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 ...

One of the symptoms of diabetes is the progressive development of neuropathies. One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells. We have tested the effects of the novel GLP-1 mimetics exenatide (exendin-4; Byetta) and liraglutide (NN2211; Victoza), which are already on the market as treatments for type 2 diabetes, on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes. GLP-1 analogues were injected subcutaneously for 4, 6, or 10 weeks once daily in three mouse models of diabetes: ob/ob mice, db/db mice, or high-fat-diet-fed mice. Twenty-four hours before perfusion, animals were injected with 5'-bromo-2'-deoxyuridine (BrdU) to mark dividing progenitor cells. By using immunohistochemistry and stereological methods, the number of progenitor cells or doublecortin-positive young neurons in the dentate gyrus was estimated. We found that, in all three mouse models, progenitor cell division was enhanced compared with nondiabetic controls after chronic i.p. injection of either liraglutide or exendin-4 by 100-150% (P < 0.001). We also found an increase in young neurons in the DG of high-fat-diet-fed mice after drug treatment (P < 0.001). The GLP-1 receptor antagonist exendin(9-36) reduced progenitor cell proliferation in these mice. The results demonstrate that GLP-1 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer's disease, because these novel drugs cross the blood-brain barrier and increase neuroneogenesis.

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 ...

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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.

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These studies show that sitagliptin can reverse memory impairment in high-fat-fed mice and is also associated with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. DPP-4 inhibitors may therefore exhibit dual benefits by improving metabolic control and reducing the decline in cognitive function.

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