We hypothesized that GIP is anabolic in human subcutaneous adipose tissue (SAT) promoting triacylglycerol (TAG) deposition through reesterification of nonesterified fatty acids (NEFA), and this effect may differ according to obesity status or glucose tolerance.
To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide).
This, together with reports on GIP antagonists that may protect against obesity, has revived the interest on the GIP/GIPR axis as a potential anti-diabetic pathway.
This review will discuss the physiological effects of GIP on fat metabolism in human adipose and other non-adipose tissues such as liver, pancreas, skeletal muscle and heart, describe where the actions of GIP may contribute to the pathophysiology of obesity, T2D and NAFLD and finally describe the therapeutic implications of GIP antagonism and agonism in these conditions.
Therefore, elevated Pro-CT and CGRP-I levels in obesity might result from GIP-induced Pro-CT and CGRP-I release in AT and might be triggered by a high-fat diet.
Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance.
Recent studies with a GIP receptor antagonist suitable for human studies have confirmed these concepts regarding the actions of endogenous GIP and point to potential beneficial metabolic effects of GIP receptor antagonists rather than agonist in the treatment of obesity and type 2 diabetes.
Nonetheless, interrogation of the GIP/GIPR axis on cardiac function in humans will involve the systemic actions of the GIPR within the myocardium and other systems (e.g. adipose tissue, vasculature), which will influence the long-term future of GIPR modification for the treatment of obesity/T2DM.
Lastly, we discuss how dysmetabolic conditions such as obesity and type 2 diabetes may shift the actions of GIP in an atherogenic direction, and we provide a perspective on the therapeutic potential of GIP receptor agonism and antagonism in cardiovascular diseases.
In this review, we first summarize our traditional understanding of the physiology of GIP and GLP-1, and our current knowledge of the relationships between GIP and GLP-1 and obesity and diabetes.
In humans, genomewide association studies have identified single nucleotide polymorphisms (SNPs) in the GIPR gene that are strongly associated with body mass index (BMI); however, it is not clear whether genetic variations in the GIP gene are involved in the development of obesity.
In conclusion, both obese and diabetic rats had an impaired early-phase insulinotropic effect of GIP due to impaired gene expression of GIP-Rs which could be a potential target to prevent transition of obesity to diabetes and to improve insulin secretion in the latter.
In addition, observations in transgenic GIP receptor deficient mice indicate that GIP directly links overnutrition to obesity, therein playing a crucial role in the development of obesity and related metabolic disorders.
Given the established roles of glucose-dependent insulinotropic polypeptide (GIP) in promoting fat storage and bone formation, we assessed the contribution of GIP to obesity and osteopenia in ovariectomized mice with a gene encoding green fluorescent protein (GFP) inserted into the GIP locus, in which GIP was either reduced (GIP<sup>gfp/+</sup> ) or absent (GIP<sup>gfp/gfp</sup> ).
Augmentation of glucose mediated insulin release, the incretin effect, was discovered soon after GIP was first isolated and only much later was its important role in the pathogenesis of obesity, through mechanism other than insulin secretion, appreciated.
As such, blockade of GIP receptor (GIPR) action has been proposed as a means to counter insulin resistance, and improve metabolic status in obesity and related diabetes.
Antagonizing the glucose-dependent insulinotropic polypeptide (GIP) receptor may open up new therapeutic modalities in the treatment of diabetes and obesity.