Colonic delivery of nutrients for management of blood glucose in type 2 diabetes patients

Abstract

Background: It is now widely accepted that bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) resolve or improve type 2 diabetes mellitus. Post-prandial 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. Expedited delivery of nutrients, such as 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 4.4 mg of sodium butyrate, compared to saline, into the colon of Zucker diabetic fatty (ZDF) rats increased GLP-1 secretion in response to an intra-duodenal glucose challenge. In a chronic study, oral dosing of 40 mg 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-hyperglymic agents, infusion of 1 g 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 90 min; p=0.001 at 120 min; 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.Conclusions: Targeted colonic delivery of L-glutamine and butyrate augments secretion of meal-stimulated GLP-1 and insulin. 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.Key words: Diabetes, nutrients, gut hormones, GLP-1, secretagogues, glucose management.