The GLP-1 Concept in the Treatment of Type 2 Diabetes—Still Standing at the Gate of Dawn?

Abstract

The pandemic explosion of type 2 diabetes incidence is well established, due to dramatic global changes in lifestyle over the past few decades and in the foreseeable future. To alter the course of this trend may take, at best, up to half a century. Until then, we need, in addition to lifestyle guidance, pharmacological solutions to reduce the markedly increasing incidence of macrovascular complications that, in its wake, confer a huge burden on patients and their families as well as an enormous economic burden to society. In the United States, for example, diabetes afflicts more than 21 million people, with an estimated cost of around $130 billion annually (http://diabetes.niddk.nih.gov/ dm/pubs/statistics/index.htm#7). The Steno 2 study has clearly demonstrated the efficacy of aggressive intervention against dyslipidemia, hypertension, and elevated glycemia brought on by diabetes (1). In daily life, however, it is also clear that less than half of the type 2 diabetic patients reach the recommended glycemic level employing so-called standard therapy, i.e. sulfonylureas, metformin, thiazolidinediones, and insulin. Hence, all new efficient blood glucose-lowering compounds without serious side effects are greeted with open arms. The glucagon like peptide-1 (GLP-1) concept holds promise. GLP-1 is mainly secreted by the intestinal L cells, although neural signals probably also contribute. The active peptides [GLP-1(7-37) and GLP-1(7-36) amide] increase insulin secretion in a glucose-dependent manner, i.e. lowering risk of hypoglycemia, decreasing basal as well as postprandial glucagon secretion, delaying gastric emptying, and increasing satiety by actions in the hypothalamus. Animal and in vitro models have shown that GLP-1 also increases -cell proliferation and neogenesis and decreases apoptosis (2). In these models, GLP-1 has other extrapancreatic effects beyond those described above, but whether these effects are also reflected in humans remains to be seen. In the circulation, GLP-1 undergoes enzymatic deactivation to GLP-1(9-37) and GLP-1(9-36) amide within minutes, primarily by dipeptidyl peptidase-4 (DPP-4), an enzyme present on the surface of lymphocytes, macrophages, and endothelial cells, and in tissues, such as the pancreas, liver, intestine, kidneys, and lungs. Localization of DDP-4 in endothelial cells indicates that degradation already takes place upon GLP-1 entry into the capillaries; endothelial DPP-4 in the liver degrades 50% of the protein. From this it can be deduced that only approximately 15% of the secreted GLP-1 reaches the pancreas in its intact form (3). DPP-4 also metabolizes other biologically active peptides of relevance in the regulation of carbohydrate metabolism such as glucose-dependent insulinotropic polypeptide, vasoactive intestinal polypeptide, and gastrin-releasing polypeptide. Active GLP-1 operates through the GLP-1 receptor (GLP-1R) belonging to the class B family of seven-transmembrane-spanning, heterotrimeric G protein-coupled receptors. Apart from the cells of the islet of Langerhans, several tissues express GLP-1R, including the heart, central nervous system, kidneys, lungs, stomach, intestine, and pituitary gland, as well as the nodose ganglion of abdominal vagal afferent nerve fibers, the central branches of which terminate in the brain stem. The presence of GLP-1Rs in skeletal muscle, liver, and adipose tissue is debatable. Due to the short half-life of native GLP-1, it is not feasible for long-term use, but its parenteral use may be of interest during acute medical and/or surgical conditions (4). For long-term therapy, two classes of pharmaceutical agents are involved and are still in development: 1) long-acting analogs, or so-called GLP-1 mimetics; and 2) DPP-4 inhibitors, or so-called incretin enhancers.