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The discovery, characterization, and clinical development of glucagon-likepeptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance., The endocrine activity of the gastrointestinal tract has been studied for more than a century, with gut hormones such as secretin emerging from the seminal studies of Bayliss and Starling [...]

Glucagon-like peptide 1 agonists and the development and growth of pancreatic [beta]-cells. Am J Physiol Endocrinol Metab 286:E875-E881, 2004; .1152/ajpendo.00007.2004.--Glucagon-like peptide 1 (GLP-1) is an intestine-derived insulinotropic hormone that stimulates glucose-dependent insulin production and secretion from pancreatic [beta]-cells. Other recognized actions of GLP-1 are to suppress glucagon secretion and hepatic glucose output, delay gastric emptying, reduce food intake, and promote glucose disposal in peripheral tissues. All of these actions are potentially beneficial for the treatment of type 2 diabetes mellitus. Several GLP-1 agonists are in clinical trials for the treatment of diabetes. More recently, GLP-1 agonists have been shown to stimulate the growth and differentiation of pancreatic [beta]-cells, as well as to exert cytoprotective, antiapoptotic effects on [beta]-cells. Recent evidence indicates that GLP-1 agonists act on receptors on pancreas-derived stem/progenitor cells to prompt their differentiation into [beta]-cells. These new findings suggest an approach to create [beta]-cells in vitro by expanding stem/progenitor cells and then to convert them into [beta]-cells by treatment with GLP-1. Thus GLP-1 may be a means by which to create [beta]-cells ex vivo for transplantation into patients with insulinopenic type 1 diabetes and severe forms of type 2 diabetes. stem cells; diabetes

Two studies published in 2003 focus on a gene mutation that could cause 5% of all obesity cases, as well as possibly causing binge eating. The mutation is in the gene for the receptor for alpha melanocyte-stimulating hormone. This hormone usually causes people to stop eating when they are full. One study found that a group of obese people who binged on food all had the mutation, whereas only 14% of another group of obese people who did not binge had the mutation.

In view of the recent success in pancreatic islet transplantation, interest in treating diabetes by the delivery of insulin-producing [beta]-cells has been renewed. Because differentiated pancreatic [beta]-cells cannot be expanded significantly in vitro, [beta]-cell stem or progenitor cells are seen as a potential source for the preparation of transplantable insulin-producing tissue. In addition to embryonic stem (ES) cells, several potential adult islet/[beta]-cell progenitors, derived from pancreas, liver, and bone marrow, are being studied. To date, none of the candidate cells has been fully characterized or is clinically applicable, but pancreatic physiology makes the existence of one or more types of adult islet stem cells very likely. It also seems possible that pluripotential stem cells, derived from the bone marrow, contribute to adult islet neogenesis. In future studies, more stringent criteria should be met to clonally define adult islet/[beta]-cell progenitor cells. If this can be achieved, the utilization of these cells for the generation of insulin-producing [beta]-cells in vitro seems to be feasible in the near future. pancreatic islets; liver oval cells; embryonic stem cells; nestin; insulin; islet-like clusters; [beta]-cell; transplantation

Background, Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose-induced insulin secretion in patients with type 2 diabetes. It has also been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs because this hormone enhances insulin-mediated glucose disposal. However, interpretations of the studies have been controversial. This study determines the effect of GLP-1 on insulin-mediated glucose disposal in elderly patients with type 2 diabetes. Methods. Studies were conducted on 8 elderly patients with type 2 diabetes (age range, 76 [+ or -] 1 years; body mass index, 28 [+ or -] 1 kg/[m.sup.2]). Each subject underwent two 180-minute euglycemic (insulin infusion rate, 40 mU/[m.sup.2]/min) insulin clamps in random order. Glucose production (Ra) and disposal (Rd) rates were measured using tritiated glucose methodology. In one study, glucose and insulin alone were infused. In the other study, a primed-continuous infusion of GLP-1 was administered at a final rate of 1.5 pmol * [kg.sup.-1] * [min.sup.-1] from 30 to 180 minutes. Results. Glucose values were similar between the control and GLP-1 infusion studies. 120- to 180-minute insulin values appeared to be higher during the GLP-1 infusion study (control, 795 [+ or -] 63 pmol/l; GLP-1, 1140 [+ or -] 275 pmol/l; p = not significant [NS]). The higher insulin values were largely due to 2 subjects who had substantial insulin responses to GLP-1 despite euglycemia and hyperinsulinemia. The 120- to 180-minute insulin values were similar in the other 6 subjects (control, 746 [+ or -] 35 pmol/l; GLP-1,781 [+ or -] 41 pmol/l; p = NS). Basal (control, 2.08 [+ or -] 0.05 mg/kg/min; GLP-1, 2.13 [+ or -] 0.04 mg/kg/min; p = NS) and 120- to 180-minute (control, 0.50 [+ or -] 0.18 mg/kg/min; GLP-1, 0.45 [+ or -] 0.14 mg/kg/min; p = NS) Ra was similar between studies. The 120- to 180-minute Rd values were higher during the GLP-1 infusion studies (control, 4.73 [+ or -] 0.39 mg/kg/min; GLP-1, 5.52 [+ or -] 0.43 mg/kg/min; p < .01). When the 2 subjects who had significant insulin responses to GLP-1 during the euglycemic clamp were excluded, the 120- to 180-minute Rd values were still higher in the GLP-1 infusion study (control, 5.22 [+ or -] 0.32 mg/kg/min; GLP-1, 6.05 [+ or -] 0.37 mg/kg/min; p < .05). Conclusions. We conclude that GLP-1 may enhance insulin sensitivity in elderly patients with diabetes.