The usefulness of GIP R antagonism for the treatment

The usefulness of GIP-R antagonism for the treatment of obesity-diabetes has been revealed in numerous studies employing knockout or chemical blockade of GIP-R signalling.*88, 89, *90, 91, 92, 93, 94, 95, 96, *97 For example, sub-chronic daily administration of (Pro3)GIP to ob/ob mice results in significant reduction in hyperglycaemia, alleviation of insulin resistance and restoration of glucose tolerance in this severe syndrome. More recent studies, involving once-daily administration of (Pro3)GIP to young ob/ob mice, also indicate that GIP-R blockade is able to prevent the onset of many of the abnormalities of genetically induced obesity-diabetes. Moreover, studies with high-fat fed and ob/ob GIP-R knockout mice illustrate strikingly similar findings.*90, 91 Thus, the inhibition of GIP-R function in GIP-R knockout mice resulted in the suppression of body weight gain, reduced adiposity, amelioration of insulin resistance and marked improvements of glucose tolerance [Fig. 1].*90, 91 These basic observations with GIP-R blockade have recently been replicated by genetic knockout of GIP-secreting K Thioguanine in mice fed a high-fat diet. The studies in GIP-R knockout mice also suggest that up-regulated levels of GLP-1 may contribute to the improved phenotype. However, observations from chemical GIP ablation are less conclusive in that the beneficial metabolic effects of (Pro3)GIP treatment were not observed following GLP-1 receptor blockade using exendin(9–39)amide, and active GLP-1 concentrations were not changed. In addition, there is evidence to suggest that the beneficial actions of (Pro3)GIP in obesity-diabetes are largely mediated through insulin-dependent mechanisms. Studies in normal mice fed a high-fat diet have progressed our understanding of the merit of GIP-R antagonism for the treatment of human obesity-diabetes. Thus, GIP-R antagonism with daily injection of (Pro3)GIP can reverse or prevent many of the metabolic abnormalities associated with dietary-induced obesity-diabetes.95, 96, *97 A key aspect of these studies was the rapid and significant restoration of insulin sensitivity. The two major abnormalities underlying insulin resistance in diabetes are increased hepatic glucose output and decreased glucose uptake, primarily by skeletal muscle. Thus, through increased energy expenditure, preferential oxidation and decreased deposition of fat, GIP-R blockade is able to clear triglyceride deposits from liver and muscle that lack GIP-Rs, thereby restoring mechanisms for suppression of hepatic glucose output and cellular glucose uptake [Fig. 2].96, 98, 99 Changes in circulating glucagon could also explain the observed benefits on insulin sensitivity, but (Pro3)GIP treatment was not associated with significant alterations in glucagon levels.93, 95, 96, *97 Circulating corticosterone was decreased by GIP-R blockade, and given its ability to antagonise insulin action, may contribute to the overall metabolic improvement. The recent demonstration that targeted knockout of GIP-producing K cells reduces obesity and insulin resistance in high-fat fed mice, further reinforces the role of GIP-R antagonists as a treatment for obesity-diabetes. Similarly, active immunisation against GIP has been shown to counter glucose intolerance in ob/ob mice. A preliminary report has also described a small-molecule GIP-R antagonist that replicates the established effects of GIP-R blockade in obese-diabetic mice, but details of specificity, toxicity and chemical identity are presently unknown. Clearly, further studies are warranted to evaluate the potential of GIP-R antagonism for human obesity-diabetes. However, proof of concept is provided by emerging evidence indicating that rapid cure of diabetes in grossly obese subjects undergoing Roux-en-Y gastric bypass surgery may be mediated by surgical bypass of GIP-secreting K cells in the upper small intestine.*101, 102
Clinical evidence form human Roux-en-Y gastric bypass surgery Roux-en-Y gastric bypass procedures are associated with dramatic early postoperative improvements of glycaemic control and insulin sensitivity, importantly even before substantial weight loss.102, 103, 104 Bariatric surgery is increasingly considered as an effective means of treating gross obesity and curing the associated diabetes. The procedure involves two distinct surgical alterations: restriction of gastric capacity and diversion of nutrients from the proximal small intestine. Recent studies now suggest that whilst diet- and surgically induced weight loss inevitably improves type 2 diabetes control, the effect of equivalent weight loss on diabetes control is much more pronounced following Roux-en-Y bypass. Bilopancreatic diversion surgery, which shares the common procedure of bypassing the proximal small intestine, is also associated with a rapid and dramatic reversion of diabetes. The magnitude of this effect of nutrient diversion bariatric surgery has perplexed scientists and clinicians for years. Thus, despite the proven effectiveness of Roux-en-Y and bilopancreatic diversion surgeries, the precise mechanisms for the prominent and immediate restoration of glycaemic control and insulin sensitivity remain obscure. The most widely accepted explanation to date is that the metabolic correction following surgery is a result of the changes in circulating gut hormones. The caloric restriction immediately before and after surgery, when the diet is liquid or pureed, may contribute to such changes, but cannot account for the rapid and sustained amelioration of hyperglycaemia and insulin resistance.