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Background: It is now widely accepted that bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) can resolve or improve type 2 diabetes mellitus. Postprandial glucagon-like peptide-1(GLP-1) increases after both RYGB and SG and blockade of the GLP-1 receptor suppresses the hypoglycemic effect post-operatively. The expedited delivery of nutrients, including L-glutamine and butyrate, to the distal small intestine and colon, where most GLP-1--secreting enteroendocrine L-cells are expressed, could explain this increase post-surgery. Pharmacological treatments that target nutrient-sensing receptors on L-cells may mimic the effects of bariatric surgeries and may ameliorate deficiencies in gut hormone responses involved in the regulation of glucose and satiety. In this study, we investigated the effects of the colonic delivery of L-glutamine and butyrate on GLP-1 secretion and glucose homeostasis in both a pre-clinical rodent model and clinical type 2 diabetes mellitus (T2DM). Results: Infusion of 4.4mg of sodium butyrate, compared to saline, into the colon of Zucker diabetic fatty (ZDF) rats increased GLP-1secretion in response to an intra-duodenal glucose challenge. In a chronic study, oral dosing of 40mg of sodium butyrate twice a day, formulated as colon-targeted sustained-release tablets, preserved glucose tolerance and insulin sensitivity in ZDF rats. In ten T2DM patients requiring oral anti-hyperglycemic agents, infusion of 1g of L-glutamine into the colon, compared to saline, increased plasma GLP-1 (p=0.017 at 30 min) and insulin (p<0.01 at 90min; p=0.001 at 120min; AUC p<0.005) after an oral glucose challenge. Similar infusion with butyrate significantly increased only insulin secretion at 120 min, compared to saline (p<0.05). Neither agent had an effect on glucose disposal. Conclusion: Targeted colonic delivery of L-glutamine and butyrate augments secretion of meal-stimulated GLP-1 and insulin; L-glutamine was more efficacious in humans. Such an approach may be valuable for the management of hyperglycemia in T2DM patients. A chronic clinical study with colon-targeted sustained-release L-glutamine is required to validate this hypothesis. [ABSTRACT FROM AUTHOR]

Insulin resistance is a uniform finding in type 2 diabetes, as are abnormalities in the microvascular and macrovascular circulations. These complications are associated with dysfunction of platelets and the neurovascular unit. Platelets are essential for hemostasis, and knowledge of their function is basic to understanding the pathophysiology of vascular disease in diabetes. Intact healthy vascular endothelium is central to the normal functioning of smooth muscle contractility as well as its normal interaction with platelets. What is not clear is the role of hyperglycemia in the functional and organic microvascular deficiencies and platelet hyperactivity in individuals with diabetes. The entire coagulation cascade is dysfunctional in diabetes. Increased levels of fibrinogen and plasminogen activator inhibitor 1 favor both thrombosis and defective dissolution of clots once formed. Platelets in type 2 diabetic individuals adhere to vascular endothelium and aggregate more readily than those in healthy people. Loss of sensitivity to the normal restraints exercised by prostacyclin (PGI(2)) and nitric oxide (NO) generated by the vascular endothelium presents as the major defect in platelet function. Insulin is a natural antagonist of platelet hyperactivity. It sensitizes the platelet to PGI(2) and enhances endothelial generation of PGI(2) and NO. Thus, the defects in insulin action in diabetes create a milieu of disordered platelet activity conducive to macrovascular and microvascular events. [ABSTRACT FROM AUTHOR]