ns and mediate its central effects. Moreover, the cleaved GLP-1 product, which suppresses hepatic glucose production and exerts antioxidant action, may also be enhanced by agents that increase GLP-1 secretion. The amino acid L-glutamine is an efficacious GLP-1 secretagogue for the colonic L-cells model GLUTag and primary murine colonic MedChemExpress Vitamin E-TPGS culture. Well-controlled type 2 diabetes patients have intact GLP-1 response to glutamine ingestion and glutamine or glutamine in combination with the DPP-4 inhibitor sitagliptin decreases postprandial glycaemia and increases circulating insulin and GLP-1 when administered with a meal. The primary aim of this randomized crossover study was to determine the glycemic effect of 4 weeks of glutamine supplementation with sitagliptin or placebo in type 2 diabetes patients treated with metformin. We hypothesized that both treatments will decrease hemoglobin A1c and fructosamine, with a greater effect exhibited in the combined glutamine-sitagliptin treatment, due to more pronounced postprandial increases in GLP-1 in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19683408 the circulation. The secondary aim was to evaluate the safety of glutamine supplementation. Methods This study was conducted according to the principles expressed in the declaration of Helsinki. The study was approved by the Human Research and Ethics Committee at St Vincent’s Hospital, Sydney. All participants gave written informed consent prior to commencement of the study. The protocol for this study and supporting CONSORT checklist are available as supporting information. The study was registered at www.ClinicalTrials.gov. Participants Type 2 diabetes patients were recruited through advertisements at the St Vincent’s Hospital precinct, Sydney and in local newspapers. Participants were recruited and followed between January 2010 and November 2011. Inclusion criteria were age 40 70 years, short diabetes duration, treatment with metformin in a stable dose for at least 3 months, HbA1c 6.59%, BMI 40 kg/m2 and stable body weight in the preceding 6 months. Exclusion criteria were treatment with oral hypoglycemic agents other than metformin, ethanol intake of 40 g/d or more, liver PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19683642 or kidney disease or abnormal full blood count, renal or liver function tests, use of weight loss medications, previous bowel surgery or documented malabsorption. Of the 108 individuals pre-screened for eligibility over the telephone, 22 were invited to a screening visit at the clinic. Fifteen participants were included and 13 completed the study. Trial design The primary endpoints of this study were the glycemic control markers HbA1c and fructosamine, determined as below. Two treatments were considered in the study and randomized crossover design was applied. Participants received glutamine with sitagliptin or placebo. Treatment allocation order was randomized according to a randomization sequence provided by Merck. A nurse not involved directly with the study was in charge of distribution of sequentially numbered containers of sitagliptin or placebo to participants and kept a list with participants’ identification numbers and treatment sequence allocation. Study participants, investigators and nurses were blinded to the treatment allocation order. HbA1c and fructosamine levels were determined at baseline. Participants were then administered their first treatment over a 4 week period. Endpoint levels were then determined. This period was followed by a 46 week washout period. The second treatment trial then followed using the sam