Helen L. Checklin

Control of transient lower esophageal sphincter relaxations and reflux by the GABAB agonist baclofen in normal subjects

BACKGROUND & AIMS Transient lower esophageal sphincter (LES) relaxations are the major mechanism of gastroesophageal reflux in normal subjects and in most patients with reflux disease. gamma-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter within the central nervous system which is present in regions of the brainstem that are believed to mediate transient LES relaxations. The aim of this study was to investigate the effect of a GABA(B) agonist baclofen on postprandial gastroesophageal reflux and transient LES relaxations. METHODS In 20 healthy volunteers, esophageal motility and pH were measured, with the subjects in the sitting position, for 3 hours after a 3000-kJ mixed nutrient meal. On separate days at least 1 week apart, 40 mg oral baclofen or placebo was given 90 minutes before the meal. RESULTS Baclofen significantly reduced the rate of reflux episodes by more than 60% from 1.0 (0.3-2.7) to 0.3 (0-1.0) per hour (median [interquartile range]). Baclofen also reduced the rate of transient LES relaxations from 5.7 (4.9-7.8) to 2.2 (1.3-3.8) per hour and increased basal LES pressure from 8.7 +/- 1.4 to 10.8 +/- 0.8 mm Hg. CONCLUSIONS In normal human subjects, the GABA(B) agonist baclofen significantly inhibits gastroesophageal reflux by inhibition of transient LES relaxations. These findings suggest that GABA(B) agonists may be useful as therapeutic agents for the management of reflux in patients with gastroesophageal reflux disease.

Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects

It has been reported that the artificial sweetener, sucralose, stimulates glucose absorption in rodents by enhancing apical availability of the transporter GLUT2. We evaluated whether exposure of the proximal small intestine to sucralose affects glucose absorption and/or the glycaemic response to an intraduodenal (ID) glucose infusion in healthy human subjects. Ten healthy subjects were studied on two separate occasions in a single-blind, randomised order. Each subject received an ID infusion of sucralose (4 mM in 0.9% saline) or control (0.9% saline) at 4 ml/min for 150 min (T = - 30 to 120 min). After 30 min (T = 0), glucose (25 %) and its non-metabolised analogue, 3-O-methylglucose (3-OMG; 2.5 %), were co-infused intraduodenally (T = 0-120 min; 4.2 kJ/min (1 kcal/min)). Blood was sampled at frequent intervals. Blood glucose, plasma glucagon-like peptide-1 (GLP-1) and serum 3-OMG concentrations increased during ID glucose/3-OMG infusion (P < 0.005 for each). However, there were no differences in blood glucose, plasma GLP-1 or serum 3-OMG concentrations between sucralose and control infusions. In conclusion, sucralose does not appear to modify the rate of glucose absorption or the glycaemic or incretin response to ID glucose infusion when given acutely in healthy human subjects.

Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial

BACKGROUND Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP-1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake. OBJECTIVE We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes. DESIGN Fourteen patients with diet-controlled type-2 diabetes [mean ± SEM glycated hemoglobin (HbA1c): 6.4 ± 0.2% (46.4 ± 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 μg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit. RESULTS Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments. CONCLUSIONS In patients with diet-controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752.

Small Intestinal Glucose Exposure Determines the Magnitude of the Incretin Effect in Health and Type 2 Diabetes

The potential influence of gastric emptying on the “incretin effect,” mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and glucagon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes.

Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans, and patients with type 2 diabetes treated with or without metformin

The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.

The Glucagon-Like Peptide 1 Receptor Agonist Exenatide Inhibits Small Intestinal Motility, Flow, Transit, and Absorption of Glucose in Healthy Subjects and Patients With Type 2 Diabetes: A Randomized Controlled Trial

The short-acting glucagon-like peptide 1 receptor agonist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 μg) or saline (−30 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq 99mTc-sulfur colloid (total volume 200 mL), was given intraduodenally (t = 0–60 min; 3 kcal/min). Duodenal motility and flow were measured using a combined manometry-impedance catheter and small intestinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was observed even in subjects with little or no nausea. The inhibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia.

