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Is Glucagon-Like Peptide 1 an Incretin Hormone?

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Is Glucagon-Like Peptide 1 an Incretin Hormone? Diabetologia (1999) 42: 373±379 Ó Springer-Verlag 1999 For debate Is glucagon-like peptide 1 an incretin hormone? Michael A. Nauck Department of Medicine, Knappschafts-Krankenhaus, Ruhr-University Bochum, Germany Summary Glucagon-like peptide-1 (GLP-1) was pre- humans has not been definitely proven. Nevertheless, dicted, based on the proglucagon gene sequence. It it has potent insulinotropic activity, especially during is synthesised by specific post-translational process- hyperglycaemia. This suggests new therapeutic op- ing in L cells (lower intestine) and secreted mainly tions for patients with Type II (non-insulin-depen- as ªtruncatedº GLP-1 [7±36 amide] in response to nu- dent) diabetes mellitus. On the other hand, most L trient ingestion. Glucagon-like peptide-1 stimulates cells are located in the lower small intestine. Potent insulin secretion during hyperglycaemia, suppresses inhibitory actions of GLP-1 on upper gastrointestinal glucagon secretion, stimulates (pro)insulin biosyn- motor and digestive functions (e.g. gastric emptying thesis and decelerates gastric emptying and acid se- and acid secretion) in response to nutrients placed cretion. On intracerebroventricular injection, GLP-1 into the ileal lumen, argue for a role of this peptide reduces food intake in rodents. A GLP-1 receptor an- as an ªileal brakeº. Malassimilation and diarrhea tagonist or GLP-1 antisera have been shown to re- leading to the erroneous presence of nutrients in the duce meal-stimulated insulin secretion in animals, lower gut may, via GLP-1, delay gastric emptying suggesting that GLP-1 has a physiological ªincretinº and reduce upper gut motility and thereby prevent function (augmentation of postprandial insulin secre- further caloric losses. [Diabetologia (1999) 42: 373± tion due to intestinal hormones) for GLP-1. In heal- 379] thy human subjects, exogenous GLP-1 slows gastric emptying. Consequently, postprandial insulin secre- Keywords Glucagon-like peptide 1, incretin hor- tion is reduced, not augmented. Thus, a participation mones, ileal brake, insulin, glucagon, motility, gastric of this peptide in the incretin effect of non-diabetic emptying Discovery of GLP-1. Glucagon-like peptide 1 (GLP- mately 50% homology) and therefore named GLP-1 1) was predicted after its nucleotide sequence was no- and GLP-2. Speculations about physiological func- ticed during sequence analysis of the preproglucagon tions were mainly based on sequence homology to gene [1]. This precursor protein contains the se- other members of the glucagon-secretin family of quence of pancreatic glucagon and has two additional gastrointestinal peptide hormones. Therefore, GLP- nucleotide stretches. If translated into the amino acid 1 and GLP-2 were first tested for insulinotropic activ- sequence, these are similar to glucagon (approxi- ity [2]. But additional effects of GLP-1 have been dis- covered and it is not decided what the physiological function of GLP-1 in healthy animals and humans Received: 4 August 1998 and in revised form: 8 October 1998 could be. Corresponding author: Professor M. Nauck, Medizinische Uni- Incretin hormones. The definition of the incretin ef- versitätsklinik, Knappschafts-Krankenhaus, In der Schornau 23±25, D-44 892 Bochum, Germany fect and incretin hormones by Creutzfeldt [3] has Abbreviations: GLP-1, Glugagon-like peptide 1; GIP, glucose- been widely accepted and used: the incretin effect de- dependent insulin-releasing peptide scribes the phenomenon of oral glucose eliciting a 374 M.A. Nauck: GLP-1 physiology greater insulin response than intravenous glucose in- fused directly into the ileal lumen release GLP-1 fusions, no matter whether the same amount of glu- [21], indicating that direct stimulation of L-cell secre- cose is infused [4] or an equivalent rise in glycaemia tion is possible in humans. Oral glucose [7, 8, 22±24], is caused by the parenteral route [5]. These experi- sucrose [25], triglycerides [22] and mixed meals also ments showed that up to 60% of the insulin secretory lead to an increment in plasma GLP-1 [14±16]. These response after an oral glucose load are not caused by nutrient-related GLP-1 responses start early (i.e. a direct interaction of glucose with beta cells in the is- within 5 min) after ingestion [8], and last for approxi- lets of Langerhans, but by the secretion and insulino- mately an hour [8, 22, 26]. It is doubtful, that nutrients tropic action of gut peptides [5]. Incretin hormones have reached portions of the gut with high L-cell den- are gut factors released by oral nutrients, which stim- sities by that time. Especially oral glucose is com- ulate insulin secretion at the typical postprandial con- pletely absorbed from the duodenum and upper je- centrations reached in the presence of hyperglycae- junum [27]. Therefore, indirect signalling pathways mia [3]. As an intravenous