Hans-Christoph Fehmann

Glucagon-like peptide-1(7–36) amide is a new incretin/enterogastrone candidate

Cloning and sequence analysis of cDNAs and DNA fragments from genomic libraries has led to a dramatic increase in understanding of the glucagon-related peptides in recent years. The primary structure of the biosynthetic precursor of glucagon (preproglucagon) has been elucidated. The complex structural connec- tions between the multiple molecular forms of the glucagon-like peptides in tissues and in the circulation have been determined [ 1,2]. Mammalian proglucagon consists of 160 amino acid residues and is synthesized in the islets of Langerhans, intestine and brain. An exciting recent finding is that in addition to glucagon the preproglucagon gene in mammals encodes two additional peptides with struc- tural similarity to glucagon, termed glucagon-like peptide-1 and -2 (GLP-I and GLP-2). The truncated form of GLP-1, GLP-1(7-36) amide, which is secreted by the mammalian intestine, strongly stimulates insu- lin secretion and inhibits gastric acid secretion. This review focuses mainly on the truncated form of GLP-1. since a rapidly increasing number of reports indicate a remarkable interest of investigators in this particular hormone, which actually fulfills the classical role of an ‘enterogastrone’ and ‘incretin’ hormone. The purpose here is to describe what is known so far about the origin, processing, organ distribution and actions of this peptide and to search for promising future direc- tions of further investigations.

Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7–36) amide on the rat pancreas

The glucose-dependent action of GLP-1 (7–36) amide (GLP-1) on insulin secretion was studied in isolated islets and in the perfused rat pancreas. In islet experiments in the presence of non-stimulatory glucose levels (<3 mmol/1) a GLP-1 concentration of 10 nmol/1 increased insulin secretion by 83%. However, higher GLP-1 concentrations (25 and 100 nmol/l) could not further enhance this effect (85 and 83%, respectively). The onset of the stimulatory action of a supramaximal GLP-1-load (25 nmol/l) was at a glucose level of 3 mmol/l. In the perfused pancreas, 25 nmol/l GLP-1 induced a strong insulin release at 5 mmol/l glucose, but under basal glucose (2.8 mmol/l) only a slight enhancement of insulin secretion occurred during the late phase (30 to 54 min) of perfusion (P<0.05). In conclusion, a slight but not dose-dependent stimulation of insulin secretion by supramaximal GLP-1 loads under basal glucose levels was found. The necessary GLP-1 concentrations to achieve this in vitro effect are beyond physiological or postprandial levels.

Cosecretion of amylin and insulin from isolated rat pancreas

Amylin, a 37 amino acid C‐terminal amidated peptide is an integral part of secretory granules of pancreatic β‐cells. Utilizing a specific radioimmunoassay system we demonstrate in the present study a cosecretion of amylin and insulin from the isolated rat pancreas. The secretion pattern of both peptides during glucose or glucose plus arginine stimulation is identical. The molar ratio of amylin amounts to 10% of that of insulin. The biological significance of amylin is still unknown, but a paracrine/endocrine role in glucose homeostasis is speculated.

Islet amyloid polypeptide (IAPP ; amylin) influences the endocrine but not the exocrine rat pancreas

The effect of synthetic rat amylin (10,100,1000 pmol/l) on glucose (10 mmol/) and arginine (10 mmol/l) -stimulated islet hormone release from the isolated perfused rat pancreas and on amylase release from isolated pancreatic acini was investigated. Amylin stimulated the insulin release during the first (+76%) and the second secretion period (+42%) at 1 nmol/l. The first phase of the glucagon release was inhibited concentration dependently by amylin and completely suppressed during the second phase. Amylin diminished the somatostatin release in a concentration dependent manner. This effect was more pronounced at the first than the second secretion period (1 nmol amylin: 1 phase: -60%, 2.phase: -22%). Amylin was without any effect on basal and CCK stimulated amylase release from isolated rat pancreatic acini. Our data suggest amylin, a secretory product of pancreatic B-cells, as a peptide with approximately strong paracrine effects within the Langerhans islet. Therefore, amylin might be involved in the regulation of glucose homeostasis.

Glucagon-like peptide-1(7–37)/(7–36)amide is a new incretin

Glucagon-like peptide-1 (GLP-1) is the main product of the intestinal processing of proglucagon. It is released from the intestinal K-cells into the circulation in response to the oral ingestion of food. At the pancreatic beta cell GLP-1 is a potent insulin secretagogue in the presence of elevated glucose levels, defining glucagon-like peptide-1 as a new incretin. Its action is mediated by specific receptors coupled to the adenylate cyclase system by a stimulatory G-protein. Finally, glucagon-like peptide-1 stimulates proinsulin gene expression and it is thus involved at several levels in the regulation of insulin synthesis and secretion.

