McClean PL, Irwin N, Cassidy RS, Holst JJ, Gault VA, Flatt PR. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am J Physiol Endocrinol Metab 293: E1746-E1755, 2007. First published September 11, 2007; doi:10.1152/ajpendo.00460.2007.-The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro 3 )GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro 3 )GIP over 50 days significantly decreased body weight compared with salinetreated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro 3 )GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro 3 )GIP-treated high-fat-fed mice. (Pro 3 )GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro 3 )GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.gastric inhibitory polypeptide; antagonist; high-fat feeding GASTRIC INHIBITORY POLYPEPTIDE (GIP) is an important gastrointestinal hormone secreted from intestinal K cells in response to feeding (35). Together with the sister incretin hormone glucagon-like peptide-1 (GLP-1), GIP comprises the hormonal arm of the enteroinsular axis involved in postprandial nutrient homeostasis (7). The most widely accepted physiological role for GIP is glucose-dependent potentiation of insulin secretion (33). The importance of pancreatic ␤-cells as a target for GIP is further illustrated by the ability of the hormone to stimulate the neogenesis, differentiation, and proliferation of insulinsecreting ␤-cells (10, 43). These various actions have given rise to GIP being implicated as a potentially important player in both the pathogenesis and potential treatment of type 2 diabetes (7,17,48).In addition to the classical ␤-cell target, the GIP receptor is expressed on various extrapancreatic tissues, including bone, intestine, heart, stomach, brain, and adipose tissue (46,49). The significance of GIP action at these sites is largely unknown, but the particularly potent and prolonged stimulation of GIP secretion after high-fat feeding (35) draws attention ...

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R)action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro 3 )GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro 3 )GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro 3 )GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro 3 )GIP-treated group. Daily injection of (Pro 3 )GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesityrelated islet hypertrophy and ␤-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro 3 )GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes. Diabetes 54:2436 -2446, 2005 G lucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is a 42-amino acid peptide hormone secreted by enteroendocrine K-cells after nutrient absorption (1). In the pancreas, GIP stimulates glucose-dependent insulin secretion through interaction with specific heterotrimeric G-protein-coupled GIP receptors (GIP-Rs) on pancreatic ␤-cells (2). Evidence suggests that GIP also stimulates proinsulin gene transcription and translation (3) and acts as a ␤-cell growth factor (4,5) and antiapoptotic agent (6,7). Receptors for GIP have been demonstrated at a number of extrapancreatic sites (8,9), suggesting a range of additional effects on nutrient metabolism. Key among these is the ability of GIP to inhibit gastric acid secretion (10), attenuate glucagon-stimulated hepatic glucose production (11), stimulate glucose uptake in muscle (12), and increase both fatty acid synthesis and lipoprotein lipase activity in adipocytes (13,14). This action profile is reminiscent, but not identical, to that displayed by glucagon-like peptide 1 (GLP-1) (15). Together, GIP and GLP-1 constitute two major physiological incretin hormones of the enteroinsular axis (16).Much recent attention has been devoted to enhancement of incretin action using dipeptidyl peptidase (DPP) IV inhibitors or stable analogs of GLP-1 and GIP for the treatment of type 2 diabetes (17,18). Such an approach is reliant on the possibility that incretin action ...

Aims/hypothesis Gastric inhibitory polypeptide (GIP) receptor antagonism with (Pro 3 )GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure/function in ob/ob mice. This study examined the ability of (Pro 3 )GIP to counter the development of obesity, insulin resistance and diabetes in mice fed high-fat and cafeteria diets. Materials and methods Young Swiss TO mice on standard chow or high-fat, cafeteria or high-carbohydrate diets received daily injections of either saline or (Pro 3 )GIP (25 nmol kg -1 day -1 ) over 16 weeks. Food intake, body weight, and circulating glucose and insulin were measured frequently. At 16 weeks, glucose tolerance, insulin sensitivity, HbA 1c , circulating hormones and plasma lipids were assessed. Adipose tissue, liver and muscle were excised and weighed, and their histology and triacylglycerol content were further examined.

