None listed
Conditions
Brief summary
A family of receptors in the gut recognises all known sweet tasting molecules, including glucose. We, and others, have shown that activation of these ‘sweet taste receptors’ triggers a series of events, mediated by gut hormones, which coordinate the absorption and metabolism of glucose, increasing the capacity for both. These gut hormones increase insulin release in the presence of glucose, and increase levels and function of the major gut glucose transporter, sodium-glucose co-transporter 1 (SGLT-1). Accordingly, the activation status of gut sweet taste receptors has the potential for substantial influence on the control of blood glucose. Patients with type 2 diabetes have increased capacity for glucose absorption from their gut, a trait which can worsen their blood glucose control, and increase disease progression. We recently published important data showing that sweet taste receptors in the duodenum were abnormal in patients with type 2 diabetes during high blood glucose, in association with increased glucose absorption. Blocking duodenal sweet taste receptors is known to reduce the release of gut hormones linked to increases in the glucose transporter SGLT-1 in both rodents and humans, however, it is unknown whether blocking sweet taste receptors in patients with type 2 diabetes can reduce glucose transporter function and, therein, glucose absorption, as a new approach to therapy. We now plan to test the effects of the sweet taste receptor blocker, lactisole, on blood glucose control in patients with type 2 diabetes following a glucose infusion.
Interventions
Healthy subjects and patients with type 2 diabetes will be screened for eligibility then undergo 2 study day visits, separated by at least 2 weeks, in a randomised, double-blinded manner.
All subjects will receive a standardised evening meal prior to the study day, then fast until the following morning, with water allowed after the meal until 10 pm. Patients treated by oral metformin will be instructed to withhold any dose due the evening for 2 days (48 hours) prior to the study visit, and to
Healthy subjects and patients with type 2 diabetes will be screened for eligibility then undergo 2 study day visits, separated by at least 2 weeks, in a randomised, double-blinded manner. All subjects will receive a standardised evening meal prior to the study day, then fast until the following morning, with water allowed after the meal until 10 pm. Patients treated by oral metformin will be instructed to withhold any dose due the evening for 2 days (48 hours) prior to the study visit, and to defer their morning dose until the meal at the end of the study. On each study day, fasted unsedated subjects will have an intravenous cannula inserted into forearm veins for blood sampling and for infusion of glucose or insulin. Insulin (0.2 IU/mL) or 25% glucose will be infused intravenously at a rate adjusted to achieve hyperglycaemia (12 mmol/L) throughout the study period. Once stably clamped, a small diameter (5.3 mm) video endoscope will be placed in position in the second part of the duodenum via an anaesthetised nostril. Five mucosal biopsies will be collected via endoscope forceps, then the endoscope will be withdrawn. A thin intraduodenal catheter (3.5 mm) will be inserted via an anaesthetised nostril into the second part of the duodenum; positioning will be maintained by continuous measurement of the transmucosal potential difference between antrum and duodenum. An automated blood pressure cuff will be placed around the arm for measurement of blood pressure and heart rate throughout the study period. Subjects will be randomised to the order of infusions containing the sweetness inhibitor lactisole, or control (no lactisole), on alternative study days. On a control study day subjects will receive a preload infusion of 0.9% saline (2 mL/min) via the intraduodenal catheter over 30 min. At 30 min (T = 0) a glucose solution will be infused for 120 min (90 g glucose dissolved in water to a volume of 240 mL, 2 mL/min; 3 kcal/min). At T = 120 min a glucose solution containing the non-metabolisable glucose analogue 3-O-methyl glucose (3-OMG, to assess glucose absorption) will be infused via the intraduodenal catheter for 60 min (45 g glucose and 2.4 g of 3-OMG dissolved in water to a volume of 120 mL, 2 mL/min; 3 kcal/min). On a lactisole study day subjects will receive a preload infusion of 450 ppm lactisole in 0.9% saline (27 mg dissolved in 60 mL; 2 mL/min) via the intraduodenal catheter over 30 min. At 30 min (T = 0) a glucose solution containing 450 ppm lactisole will be infused for 120 min (90 g glucose and 108 mg lactisole dissolved in water to a volume of 240 mL, 2 mL/min; 3 kcal/min). At T = 120 min a glucose solution containing 450 ppm lactisole and the non-metabolisable glucose analogue 3-O-methyl glucose (3-OMG, to assess glucose absorption) will be infused via the intraduodenal catheter for 60 min (45 g glucose, 54 mg lactisole and 2.4 g of 3-OMG dissolved in water to a volume of 120 mL, 2 mL/min; 3 kcal/min). At the end of glucose infusions (T = 180 min), the intraduodenal catheter will be removed and the endoscope inserted again to collect 5 more duodenal biopsies; bloods will be collected regularly over the 5 hour study. A log of infusion administration will be kept to monitor protocol adherence.