Synergistic stimulatory effect of glucagon‐like peptide‐1 (7–36) amide and glucose‐dependent insulin‐releasing polypeptide on the endocrine rat pancreas

The interaction of glucagon‐like peptide‐1 (7–36)amide (GLP‐1) and glucose‐dependent insulin‐releasing polypeptide (GIP) on insulin release from the perfused rat pancreas was studied. The GLP‐ 1 stimulated (0.5 nmol/l), glucose‐induced (6.7 mmol/l) insulin secretory answer was enhanced by GIP (0.1, 1.0 and 10.0 nmol/l) to the arterial perfusate. This effect was maximal at 1 nmol/l GIP and smaller but still significant at 0.1 nmol/l GIP. The high GIP concentration of 10 nmol/l GIP did not further increase insulin secretion compared to the stimulation by 1 nmol/l GIP. Our data demonstrate an additive synergistic effect of GLP‐ 1 and GIP on the glucose‐induced insulin release. This supports the concept of an action ‘in concert’ of gastrointestinal incretin hormones postprandially released on the endocrine pancreas to guarantee adequate insulin answers after meals.

The effects of glucagon-like peptide-I (GLP-I) on hormone secretion from isolated human pancreatic islets

Glucagon-like peptide-I (GLP-I) is a potent in-cretin hormone that is now considered as a new therapeutic tool in the treatment of diabetes mellitus. In this study we characterized the effects of GLP-I on peptide hormone release from isolated human pancreatic islets. GLP-I stimulated insulin release in the presence of 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 166%; 10 mM glucose + 10 nM GLP-I, 222%) but had only a weak insulinotropic effect (128%) at 2.8 mM glucose. Glucagon release was inhibited by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 72%) and by 10 nM GLP-I at 2.8 mM glucose (67%). Somatostatin secretion was increased by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 166%). GLP-I stimulated somatostatin release in the presence of 2.8 mM glucose (172%). Pancreatic polypeptide (PP) secretion was enhanced by 10 mM glucose (2.8 mM glucose, 100%; 10 mM glucose, 236%). GLP-I induced PP release only in the presence of 2.8 mM glucose (184%).

Leptin inhibition of insulin secretion from isolated human islets

Abstract Leptin is a hormone produced and secreted from the adipose tissue. Its physiological actions include the regulation of satiety, food intake and energy balance. The production of leptin is increased by high insulin levels. Here, we demonstrate that leptin acts as an inhibitor of glucose-induced (20 mM) insulin secretion from isolated human islets. No effect was observed in the presence of lower glucose levels (2.8 and 10 mM glucose). The pancreatic β-cell might represent a target of a direct physiological action of leptin. We suggest the presence of an “adipo-insular axis” in which leptin mediates negative feedback from the adipose tissue to the endocrine pancreas.

Characterization of GIP(1-30) and GIP(1-42) as stimulators of proinsulin gene transcription.

Originally characterized in terms of its gastric acid inhibitory properties, GIP (gastric inhibitory polypeptide) expressed in the upper small intestine, was subsequently shown to exert strong glucose-dependent insulin-releasing properties. This action is generally attributed to GIP(1-42) and, so far, no evidence for the contribution of other relevant GIP forms exists. In this study, we compared the effects of GIP(1-42) and C-terminally truncated GIP(1-30) on cAMP production and proinsulin gene transcription at clonal insulin-secreting cell lines (RIN 1046-38, beta TC-3). Both peptides were equally potent stimulators of cAMP generation in both cell lines. Insulin release from RIN 1046-38 cells stimulated by both GIP forms was identical. In both B-cell lines GIP(1-42) and GIP(1-30) stimulated proinsulin gene expression equipotently. GIP not only enhances insulin secretion but also insulin gene expression and, therefore, it is a true insulinotropic hormone.

Intestinal effects of α-glucosidase inhibitors: absorption of nutrients and enterohormonal changes

The present paper addresses the question how α‐glucosidase inhibitors affect glucose homeostasis. To facilitate this already established data on the effects of induced malabsorption on gut hormones such as gastric inhibitory polypeptide (GIP) in connection with preliminary findings which deal with the new incretin hormone glucagon‐like peptide 1 (7–36) amide (GLP‐1) are discussed. To emphasize the possibly important impact of a regulated GLP‐1 release in response to glucosidase inhibitor treatment we evaluate the recently introduced concept of ‘glucose competence’ of pancreatic β‐cells.