia, and gastrointestinal distress. Thus, there is a clear need for alternative therapies that can overcome the limitations associated with current antihyperglycemic medications.
Incretin-based therapies represent a novel class of therapeutic agents for the treatment of type 2 diabetes that not only target deficits in insulin secretion, but also reduce postprandial glucose and glucagon levels. Furthermore, preclinical studies with incretin agents have demonstrated preservation or restoration of beta-cell mass, thus providing the potential for sustained therapeutic benefits with long-term therapeutic administration.
Incretin Actions and Blood Glucose Regulation
Incretins are peptide hormones secreted from the gastrointestinal tract following meal ingestion that augment glucose-stimulated insulin secretion.[2] The 2 major incretin hormones identified to date are GLP-1 and glucose-dependent insulinotropic peptide (GIP). Both GLP-1 and GIP stimulate insulin secretion in a glucose-dependent manner and enhance insulin gene transcription and biosynthesis.[3-5] Moreover, preclinical studies have shown that GLP-1 and GIP can increase beta-cell mass via stimulation of beta-cell proliferation and neogenesis and inhibition of beta-cell apoptosis.[6]
In individuals with type 2 diabetes, GLP-1 receptor agonists enhance insulin release and inhibit glucagon secretion, and because both effects are glucose-dependent, the risk for hypoglycemia is low with GLP-1-based therapies.[7] In addition, GLP-1 receptor agonists delay gastric emptying, improve insulin sensitivity, and lower fasting and postprandial blood glucose levels in patients with diabetes.[8] GLP-1 also activates regions in the central nervous system that control satiety, and longer-term studies demonstrate that exogenous GLP-1 receptor agonist administration promotes satiety and reduces body weight in diabetic patients. More recently, studies with animal models suggest that GLP-1 receptor agonists may also enhance insulin-independent glucose disposal in peripheral tissues, potentially via stimulation of glucose sensors located in the portal vein and subsequent activation of neuronal pathways that modify glucose clearance.[9,10] In addition to glucoregulatory actions, GLP-1 receptor agonists exhibit protective effects in the cardiovascular and nervous systems following experimental injury.[11-17] The major actions of GLP-1 receptor agonists are illustrated in Figure 1http://www.medscape.com/viewarticle/530215_2 Go to bottom of the page.
Posted 04/26/2006
Laurie L. Baggio, PhD; Daniel J. Drucker, MD
Introduction
http://www.medscape.com/viewarticle/530215?src=mp
The pathogenesis of type 2 diabetes is characterized by a combination of factors that ultimately lead to loss of glycemic control, including (1) insulin resistance in liver, muscle, and adipose tissues; (2) a progressive decline in beta-cell mass and function resulting in relative insulin insufficiency; and (3) defective suppression of postprandial glucagon levels leading to increased hepatic glucose production.
Several classes of antidiabetic agents, including insulin and insulin analogs; glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide; sulfonylureas; meglitinides; thiazolidinediones; alpha-glucosidase inhibitors; and biguanides (metformin), are currently in use, either as monotherapies or in combination, to improve glycemic control in patients with diabetes.[1] However, these medications are frequently unable to address all of the underlying pathophysiologic defects in patients with type 2 diabetes, including postprandial hyperglycemia and hyperglucagonemia, defective insulin action, and a progressive decline in beta-cell function. Furthermore, these agents frequently exhibit reduced efficacy over time, leading to inadequate glycemic control. Moreover, several of these agents may be associated with adverse side effects that include weight gain, hypoglycemia, and gastrointestinal distress. Thus, there is a clear need for alternative therapies that can overcome the limitations associated with current antihyperglycemic medications.
Incretin-based therapies represent a novel class of therapeutic agents for the treatment of type 2 diabetes that not only target deficits in insulin secretion, but also reduce postprandial glucose and glucagon levels. Furthermore, preclinical studies with incretin agents have demonstrated preservation or restoration of beta-cell mass, thus providing the potential for sustained therapeutic benefits with long-term therapeutic administration.
Incretin Actions and Blood Glucose Regulation
Incretins are peptide hormones secreted from the gastrointestinal tract following meal ingestion that augment glucose-stimulated insulin secretion.[2] The 2 major incretin hormones identified to date are GLP-1 and glucose-dependent insulinotropic peptide (GIP). Both GLP-1 and GIP stimulate insulin secretion in a glucose-dependent manner and enhance insulin gene transcription and biosynthesis.[3-5] Moreover, preclinical studies have shown that GLP-1 and GIP can increase beta-cell mass via stimulation of beta-cell proliferation and neogenesis and inhibition of beta-cell apoptosis.[6]
In individuals with type 2 diabetes, GLP-1 receptor agonists enhance insulin release and inhibit glucagon secretion, and because both effects are glucose-dependent, the risk for hypoglycemia is low with GLP-1-based therapies.[7] In addition, GLP-1 receptor agonists delay gastric emptying, improve insulin sensitivity, and lower fasting and postprandial blood glucose levels in patients with diabetes.[8] GLP-1 also activates regions in the central nervous system that control satiety, and longer-term studies demonstrate that exogenous GLP-1 receptor agonist administration promotes satiety and reduces body weight in diabetic patients. More recently, studies with animal models suggest that GLP-1 receptor agonists may also enhance insulin-independent glucose disposal in peripheral tissues, potentially via stimulation of glucose sensors located in the portal vein and subsequent activation of neuronal pathways that modify glucose clearance.[9,10] In addition to glucoregulatory actions, GLP-1 receptor agonists exhibit protective effects in the cardiovascular and nervous systems following experimental injury.[11-17] The major actions of GLP-1 receptor agonists are illustrated in Figure 1http://www.medscape.com/viewarticle/530215_2 Go to bottom of the page.