Acute effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate responses to intraduodenal glucose infusion in type 2 diabetes

Aim: To evaluate the effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate during an intraduodenal glucose infusion in type 2 diabetes. Methods: Nine subjects with type 2 diabetes were randomised to receive intravenous exenatide or saline control in a crossover design. Glucose (3 kcal min−1) was infused via an intraduodenal manometry catheter for 60 min. Blood pressure, heart rate, and the frequency and amplitude of duodenal pressure waves were measured at regular intervals. Gastrointestinal symptoms were monitored using 100 mm visual analogue scales. Results: During intraduodenal glucose infusion (0–60 min), diastolic (p(0–60) = 0.03) and mean arterial (p(0–60) = 0.03) blood pressures and heart rate (p(0–60) = 0.06; p(0–120) = 0.03)) were higher with exenatide compared to placebo. The increase in the area under the curve for diastolic blood pressure and mean arterial blood pressure was related directly to the suppression of the duodenal motility index with exenatide compared to control (p = 0.007 and 0.04, respectively). Conclusion: In type 2 diabetes, intravenous exenatide increases mean arterial blood pressure and heart rate during an intraduodenal glucose infusion, supporting the need for further research with exenatide for its potential use in postprandial hypotension.

A whey/guar "preload" improves postprandial glycaemia and HbA(1c) in type 2 diabetes: a 12-week, single-blind, randomised and placebo controlled trial

