Does pre-prandial (before meals) compared to prandial (with meals) ingestion of metformin optimise glucose lowering in people with type 2 diabetes?

Prior to being assigned a randomisation code, participants will undergo a screening visit at the Adelaide University Clinical Research Facility (CRF) within the AHMS Building, to evaluate their eligibility. Prior medical history will be collected via a standardised questionnaire by the study investigators. Individuals will have had prior opportunity to read the Participant Information and to discuss their participation with their family and friends, if they wish. Investigators will explain the study protocol and answer any questions the volunteers may have about what is involved, before the volunteers provide written, informed consent, and 10 mL fasting venous blood will be collected for HbA1c, glucose, and liver and kidney function. After enrolment, each participant will undergo a 10-day trial in a double-blind, randomised, crossover design, with treatment allocation assigned by the Royal Adelaide Hospital Pharmacy. Metformin and placebo (cellulose) will be encapsulated in identical gelatin capsules and packed by the Royal Adelaide Hospital Investigational Drugs Pharmacy. Only the designated pharmacists at the Royal Adelaide Hospital Investigational Drugs Pharmacy will dispense the study compounds. The study includes two 3-day treatment periods: (i) immediate-release metformin 500mg 3 times daily, administered 60 min before breakfast, lunch and dinner, with matched placebo administered with meals; and (ii) immediate-release metformin 500mg 3 times daily, administered with breakfast, lunch and dinner, with matched placebo administered 60 min before meals. On Day 0, participants will attend the CRF, where a continuous glucose monitoring (CGM) sensor (FreeStyle Libre Pro, Abbott, IL, USA) will be fitted by one of the investigators to record glucose levels throughout the study period. Participants will continue their usual metformin regimen on Day 1 to establish baseline glucose profiles. Between Days 2-4 and Days 8-10, participants will cease their usual metformin regimen and receive one of the two study treatments. Participants will ingest treatments themselves and be reminded by daily text messages. The treatment periods will be separated by a 3-day washout period (Days 5-7), during which participants will resume their usual metformin regimen. The blister pack of the study drug checked at each study day (Days 4 and 10) to monitor adherence to the intervention. On Days 4 and 10 (the final day of each treatment period), participants will attend a study visit and be provided with 3 standardised test meals. On the evening preceding each visit (~1900h), they will be given a standardised evening meal (frozen beef lasagne, McCain Foods Proprietary Ltd, VIC, Australia; 2472kJ). Following this meal, they will be asked to fast from solids and liquids (water may be consumed until midnight) until the following morning, when they will attend our CRF at ~0800h. Upon arrival, participants will be fitted an ambulatory blood pressure machine. Blood pressure will be monitored every 15 min for 3 hours after breakfast, lunch and dinner on each study day (from 0800h to 2100h). Gastrointestinal symptoms during the treatment period will be assessed using the validated Gastroparesis Cardinal Symptom Index Daily Diary. At ~0900h, participants will consume a standardised mashed potato meal as their breakfast comprising 65 g powdered potato (Continental Deb instant mashed plain potato, Epping, NSW) and 20 g glucose reconstituted with 250 mL boiling water and one egg yolk containing 100 uL 13C-octanioc acid (368.5 kCal). Breath samples will be collected every 5 min in the first 30 min and every 15 min for another 210 min for the measurement of gastric emptying. At ~1300h, participants will consume a standardised lunch and then be free to leave the laboratory. At ~1900h, participants will consume a standardised dinner at home. Participant will be able to choose their lunch and dinner meals from a range of frozen meal options, which will remain consistent throughout the study period (e.g. Beef Rissoles 320g, 1520kJ, On The Menu; Chicken Parmigiana 320g, 1670kJ, On The Menu; Slow Cooked Lamb 320g, 1240 kJ, On The Menu; Vegetarian options: Quorn Meat-Free Loaded Beefy Mac & Cheese 350g, 1630kJ, Kitchen Roasted Vegetable Lasagne 400g, 1670kJ). On Day 11, the CGM sensor will be removed by the investigator at CRF of the AHMS building.