Effects of endogenous bile acids on postprandial glucose levels in health and type 2 diabetes

INTERVENTION: Following enrolment, each subject will be studied on 3 occasions, separated by at least 7 days, in a single‐blind, randomized fashion. On each study day, a silicone rubber catheter will be inserted by an experienced research officer through an anaesthetised nostril into the stomach, and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the two infusion ports (i.e. proximal and distal small intestinal infusion ports) located at 50 cm (i.e. the jejunum) and 190 cm (i.e. the ileum) beyond the pylorus, respectively, while subjects laid in a supine position. An inflatable self‐contained balloon (5 cm in length, with a maximum volume of 100 mL) situated 30 cm below the pylorus, that can be inflated as a barrier between the duodenum and the jejunum, and an aspiration channel 25 cm distal to the pylorus (to aspirate endogenous bile). The correct positioning of the catheter will be monitored continuously by measurement of the transmucosal potential difference in the stomach ( ‐40 mV) and the duodenum ( 0 mV). For this purpose, an intravenous cannula will be placed subcutaneously in the left forearm by our experienced research office rand filled with sterile saline as a reference electrode. An intravenous cannula will be placed into a vein on the dorsum of the hand, which will be kept warm with a heat pad to allow sampling of “arterialisedâ€? blood. Once the intraluminal catheter is correctly positioned, the balloon will be slowly inflated with air ( 30‐40 mL) until the subject reports a sensation of pressure without discomfort. An intra‐balloon pressure of at least 20 mmHg (a known pressure to be sufficient to achieve full blockade) will be maintained by continuous monitoring with a pressure gauge throughout the study (t = 0 ‐ 180 min). The aspiration channel will be connected to negative pressure drainage to allow constant aspiration of secretions from the duodenum. At t = 0 min, subjects will receive intraj CONDITION: Diet and Nutrition ‐ Obesity Metabolic and Endocrine ‐ Diabetes Type 2 diabetes;Obesity; ; Type 2 diabetes ; Obesity PRIMARY OUTCOME: the difference in the iAUC for plasma glucose between the treatments[t= 0, 15, 30, 45, 60, 90, 120, 150 and 180 min, where t = 0 is when intrajejunal glucose infusion starts. ] INCLUSION CRITERIA: (i) Patients with type 2 diabetes (World Health Organisation (WHO) criteria), HbA1c less than or equal to 8.5%, managed by diet or metformin alone, body mass index from 20 to 35 kg/m2, both males and females aged from 18 to 75 years (ii) Healthy volunteers, matched as closely as possible to the diabetic subjects for age, sex, and BMI. Additional inclusion criteria include: haemoglobin above the lower limit of the normal range (ie. more than 135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. more than 30ng/mL for men and 20mg/mL for women) SECONDARY OUTCOME: the differences in the iAUCs for plasma C‐peptide between treatments[t= 0, 15, 30, 45, 60, 90, 120, 150 and 180 min, where t = 0 is when intrajejunal glucose infusion starts. ] the differences in the iAUCs for plasma FGF19 between treatments[t= 0, 15, 30, 45, 60, 90, 120, 150 and 180 min, where t = 0 is when intrajejunal glucose infusion starts. ] the differences in the iAUCs for plasma glucagon between treatments[t= 0, 15, 30, 45, 60, 90, 120, 150 and 180 min, where t = 0 is when intrajejunal glucose infusion starts. ] the differences in the iAUCs for plasma insulin between the treatments[t= 0, 15, 30, 45, 60, 90, 120, 150 and 180 min, where t = 0 is when intrajejunal glucose infusion starts. ] the differences in the iAUCs for plasma total GLP‐1 between the treatments[t= 0, 15, 30, 45, 60, 90, 120, 150 and 180 min, where t = 0 is when intrajejunal glucose infusion starts. ]