infusion of glucose-depen- may exist that stimulate L-cell secretion if glucose is dent insulin-releasing peptide (GIP) and glucose, present in the duodenum. which leads to similar concentrations of glucose and Glucose-dependent insulin-releasing peptide is, GIP as an oral glucose load, augments insulin secre- however, released from the duodenum and upper je- tion to the same extent [6±8], GIP was identified as junum, where K cells are abundant [6]. First GIP in- the first incretin candidate [3, 9]. Based on the insuli- crements are seen within 15 min after nutrient inges- notropic activity of intestinal mucosal extracts which tion and can last for several hours [28]. Therefore, had been depleted of GIP [10], and on a continuing GIP may qualify for an incretin role especially re- incretin effect when circulating GIP was inactivated garding the later postprandial insulin secretory re- by anti-GIP antibodies [11], additional incretin hor- sponse. mones were, however, postulated. Then GLP-1 was Glucose-dependent insulin-releasing peptide ap- discovered. This peptide was found to be insulino- pears to be an ªupper gut signalº for the release of tropic, i.e. to stimulate insulin secretion, especially GLP-1 in rodents [29], but not in humans [26]. at raised glucose concentrations [2]. It had been pre- Lower gut resections (removing the most abun- dicted [2] and later shown that this ability was much dant stores of GLP-1) do not alter GLP-1 responses more pronounced in the case of ªtruncatedº GLP-1 after oral glucose [23]. Quantitative considerations (GLP-1 [7±36 amide]) [12, 13]. Therefore, it was sug- allow the conclusion that the amount of GLP-1 pre- gested that GLP-1 is an incretin hormone [7, 8] con- sent in the upper jejunum is still several fold higher tributing to meal-stimulated insulin secretory re- than the amount released in response to a single nu- sponses. trient stimulus [23]. Glucagon-like peptide-1 has a short plasma half- Synthesis, processing and secretion of GLP-1, recep- life and is inactivated by dipeptidyl peptidase IV pre- tor and signal transduction. For basic information on sent in blood plasma [30, 31]. After intravenous infu- the biology of GLP-1, readers are referred to several sions with GLP-1, more than 70% of GLP-1-like ma- excellent reviews [14±16]. The proglucagon gene is terial measured with non-specific assays was N-termi- expressed in alpha cells of the islets of Langerhans nally degraded [31]. and in L cells of the gut. These are endocrine cells Binding sites for GLP-1 are present on insulinoma present in large numbers in the ileum and colon and cells [32] and a receptor has been cloned [33, 34]. It in much smaller numbers in the duodenum and je- belongs to the 7 trans-membrane-domain family of junum [17]. Whereas the main product of post-trans- receptors and is expressed in islets of Langerhans lational processing of proglucagon in the endocrine (beta cells, delta cells, and possibly alpha cells) [35]. pancreas is glucagon, in L cells glicentin (ªenteroglu- The major second messenger is cAMP [36]. In addi- cagonº), GLP-1 and GLP-2 are the main final prod- tion, the activation of other signal transduction path- ucts. Differential processing is thought to be due to ways leading to increased intracellular Ca++ concen- different prohormone convertases. The final form of trations have also been described [37]. GLP-1 that is produced in L cells is ªtruncatedº GLP-1 [12]. It occurs mainly in the C-terminally ami- Effects of GLP-1 in normal animals and humans. In- dated form (GLP-1 [7±36 amide]). A minor product sulinotropic effects of GLP-1 have already been men- is the glycine-extended (i.e. non-amidated) GLP-1 tioned, but this is not the only biological action of [7±37] [18]. The term ªtruncationº refers to the origi- GLP-1. nally proposed sequences GLP-1 [1±36 amide] (or [1±37]), which does not occur as such in larger quanti- (1) GLP-1 stimulates insulin secretion in isolated is- ties [14]. lets of Langerhans [2], in the perfused pancreas [12, Glucagon-like peptide-1 is secreted from isolated 13], and in whole organisms, both in animals and hu- perfused ileum preparations [19, 20] when glucose or mans [7, 8, 38]. Its effects are glucose-dependent, fat are infused through the gut lumen. Nutrients in- with greater effects occurring at higher glucose con- M.A. Nauck: GLP-1 physiology 375 centrations [7, 8, 39]. At normal fasting glucose con- trients [56]. This is of interest because in the first case centrations only small effects on insulin secretion potential effects on gastric emptying should not be of can be achieved which are not strong enough to cause any importance, whereas in the second, deceleration clinically manifest hypoglycaemia [39]. of gastric emptying due to GLP-1 might occur. An ex- (2) GLP-1 is able to suppress glucagon secretion in is- plicit measurement of gastric emptying, however, has lets [40], the perfused pancreas [41], and in whole or- not been taken under these study conditions.
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