Incretin-Based Therapies for Type 2 Diabetes Mellitus: Properties, Functions, and Clinical Implications
Section snippets
Impairment of the Incretin Effect in Type 2 Diabetes Mellitus
The incretin effect is greatly reduced in patients with type 2 diabetes mellitus, and this “defect” plays an important contributory role in the insulin insufficiency and chronic hyperglycemia characteristic of this disorder.16, 22, 23 Initial investigations into the incretin defect focused on an hypothesized impairment in the secretion of GLP-1.24, 25, 26 Evidence concerning this proposed secretion defect has, however, been unconvincing. The preponderance of studies have reported similar GLP-1
Glucagonlike Peptide–1 in the Treatment of Type 2 Diabetes Mellitus
In patients with type 2 diabetes, infusion of endogenous GLP-1 has been shown to provide not only improved glycemic control but also beneficial effects on β-cell function, weight, and cardiovascular risk factors.1 Intravenous administration of GLP-1 normalizes or greatly improves glycemia.57 This effect is seen even in patients with longstanding disease who have not responded to other treatments. Infusion of GLP-1 normalizes β-cell responsiveness to glucose, and restores first- and second-phase
Dipeptidyl Peptidase–4
The plasma membrane glycoprotein DPP-4 (also known as T-cell antigen CD26) is widely expressed throughout the human body and is involved in a broad spectrum of physiologic processes. DPP-4 is found on endothelial and epithelial cells throughout the vascular bed, and in the kidneys, intestines, exocrine pancreas, gastrointestinal tract, biliary tract, thymus, lymph nodes, uterus, placenta, prostate, myocardium, and brain, as well as the adrenal, sweat, salivary, and mammary glands. In addition,
Incretin Therapies: Clinical Trial Results
Incretin-based treatments for type 2 diabetes come in 2 classes: those that inhibit the enzymatic action of DPP-4, and those that mimic the biological activities and receptor stimulation of the endogenous hormone but have reduced susceptibility to enzymatic inactivation.
Sitagliptin is a triazolopiperazine-based DPP-4 inhibitor that binds selectively and reversibly to the active site of DPP-4. It is approved in the European Union and the United States for the treatment of type 2 diabetes in
Summary
GLP-1 is 1 of a group of incretin hormones that play a vital role in the metabolic response to nutrient intake and glucose disposal. The glycemic and extraglycemic effects of GLP-1 are blunted in type 2 diabetes. DPP-4 is a ubiquitously expressed plasma membrane glycoprotein engaged in the regulation of a large number of peptides, including the incretin hormones GLP-1 and GIP. Despite the many physiologic processes in which DPP-4 plays a regulatory role, inhibition of the enzyme as part of a
Author Disclosures
The author of this article has disclosed the following industry relationships:
Michael A. Nauck, MD, PhD, serves on the advisory boards of Amylin Pharmaceuticals, Inc., ConjuChem, Inc., Eli Lilly and Company, GlaxoSmithKline, Hoffman-La Roche Inc., Novartis AG, Novo Nordisk A/S, Probiodrug AG, Restoragen Inc. (formerly BioNebraska, Inc.), and sanofi-aventis; has worked as a consultant to AstraZeneca, Bayer Vital Pharma, Berlin Chemie/Menarini, Biovitrum AB, ConjuChem, Inc., Eli Lilly and
References (189)
- et al.
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes
Lancet
(2006) Glucagon-like peptide 1 (GLP-1): an intestinal hormone, signalling nutritional abundance, with an unusual therapeutic potential
Trends Endocrinol Metab
(1999)What do we know about the secretion and degradation of incretin hormones?
Regul Pept
(2005)- et al.
Glucagon-like peptide-1 7–36: a physiological incretin in man
Lancet
(1987) - et al.
Release of immunoreactive gastric inhibitory polypeptide (IR-GIP) by oral ingestion of food substances
Am J Surg
(1975) The contribution of incretin hormones to the pathogenesis of type 2 diabetes
Best Pract Res Clin Endocrinol Metab
(2009)- et al.
Typical Danish Caucasian type 2 diabetic patients do not commonly carry genetic variants in GIP and GLP-1 encoding regions of the proGIP and proglucagon genes
Regul Pept
(2004) - et al.
Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study
Lancet
(2002) Unraveling the science of incretin biology
Am J Med
(2009)- et al.
Glucagon-like peptide 1 and its derivatives in the treatment of diabetes
Regul Pept
(2005)
GLP-1 inhibits and adrenaline stimulates glucagon release differential modulation of N- and L-type Ca2+ channel-dependent exocytosis
Cell Metab
Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting
Am J Cardiol
Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure
J Card Fail
Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes
Bioorg Med Chem
Dipeptidyl peptidase IV inhibitors: how do they work as new antidiabetic agents?
Regul Pept
Decrease of serum dipeptidylpeptidase activity in severe sepsis patients: relationship to procalcitonin
Clin Chim Acta
Incretins, insulin secretion and Type 2 diabetes mellitus
Diabetologia
Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide
Endocr Rev
Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man
Histochemistry
Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man
Eur J Clin Invest
Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide 1 in humans
Diabetes
Neural regulation of glucagon-like peptide-1 secretion of pigs
Am J Physiol Endocrinol Metab.
Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients
Digestion
Glucagon-like peptide 1 (7–36 amide) secretion in response to luminal sucrose from the upper and lower gut: a study using α-glucosidase inhibition (acarbose)
Scand J Gastroenterol
Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1
Proc Natl Acad Sci U S A
Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes
Diabetologia
Intestinal factors in the control of insulin secretion
J Clin Endocrinol Metab
Plasma insulin response to oral and intravenous glucose administration
J Clin Endocrinol Metab
Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses
J Clin Endocrinol Metab
Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day
Scand J Gastroenterol
Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near physiological insulinotropic hormone and glucose concentrations
J Clin Endocrinol Metab
Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans
Am J Physiol Endocrinol Metab
Absence of incretin effect in obese type 2 and diminished effect in lean type 2 and obese subjects
Diabetes Res Clin Pract
Determinants of the impaired secretion of glucagon-like peptide–1 in type 2 diabetic patients
J Clin Endocrinol Metab
Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients
Diabetes
Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients
Diabetes
Is secretion of glucagon-like peptide-1 reduced in type 2 diabetes mellitus?
Nat Clin Pract Endocrinol Metab
Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance
Diabetes
Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine
J Clin Invest
The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus
Diabetologia
Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus
Diabetes
The role of incretins in glucose homeostasis and diabetes treatment
Pharmacol Rev
Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus
J Clin Invest
Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes
Diabetes
Glucagon-like peptide-1 in type-2 diabetes: the β-cell and beyond
Diabetes Obes Metab
Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes
Diabetes
Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients
Diabetologia
Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes
Diabetes
The pathogenesis of NIDDM involves a defective expression of the GIP receptor
Diabetologia
Identification of two missense mutations in the GIP receptor gene: a functional study and association analysis with NIDDM—no evidence of association with Japanese NIDDM subjects
Diabetes
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Statement of author disclosure: Please see the Author Disclosures section at the end of this article.