The hormone glucose-dependent insulinotropic polypeptide (GIP) potently stimulates insulin secretion and promotes ␤-cell proliferation and cell survival. In the present study we identified Forkhead (

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert β-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced β-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down-regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis.

Glucose-dependent insulinotropic polypeptide (GIP) has been mainly studied because of its glucose-dependent insulinotropic action and its ability to regulate ␤-cell proliferation and survival. Considerably less is known about the effects of GIP on fat metabolism, and the present study was directed at identifying the mechanisms underlying its stimulatory action on lipoprotein lipase (LPL). In differentiated 3T3-L1 adipocytes, GIP, in the presence of insulin, increased LPL activity and triglyceride accumulation through a pathway involving increased phosphorylation of protein kinase B (PKB) and reductions in phosphorylated LKB1 and AMP-activated protein kinase (AMPK). Knockdown of AMPK using RNA interference and application of the AMPK inhibitor, Compound C, supported this conclusion. In contrast, the other major incretin hormone, glucagon-like peptide-1, exhibited no significant effects on LPL activity or PKB, LKB1, or AMPK phosphorylation. Cultured subcutaneous human adipocytes showed similar responses to GIP but with greater sensitivity. Chronic elevation of circulating GIP levels in the Vancouver diabetic fatty Zucker rat in vivo resulted in increased LPL activity and elevated triglyceride accumulation in epidydimal fat tissue, combined with a modulation of PKB, LKB1, and AMPK phosphorylation similar to that observed in vitro. This appears to be the first demonstration of a GIP-stimulated signal transduction pathway involved in increasing fat storage in adipocytes. Glucose-dependent insulinotropic polypeptide (GIP)2 is a pleiotropic hormone that is released from gut endocrine cells in response to nutrient ingestion (1-3). There is strong evidence that GIP and glucagon-like peptide-1 (GLP-1) are the two most important gut-derived insulinotropic hormones, or incretins (1-4). Both incretins also exert powerful positive effects on pancreatic ␤-cell growth, development, and survival (5, 6). A number of studies have demonstrated that GIP plays an important role in the regulation of fat metabolism (7-9). GIP is released in response to administration of triglycerides (TG) (1, 2), with long chain fatty acids (FAs) being responsible for stimulating secretion (1). In dogs, GIP has been shown to promote clearance of chylomicron-associated TG from blood (10), and in rats, it has been shown to promote infusion of GIP-lowered plasma TG responses to intraduodenal fat (11). GIP enhanced FA synthesis from acetate in adipose tissue explants (12) as well as potentiating insulin-stimulated FA incorporation into adipose tissue (13) and stimulating lipoprotein lipase (LPL) activity in cultured preadipocytes (14) and mature adipocytes (15). These studies pointed to a significant role for GIP in the regulation of adipogenesis, and its physiological importance was emphasized by the demonstration by Miyawaki et al. (16) that GIP receptor knock-out mice exhibited reduced adipose tissue accretion on a high fat diet.The GIP receptor is a member of the class B seven-transmembrane G protein-coupled family to which the receptors for glucagon,...

The therapeutic potential of glucose-dependent insulinotropic polypeptide (GIP) for improving glycemic control has largely gone unstudied. A series of synthetic GIP peptides modified at the NH2-terminus were screened in vitro for resistance to dipeptidyl peptidase IV (DP IV) degradation and potency to stimulate cyclic AMP and affinity for the transfected rat GIP receptor. In vitro experiments indicated that [d-Ala2]GIP possessed the greatest resistance to enzymatic degradation, combined with minimal effects on efficacy at the receptor. Thus, [d-Ala2]GIP1–42 was selected for further testing in the perfused rat pancreas and bioassay in conscious Wistar and Zucker rats. When injected subcutaneously in normal Wistar, Fa/?, or fa/fa Vancouver Diabetic Fatty (VDF) Zucker rats, both GIP and [d-Ala2]GIP significantly reduced glycemic excursions during a concurrent oral glucose tolerance test via stimulation of insulin release. The latter peptide displayed greater in vivo effectiveness, likely because of resistance to enzymatic degradation. Hence, despite reduced bioactivity in diabetic models at physiological concentrations, GIP and analogs with improved plasma stability still improve glucose tolerance when given in supraphysiological doses, and thus may prove useful in the treatment of diabetic states.

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