Sponsors
Royal Adelaide Hospital
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
(Healthy) Nondiabetic, healthy volunteers matched as closely as possible for sex and body mass index; body mass index 20-30 kg/m2; HbA1c less than or equal to 7.0% (Type 2 Diabetic) Volunteers with type 2 diabetes (World Health Organisation criteria) managed by diet alone or metformin; body mass index >20 kg/m2; HbA1c >7.0%
Exclusion criteria
Exclusion (Healthy) Significant illness including impairment to cardiovascular or respiratory function that limits a subject’s activity and therefore would represent a risk to undertaking endoscopy safely (American Society of Anaesthesiologists Grade 3 or more); History of gastrointestinal disease, including significant upper gastrointestinal symptoms (assessed by a validated gastrointestinal symptom questionnaire), pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendectomy or cholecystectomy); Diffuse mucosal disease involving the upper gastrointestinal tract, including Crohn’s disease, coeliac disease, or ischaemic changes, evident either macroscopically or on histopathological examination of mucosal biopsies; Haemoglobin below the lower limit of the normal range (ie. <135g/L for men and 115g/L for women), and ferritin below the lower limit of normal (below 20ng/mL for women and 30ng/mL for men); Significant history of migraine; Impaired renal or liver function (as assessed by calculated creatinine clearance < 90 mL/min or abnormal liver function tests, > 2 times upper limit of normal); Body mass index greater than 30 kg/m2 or less than 20 kg/m2; Donation of blood within the previous 3 months; Participation in any other research studies within the previous 3 months; Subjects requiring the use of anticoagulant drugs, antiplatelet agents or NSAIDS; Subjects with known coagulopathy; Presence of mucosal abnormalities at endoscopy; Subjects requiring medication that may influence gastrointestinal function; Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes per day; Female patients not using appropriate contraceptive method (ie oral contraceptive pill, diaphragm, DepoProvera hormonal contraceptive injection, intrauterine device (IUD), Norplant method); Vegetarian, lactation or pregnancy (verified by urine testing in women of reproductive age; in these subjects, study will be completed during the follicular phase of the menstrual cycle) (Type 2 Diabetics) Significant illness, other than type 2 diabetes, including impairment to cardiovascular or respiratory function that limits a subject’s activity and therefore would represent a risk to undertaking endoscopy safely (American Society of Anesthesiologists Grade 3 or more); History of gastrointestinal disease, including significant upper gastrointestinal symptoms (assessed by a validated gastrointestinal symptom questionnaire), pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendectomy or cholecystectomy); Diffuse mucosal disease involving the upper gastrointestinal tract, including Crohn’s disease, coeliac disease, or ischaemic changes, evident either macroscopically or on histopathological examination of mucosal biopsies; Haemoglobin below the lower limit of the normal range (ie. <135g/L for men and 115g/L for women), and ferritin below the lower limit of normal (below 20ng/mL for women and 30ng/mL for men); Significant history of migraine; Impaired renal or liver function (as assessed by calculated creatinine clearance < 90 mL/min or abnormal liver function tests (> 2 times upper limit of normal)); Subjects medicated with anti-diabetics other than metformin; Subjects unable to self-monitor blood glucose levels; Volunteers with body mass index less than 20 kg/m2; Donation of blood within the previous 3 months; Participation in any other research studies within the previous 3 months; Subjects requiring the use of anticoagulant drugs, anti-platelet agents or NSAIDS; Subjects with known coagulopathy; Presence of mucosal abnormalities at endoscopy; Subjects requiring medication that may influence gastrointestinal function; Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes per day; Female patients not using appropriate contraceptive method (ie oral contraceptive pill, diaphragm, DepoProvera hormonal contraceptive injection, intrauterine device (IUD), Norplant method); Vegetarian, lactation, or pregnancy (verified by urine testing in women of reproductive age; in these subjects, the study will be completed during the follicular phase of the menstrual cycle)
Outcome results
None listed