These various observations indicate that

These various observations indicate that GIP plays an important role in the normal compensatory islet response to high fat feeding. This likely reflects the loss of the combined actions of intra-islet GIP together with intestinally-derived GIP entering the islet vasculature following secretion from distant K-cells which are stimulated powerfully by dietary fats [7], [38]. In this regard, it is notable that the potential action of circulating GIP is limited by extensive DPPIV-mediated degradation which results in a half-life of 7min, with >95% reaching the islet as inactive GIP(3–42) [39], [40]. In contrast, evidence for an effect at islet level concerns a paradoxical increase of pancreatic GIP and remarkable decreases of pancreatic GLP-1 content and GLP-1 staining of the alpha Quinidine in the poorly adapted islets of high fat fed GIPRKO mice. This suggests that part of the beneficial effect of islet derived GIP may be related to positive effects on alpha cell expression and intra-islet actions of GLP-1. Further studies are required to test this hypothesis, including the use of tissue specific GIPRKO mice, but such a relationship between GIP and GLP-1 has been observed in intestinal L-cells [6], [38], [41]. In addition, it would be of interest to determine whether the decrease in expression of GLP-1 is common to both islet and intestinal-GLP-1. Overall these data demonstrate that GIP released locally in islets from alpha cells or secreted from intestinal K-cells plays an important role in the positive islet adaptations to high fat feeding. The loss of compensation in GIPRKO mice indicates that the well-known actions of high concentrations of GIP on the stimulation of beta cell proliferation and inhibition of apoptosis [42], [43] are physiologically relevant. Such effects are possibly reinforced by positive effects of GIP on the intra-islet production of GLP-1.
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Acknowledgements This study was funded in part by an EFSD/Boehringer Ingelheim Grant, University of Ulster Research Strategy Funding and a research scholarship to RCM from the Department of Education and Learning, Northern Ireland. Professor B Thorens (Lausanne, Switzerland) is thanked for the provision of GIPRKO mice.
Introduction Obesity is a significant global problem that considerably increases risk of cardiovascular disease, type 2 diabetes, insulin resistance and hyperlipidemia [1]. High caloric intake, whether from consumption of foods containing more fat or overeating, and inactive lifestyle, disrupt the balance between energy intake and output and worsen obesity [2], [3], [4]. Despite considerable efforts by both academia and industry, there are presently few effective treatment options for obesity. Given the role of the gut in the absorption of nutrients and production of potent regulatory peptides that coordinate nutrient disposal and satiety, it represents an important target organ for therapeutic strategies to combat both diabetes and obesity, particularly with members of the glucagon receptor family [5]. Ingested nutrients are sensed and absorbed by the intestine, triggering the release of hormones from enteroendocrine cells lining the gut epithelium. Two such hormones are the incretins gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Mice with knockout of either the GIP receptor or GLP-1 receptor display glucose intolerance associated with blunted insulin secretion [6], [7]. The ability of these hormones to act directly on β-cells to augment insulin secretion during meals in a glucose-dependent manner is the basis for the treatment of diabetes by incretin mimics and inhibitors of the enzyme dipeptidyl-peptidase 4 (DPP-4) that rapidly degrades GIP and GLP-1 [8]. GIP is secreted by K-cells during meals, particularly when the cells come in contact with fat or glucose [9]. In addition to stimulating brisk release of insulin [10], GIP promotes adipogenesis and lipid accumulation in adipocytes [11], [12]. Therefore, there has been some debate over whether GIP agonists used to improve glucose homeostasis may increase adiposity while GIP antagonists could promote weight loss [13]. Several studies have convincingly demonstrated glucose lowering effects following long-term administration of DPP-4 resistant GIP analogs in rodents [14], [15], [16], [17]. Moreover, somewhat surprisingly, chronic overexpression of GIP in mice reduced diet-induced obesity and steatosis, in addition to improving glucose homeostasis [18]. Yet a seminal study revealed that mice with knockout of the GIP receptor are protected from high fat diet induced obesity and the development of insulin resistance [12]. Moreover, inhibition of GIP signaling in this model increases fat oxidation in peripheral tissues in associated with increased adiponectin levels [19]. These findings are bolstered by studies demonstrating that reducing circulating GIP levels with K-cell ablation [20], disruption of GIP gene expression [21], immunoneutralization [22], or vaccination against GIP [23] also reduced weight gain in mice following high fat diet, without impairing glucose homeostasis.