Regulation of pancreatic and gastric endocrine secretion by GIP and GLP-1(7-36) amide
Creators: name: Jia, Xiaoyan
Publisher: name: University of British Columbia
Year: 2009

description: The gastrointestinal hormones gastric inhibitory polypeptide/glucosedependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1; GLP-K7-36) and GLP-K7-37)) are capable of both stimulating insulin secretion and inhibiting gastric acid secretion, these being referred to as their incretin and enterogastrone actions, respectively. It has not yet been established as to whether either peptide is predominantly responsible for these actions physiologically, or whether they act in concert to achieve a common end point. There are, however, studies described in the literature which suggest that tGLP-1 exhibits stronger insulinotropic activity than GIP in humans, rat islets or perfused pancreases. There are also data suggesting that tGLP-1 and GIP exert similar effects on gastric somatostatin secretion, a component of their enterogastrone activity, but opposite effects on gastrin release. These suggestions were reassessed in the studies described in this thesis. In addition, there is evidence for possible roles both for GIP and tGLP-1 in the pathophysiology of obesity and noninsulin dependent diabetes mellitus (NIDDM) in humans. In previous studies on GIP in an animal model of obesity with accompanying hyperinsulinaemia, the Zucker rat, it was found that circulating GIP levels were normal in obese animals but the glucose threshold for the insulinotropic activity of GIP was greatly reduced. This raised the possibility that there was a general defect in the enteroinsular axis in these animals, and that alterations in the secretion and/or actions of tGLP-1 may exist. Responses of immunoreactive (IR-) GLP-1 in lean and obese animals to an oral glucose tolerance test, and the glucose-dependence of the insulinotropic activity of GLP-l(7-36) in their perfused pancreases, were therefore investigated. In order to assess whether tGLP-1 and GIP exhibit different insulinotropic activities gradient perfusions of peptides were administered to an isolated perfused rat pancreas preparation. This enabled the accurate measurement of peptide thresholds for insulinotropic activity and the maximal effects of the peptides. In addition, glucose thresholds for action were determined with a similar gradient system. These studies demonstrated that insulin secretion was increased by both synthetic porcine (sp) GIP and GLP-1 (7-36) at concentrations of -16 pmol/L. Mean maximal responses to GLP-1 (7-36) in the presence of 16.7 mmol/L glucose were slightly greater than to sp GIP or natural porcine (np) GIP, but in the presence of 10 mmol/L glucose sp GIP and GLP-1 (7-36) exerted similar effects. In contrast, responses to synthetic human (sh) GIP were greatly reduced when compared to those to the porcine peptide. In the presence of 50 pmol/L sp GIP or GLP-1 (7-36) the glucose thresholds were identical: 4.5 ± 0.11 mmol/L. Interestingly, increasing either peptide concentration from 50 to 300 pmol/L did not have a major effect on maximal responses to the glucose gradient plus peptide, the reason for which is obscure. Gastric endocrine secretory responses to different preparations of GIP or tGLP-1 were studied in an isolated perfused stomach preparation also using gradient perfusion of peptide. A l l peptides increased the secretion of somatostatinlike immunoreactivity (SLI) with a threshold concentration of -50 pmol/L. The initial rate of increase in response to sp GIP (119 ± 39 pg/min) was greater than with other forms of GIP or with tGLP-1. Maximal increases with sp GIP and np GIP did not differ. Gastrin secretion was stimulated by similar concentrations of sp GIP and np GIP to those effective on SLI secretion. In contrast, both GLP-1 (7- 36) and GLP-1 (7-37) suppressed gastrin secretion. Gastrin and SLI responses to sh GIP were greatly reduced compared to the porcine peptides. Obese Zucker rats were hyperinsulinemic and demonstrated exaggerated responses to the oral glucose tolerance test compared to their lean litter mates. Basal glucose levels were slightly elevated in the obese rats but responses to the oral load did not differ from those in the lean animals. Significant increases in IRGLP- 1 levels in response to oral glucose were only observed in the obese animals. Perfused pancreases from obese rats hypersecreted insulin at all glucose concentrations tested, and exhibited potentiated responses to GLP-1 (7-36). In the presence of 4.4 mmol/L glucose GLP-1 (7-36) increased insulin secretion in the perfused pancreases from obese animals ~25-fold, whereas there was only a 5-fold increase in pancreases from lean animals. Pancreases from obese rats perfused with a glucose gradient (2.8-11 mmol/L) in the presence of GLP-1 (7-36) responded with an immediate increase in insulin secretion at a glucose concentration as low as 2.8 mmol/L, whereas pancreases from lean animals required a minimum of 4.22 mmol/L glucose for stimulation. In the presence of high glucose (16.7 mmol/L) both obese and lean pancreases exhibited similar concentration thresholds for GLP-1 (7-36) of &lt;50 pmol/L. In summary, these studies provide clear evidence that GLP-1 (7-36) and porcine GIP are equally insulinotropic in the perfused rat pancreas, and share the same glucose threshold for activity, whereas sh GIP is less active. The latter result is probably due to problems in the chemical synthesis of the peptide. It is speculated that, although both GIP and tGLP-1 are physiological incretins, at the concentrations observed postprandially GIP is likely to be more important. The results of these studies also show that GIP, GLP-1 (7-36) and GLP-1 (7-37) all stimulate SLI secretion from the perfused stomach but that, whereas GIP stimulates the release of gastrin both forms of GLP-1 inhibit secretion. The possible significance of this to the regulation of gastric function is discussed. Finally, IR-GLP-1 responses to oral glucose are exaggerated in the obese Zucker rat, and the glucose threshold for the insulinotropic action of GLP-1 (7-36) is aberrant, suggesting that there is a general alteration in the hormonal component of the enteroinsular axis in these animals which may contribute to the fasting hyperinsulinemia and exaggerated insulin responses to glucose.