Two pathways have emerged to explain the beneficial metaboli

Two pathways have emerged to explain the beneficial metabolic effect of Roux-en-Y bypass [Fig. 3]. Firstly, the rapid delivery of nutrients to the distal small intestine and bowel might up-regulate secretion of a physiological stimulus that improves glucose homeostasis. As such, GLP-1 represents an ideal candidate mediator of these beneficial actions. Secreted from the L praziquantel biltricide of the distal intestine and bowel, GLP-1 potentiates postprandial insulin release, improves pancreatic beta-cell function and inhibits food intake in humans, and moreover is currently a recognised treatment option for type 2 diabetes. Furthermore, PYY and oxyntomodulin are also secreted from the enteroendocrine L cells and have putative anorexigenic and metabolic effects. However, since peptide levels would only be modestly elevated and for a limited duration compared to normal physiological circulating concentrations, enhanced L-cell secretions are unlikely to account for the rapid improvement of insulin sensitivity and restoration of diabetes control observed in patients. More importantly, none of these products of the proglucagon gene can account for the mechanism behind the amelioration of insulin resistance which is the key metabolic driver. The second pathway revolves around exclusion of nutrient transit from the upper small intestine that might result in inhibition of the secretion of a hormone-promoting insulin resistance and deposition of fat stores [Fig. 3]. The aforementioned actions of GIP on lipid metabolism and fat deposition, together with the striking similarity of the effects of Roux-en-Y surgery with results of chemical and genetic GIP-R blockade in animal models [Table 2], suggest that GIP signalling is important for the success of these surgeries. Thus, it appears GIP links obesity to insulin resistance and diabetes in humans. Consistent with this view, several recent studies have shown that GIP is decreased rapidly following Roux-en-Y surgery in humans.102, 103, 110 Overall, the observations support the view that the benefits of Roux-en-Y may be linked to surgical ablation of GIP-secreting cells. Thus, replicating the hormonal milieu that follows Roux-en-Y surgery with chemical GIP-R antagonists is an attractive potential option for the treatment of obesity-diabetes, particularly since obesity may be a contraindication to surgery itself.
Clinical considerations To date, there are little clinical data regarding GIP-based therapeutics. However, the report of a long-acting GIP analogue, AC163794 from Amylin Pharmaceuticals with antidiabetic potential, and coupled with exciting preclinical data on other GIP agonists53, 54, 55, 56, 57, 58, 61, 62, 63, 64, 65, 66, 67 would indicate that these studies are coming closer to realisation. A drawback with GLP-1-based therapies is the reported side effects, including nausea, vomiting, dizziness and headaches. Nausea is less likely to occur with GIP analogues since this incretin hormone does not inhibit gastric emptying. However, currently, the lack of published clinical data on GIP analogues makes their safety and tolerability difficult to assess. The positive actions of GIP on the growth, survival and function of pancreatic beta cells might suggest an additional role in islet transplantation patients. Recently, a long-acting GLP-1 mimetic, liraglutide, was shown to improve glucose homeostasis in marginal mass islet transplantation in mice. Furthermore, it is increasingly clear that GIP plays an important role in lipid metabolism, promoting the efficient deposition of dietary fat into adipose tissue stores. Thus, by improving insulin resistance in combination with beta-cell sparing, GIP antagonists may offer a potentially new class of drugs for the treatment of obesity-diabetes. This viewpoint is strengthened by the uncoupling of the effects of GIP signalling in animal models of obesity-diabetes and the surgical GIP ablation in obese humans by Roux-en-Y surgery.
Conclusion Owing to its glucose-dependent insulinotropic properties, longer-acting GIP-R agonists have been suggested as potential therapeutic options for type 2 diabetes. Similar to the actions of sulphonylureas, GIP-R agonists will act via stimulation of insulin secretion. However, their glucose-dependent nature and ability to nurture beta cells and promote insulin synthesis indicate superior mode of action. Moreover, given that the question regarding GIP sensitivity in type 2 diabetes has largely been answered, the realisation of such therapies may be closer than first anticipated. Finally, recent research suggests that GIP-R antagonists may afford an entirely new class of drugs for alleviation of obesity-related insulin resistance with beta-cell sparing effects. Given the close parallels between Roux-en-Y surgery in humans and studies of GIP-R blockade in animal models of obesity-diabetes, GIP-R antagonists may offer an exiting new treatment option for obesity-diabetes.