The Impact of Pancreatic Exocrine Insufficiency and Pancreatic Enzyme Replacement Therapy on Gastric Emptying, Gut Hormone and Glycaemic Responses to a Meal in Type 2 Diabetes Mellitus

This is a double-blind randomised-placebo controlled cross-over study evaluating the effect of pancreatic enzyme replacement therapy (PERT) on postprandial glycaemia, gastric emptying and incretin response in subjects with type 2 diabetes with evidence of exocrine pancreatic insufficiency on faecal elastase testing. We will evaluate the effects of PERT versus placebo on postprandial glycaemia, gastric emptying and incretin responses following a high fat/high carbohydrate meal. The presence and potential reversibility of postprandial hypotension will also be evaluated. After providing written and informed consent, each participant will be provided with a lasagne dinner the night prior to attending the trial. After the lasagne dinner, participants will undergo an overnight fast and then arrive at the Nuclear Medicine Department at the Royal Adelaide Hospital in the morning (0800) on two separate occasions. Participants will be given a high fat/high carbohydrate mashed potato meal (60g fat, 60g carbohydrate - 50% energy from fat and 50% energy from carbohydrate) to be eaten over 10 minutes (t = -10 to 0 minutes), labelled with 20 MBq 99mTc calcium phytate and C13 octanoic acid. Participants will be asked to withhold their usual morning antihypertensive medication until after the 4 hour-study. Participants will eat the meal while seated in an upright position. The management of the participant’s usual management for type 2 diabetes will be supervised by an endocrinologist (Dr Liza Phillips) who will determine requirement for any changes to usual treatment (e.g. possible dose modification of insulin). At the same time as the meal they will take two capsules of pancrelipase (total 50, 000 U) or matching placebo. Venous blood samples will be sampled at t = -15, 0, 15, 30, 60, 90, 120, 180, 240 minutes for blood glucose and plasma insulin, C-peptide, glucagon, GIP and GLP-1 concentrations. Gastric emptying will be measured using scintigraphy; images will be acquired using the gamma camera for 240 minutes (60-second frames for the first 60 minutes and 3-minute frames thereafter). Breath tests will also be collected as a contingency measure as access to Nuclear Medicine facilities may be interrupted for a substantial period during the nRAH and Medical School Building moves that will occur during 2017. The breath tests will be collected but only analysed if scintigraphy proves unfeasible for the whole cohort. We do not plan to use the gastric emptying data derived from scintigraphy and breath tests interchangeably. Appetite will be evaluated using a standardised visual analogue (VAS) scale 15 minutely for the first 2 hours and 30 minutely thereafter. Other questionnaires to be completed at each visit include the Diabetes Bowel Symptom Questionnaire (15, 16) which has been modified to include some specific questions pertaining to steatorrhea and the Bristol Stool chart. These questionnaires are designed to evaluate bowel symptoms in diabetes and capture symptoms relating specifically to pancreatic exocrine insufficiency. Blood pressure will be taken prior to ingestion of the test meal and then 3 minutely thereafter with an automated BP cuff (DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI, USA). Standardised tests of cardiovascular autonomic function will be undertaken on the first study visit in the fasted state. There will be a minimum ‘washout’ period of 72 hours. Dose Administered: Two Pancrelipase capsules 25, 000 Units (total 50, 000 units), Duration of Dose: Single dose - on two separate study days Mode of Administration: Oral capsule