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Pharmacological and Surgical Interventions to Improve Brain Insulin Resistance
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Linus Haberbosch, Lukas Maurer, Reiner Jumpertz-von Schwartzenberg
GIP is an incretin hormone stimulating insulin secretion and reducing hypoglycemia similar to GLP-1. Outside of the pancreas, GIP receptors (GIPR) are expressed in neurons of hypothalamic nuclei linked to appetite control (62). Recent evidence shows improved glucose metabolism and reduced weight gain in CNS-specific humanized GIPR knockout mice, as indicated by enhanced glucose tolerance and decreased fasting levels of glucose and insulin (63). Conversely, GIP application centrally and peripherally showed similar results in the same study. However, when applied in CNS-specific GIPR knockout mice, the effects of GIP on body weight were lost, but improvements in glucose metabolism were replicated (63). While centrally applied GIP improved glycemic control in central GIPR knockout mice, these data suggest a more important role of peripheral/pancreatic GIP effects on glucose metabolism. GIP analogues have shown some promise in reducing oxidative stress and amyloid plaque load in cortex and hippocampus, indirectly improving brain insulin sensitivity by reverting amyloid mediated receptor desensitization (64), however relevant direct effects have not been demonstrated yet.
The Enteroinsular Axis
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
These actions of GIP have led to the hypothesis that the hormone might play a role in the etiology of obesity. GIP secretion is sensitive to chronic changes in diet, in particular, to changes in the dietary fat content; diets high in fat content increase intestinal K cell number [44], GIP expression, and circulating GIP levels [45]. Obesity is typically associated with hyperinsulinemia, and the anabolic activity of GIP could combine with insulin to promote adipose tissue fat deposition. The gene encoding GIP could be considered a thrifty gene, maximizing nutrient storage and valuable to our hunter/gatherer forebears. However, this feature of GIP physiology could be maladaptive in people consuming energy-dense, fat-rich Western diets, and could contribute towards their obesity (Figure 2.2). The hypothesis has gained much recent support from studies of GIP-receptor knock-out mice (GIPR–/–) in which GIP-receptor expression is disrupted. In contrast to normal control animals, these mice did not gain weight or become obese when placed on a high-fat diet. Food intake was not significantly different between the two groups, but the GIPR–/– mice exhibited a higher energy expenditure and appeared to oxidize triglycerides preferentially. In addition, crossing hyperphagic, genetically obese ob/ob mice with GIPR–/– mice reduced the severity of obesity by 23 percent in their homozygous offspring. These findings collectively indicate that GIP is an important hormone in lipid metabolism, which links overnutrition with the development of obesity.
Design of novel therapeutics targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss
Published in Expert Opinion on Drug Discovery, 2023
Appetite reduction is responsible for the observed body weight reduction with the GIPR antagonists. Kaneko et al, when investigating the effects of central infusion of Gipg013, proposed that the reason for the observed reduction in appetite was an improvement in leptin sensitivity (an anorexigenic adipokine) [35]. This hypothesis was derived from a few key observations. First, Gipg013 was only able to reduce body weight in HFD-induced obese mice that have been reported to have impaired leptin sensitivity; lean mice (with normal leptin sensitivity) and ob/ob mice (an obese mouse model with a mutated leptin gene) were unaffected by Gipg013 infusion. Key evidence was provided following leptin infusions into WT and GIPR-KO mice, fed either a chow or HFD. In WT and GIPR-KO mice fed a chow diet, leptin infusion reduced food intake identically in both mouse models. However, in WT mice fed a HFD, only a slight reduction in food intake and body weight was seen upon leptin infusion, suggestive of impaired leptin sensitivity. Importantly, the reduction in appetite and body weight was more significant when leptin was infused into GIPR-KO mice, suggestive of restored leptin sensitivity. The authors went on to show that acute GIP infusion increased hypothalamic mRNA expression of suppressor of cytokine signaling 3 (Socs3), an inhibitor of leptin’s actions, and that GIP’s reductions in leptin sensitivity were dependent on the actions of both exchange protein activated by cyclic-AMP (EPAC-2) and Ras-proximate-1 (RAP1).
GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2023
Ryan A. Lafferty, Peter R. Flatt, Nigel Irwin
Interestingly, the discovery of GIP was made over a decade prior to that of GLP-1 [109,110], hence it poses the question as to why its therapeutic application has taken this long to be realized? The answer is probably two-fold and relates to a documented inefficacy of GIP in patients with T2DM [65], although this phenomenon appears to be reversible when glycemia is returned to more normal values [111]. Secondly, a continuing debate remains as to whether GIPR agonism or antagonism is of most benefit in T2DM and obesity? In this regard, GIP was once referred to as an ‘obesity hormone,’ due to direct actions on GIPR present on adipocytes that promote lipid accumulation [112]. Additionally, GIPR KO mice were reported to be resistant to the adipogenic effects of a high fat diet [113], but this is also true for GLP-1 R KO mice [114]. Conversely, the hormone has been demonstrated to also possess a lipolytic effect [115], albeit in in vitro settings. Either way, it is clear that GIP exerts important direct actions on lipid metabolism that merit further investigation [116,117].
Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
Published in mAbs, 2020
Xiaoshan Min, Junming Yie, Jinghong Wang, Ben C. Chung, Ching-Shin Huang, Haoda Xu, Jie Yang, Liying Deng, Joanne Lin, Qing Chen, Christina M. Abbott, Caroline Gundel, Stephen A. Thibault, Tina Meng, Darren L. Bates, David J. Lloyd, Murielle M. Véniant, Zhulun Wang
GIP is a 42-amino-acid peptide secreted by the K-cells, which are located in the upper tract of the small intestine, duodenum, and jejunum. Similar to GLP-1, GIP is quickly inactivated by DPP-4 mediated cleavage post secretion.5 The signaling of GIP is initiated after binding to its receptor, GIPR, a Gs-coupled class B G-protein-coupled receptor (GPCR) that shares sequence similarity with GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR). GIPR is predominantly expressed in the pancreatic beta cells, the adipose tissue, and certain regions of the brain.1,6 The binding of GIP to GIPR leads to the activation of Gαs and stimulation of adenylate cyclase, which is coupled to the increases in cAMP level.1,6 In pancreas, GIP stimulates glucose-dependent insulin secretion, whereas in adipose tissues, GIP facilitates insulin’s ability to promote fatty acid uptake and incorporation into adipose tissues,7,8 and demonstrates insulin-like lipogenic effects by increasing free fatty acid re-esterification and stimulating lipolysis.9 Moreover, it has been shown that GIP stimulates glucagon secretion, which might contribute to the postprandial hyperglycemia in patients with type 2 diabetes.10–12