Recent evidence suggests that the classic gut peptide, Peptide YY (PYY), could play a fundamental role in endocrine pancreatic function. In the present study expression of PYY and its NPY receptors on mouse islets and immortalised rodent and human beta-cells was examined together with the effects of both major circulating forms of PYY, namely PYY(1-36) and PYY(3-36), on beta-cell function, murine islet adaptions to insulin deficiency/resistance, as well as direct effects on cultured beta-cell proliferation and apoptosis. In vivo administration of PYY(3-36), but not PYY(1-36), markedly (p < 0.05) decreased food intake in overnight fasted mice. Neither form of PYY affected glucose disposal or insulin secretion following an i.p. glucose challenge. However, in vitro, PYY(1-36) and PYY(3-36) inhibited (p < 0.05 to p < 0.001) glucose, alanine and GLP-1 stimulated insulin secretion from immortalised rodent and human beta-cells, as well as isolated mouse islets, by impeding alterations in membrane potential, [Ca(2+)]i and elevations of cAMP. Mice treated with multiple low dose streptozotocin presented with severe (p < 0.01) loss of beta-cell mass accompanied by notable increases (p < 0.001) in alpha and PP cell numbers. In contrast, hydrocortisone-induced insulin resistance increased islet number (p < 0.01) and beta-cell mass (p < 0.001). PYY expression was consistently observed in alpha-, PP- and delta-, but not beta-cells. Streptozotocin decreased islet PYY co-localisation with PP (p < 0.05) and somatostatin (p < 0.001), whilst hydrocortisone increased PYY co-localisation with glucagon (p < 0.05) in mice. More detailed in vitro investigations revealed that both forms of PYY augmented (p < 0.05 to p < 0.01) immortalised human and rodent beta-cell proliferation and protected against streptozotocin-induced cytotoxicity, to a similar or superior extent as the well characterised beta-cell proliferative and anti-apoptotic agent GLP-1. Taken together, these data highlight the significance and potential offered by modulation of pancreatic islet NPY receptor signalling pathways for preservation of beta-cell mass in diabetes.

Gastric inhibitory polypeptide (GIP) is a physiological gut peptide secreted from the intestinal K-cells with well documented insulin-releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex and brain, suggesting that it may have other functions. The presence of functional GIP receptors on adipocytes and the key role played by GIP in lipid metabolism and fat deposition suggest a possible beneficial effect of compromised GIP action in obesity and insulin resistance. Several key observations in animal models of obesity-related diabetes with chemically or genetically mediated biological GIP deficiency support this concept. Thus, obese diabetic animals with compromised GIP action due to peptide-based GIP receptor antagonists, small molecular weight GIP receptor antagonists, vaccination against GIP, genetic knockout of GIP receptor or targeted K-cell destruction are protected against obesity and associated metabolic disturbances. In addition, by causing preferential oxidation of fat, blockade of GIP signalling clears triacylglycerol deposits from liver and muscle, thereby restoring mechanisms for suppression of hepatic glucose output and improving insulin sensitivity. Emerging evidence also suggests that rapid cure of diabetes in grossly obese patients undergoing bypass surgery is mediated, in part, by surgical removal of GIP-secreting K-cells in the upper small intestine.

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Aims/hypothesis Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8. Methods The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice. Results (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p<0.05 to p<0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p<0.01 to p<0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p<0.05 to p<0.001), accumulated food intake (p< 0.05 to p<0.001), non-fasting glucose (p<0.05) and triacylglycerol deposition in pancreatic (p<0.01), adipose (p< 0.05) and liver (p<0.001) tissue, and improved oral (p< 0.05) and i.p. (p<0.05) glucose tolerance and insulin sensitivity (p<0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology. Conclusions/interpretation These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

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