Background and aims: Social jetlag is the discrepancy between our internal circadian clock and social clock and is a measure of circadian misalignment. Previous studies have shown that up to two thirds of the general population, aged 18-35y, suffer from social jetlag and its negative effects on metabolic parameters. As data from the general population over 40+y is missing, the aim of this study is to examine the prevalence of social jetlag and the association between social jetlag, the metabolic syndrome and type 2 diabetes in a 40+yearold, population-based cohort. Materials and methods: We used cross-sectional data from the New Hoorn study cohort, n=1734, 48% male, aged 45-73y. Social jetlag was measured using a questionnaire, calculated as the difference in mid-point sleep on week and weekend days and defined as 0-1h, 1-2h or >2h social jetlag.Metabolic syndrome was defined according to the Adult Treatment Panel III, including waist circumference, hypertension and levels of fasting plasma glucose, HDL-C and triglycerides. Pre-diabetes and Type 2 diabetes were defined according to the WHO guidelines; glucose levels > 6.1 mmol/l, HbA1c > 6% or use of diabetes medication. Results: In our 40+year-old population-based cohort, we observed that only 15% of the unemployed/retired participants had social jetlag of >1h and 65% of the employed participants. In the unemployed/retired group no significant associations were observed between social jetlag status, (parameters of) metabolic syndrome and (pre-)diabetes. However, in the employed group, logistic regression adjusted for age, sex and sleep duration showed a positive association between social jetlag, metabolic syndrome and (pre-)diabetes, with respectively OR 1.1 (95%CI 0.7-1.7) and OR 1.7 (95%CI 1.2-2.4) for participants with 1-2h social jetlag, as well as OR 2.1 (95%CI 1.2-3.6) and OR 2.3 (95%CI 1.5-3.8) for >2h of social jetlag, when compared to participants with 0-1h social jetlag. Conclusion: Social jetlag is associated with metabolic syndrome and (pre-)diabetes in working, 40+year-old participants.Abstracts of 52nd EASD Annual Meetings of 52nd EASD Annual Meeting OP 01 GLP-1 receptor agonists: combinations, type 1 diabetes and long-term use 1 Switching from sitagliptin to liraglutide in subjects with type 2 diabetes: analysis of composite endpoints from the LIRA-SWITCH randomised trial T. Bailey, R. Takács, F.J. Tinahones, P.V. Rao, G.M. Tsoukas, S.B. Christensen, M.S. Kaltoft, M. Maislos; AMCR Institute, Escondido, USA, University of Szeged, Szeged, Hungary, Hospital Universitario Virgen de la Victoria, Malaga, Spain, Ramdevrao Hospital, Hyderabad, India, McGill University, Montreal, Canada, Novo Nordisk A/S, Soeborg, Denmark, Soroka University Medical Centre, Beer Sheva, Israel. Background and aims: There is limited clinical evidence to guide treatment choices beyond the addition of another drug to achieve glycaemic target when second-line therapy is inadequate for patients with type 2 diabetes (T2D). The randomised, parallel-group, double-blind, doubledummy, active-controlled LIRA-SWITCH trial compared the efficacy and safety of switching from sitagliptin (sita) to liraglutide (lira) as addon to metformin (MET) in subjects with T2D not achieving adequate glycaemic control with sita + MET. The aim of this analysis was to compare the proportion of subjects meeting four composite endpoints at 26 weeks, relating to glycaemia, body weight, systolic blood pressure (SBP) and hypoglycaemia outcomes. Materials and methods: Eligible subjects (≥18 years, HbA1c 7.5-9.5% [58-80 mmol/mol], BMI ≥20 kg/m), previously treated with stable doses of sita (100 mg/day) and MET (≥1500 mg/day or maximum tolerated dose ≥1000 mg/day) for ≥90 days, were randomised 1:1 to switch to lira 1.8 mg or continue sita 100 mg once daily, both + MET. A series of composite endpoints at week 26 were pre-defined: HbA1c <7.0% (53 mmol/mol) with no weight gain; HbA1c <7.0%, with no weight gain and SBP <140 mmHg; and HbA1c reduction ≥1.0% with no weight gain. In addition, a post hoc analysis of a further endpoint was conducted: HbA1c <7.0%, with no weight gain and no confirmed hypoglycaemic episodes. These dichotomous endpoints were analysed by logistic regression. Results: In total, 407 subjects (male 60%,mean age 56 years, BMI 32 kg/ m, HbA1c 8.3% [67 mmol/mol], T2D duration 8 years) were randomised (lira: 203; sita: 204). At week 26, more subjects achieved each of the four composite endpoints by switching from sita to lira compared with continued sita. HbA1c <7.0% with no weight gain: 48.3% vs. 24.2% (lira and sita, respectively), OR 3.40, 95% CI 2.11; 5.49, p<0.0001. HbA1c <7.0%, with no weight gain and SBP <140 mmHg: 44.9% vs. 19.2%, OR 3.88, 95% CI 2.36; 6.39, p<0.0001. HbA1c reduction ≥1.0% with no weight gain: 52.8% vs. 29.1%, OR 2.85, 95% CI 1.82; 4.47, p<0.0001. HbA1c <7.0%, with no weight gain and no confirmed hypoglycaemic episodes: 48.3% vs. 24.2%, OR 3.40, 95% CI 2.11; 5.49, p<0.0001 (Figure). Conclusion: Switching to lira resulted in more subjects achieving each of the composite endpoints analysed, compared with continued sita treatment. By switching from lira to sita, patients insufficiently controlled on sita and MET have higher probabilities of meeting clinically relevant composite endpoints relating to glycaemia, body weight, SBP and hypoglycaemia. Clinical Trial Registration Number: NCT01907854 Supported by: Novo Nordisk Disclosure: T. Bailey: Employment/Consultancy; AstraZeneca, Bayer, Becton Dickinson, Eli Lilly & Co, Medtronic, Novo Nordisk, Sanofi. Grants; Abbott, ACON, Bayer, Bristol-Myers Squibb, Dexcom, GlaxoSmithKline, Insulet, Janssen, Lexicon, Lifescan, Eli Lilly & Co, Medtronic, Merck, Novo Nordisk, Sanofi. Lecture/other fees; Abbott, Insulet, Novo Nordisk, Sanofi. 2 Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes, the ADJUNCT ONETM treat-to-target randomised trial B. Zinman, B. Bode, J.U. Hemmingson, V. Woo, P. Colman, E. Christiansen, M. Linder, C. Mathieu; Medicine, Mt Sinai Hospital, Toronto, Canada, Atlanta Diabetes Associates, USA, Capio St Gorans Hospital and Karolinska Institute, Stockholm, Sweden, Health Sciences Centre Winnipeg, Canada, Royal Melbourne Hospital, Melbourne, Australia, Novo Nordisk A/S, Bagsværd, Denmark, Katholieke Universiteit, Leuven, Belgium. Backgroundand aims:To investigate if adjunct treatment with liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces insulin requirements and body weight in type 1 diabetes (T1D). Materials and methods: A 52-week double-blinded multinational treatto-target (TTT) trial in adults with T1D in suboptimal glycaemic control DOI 10.1007/s00125-016-4046-9 Diabetologia (2016) 59 (Suppl 1):S1–S581

Effect of duodenal glucose load on blood pressure in type 2 diabetes

Postprandial hypotension occurs frequently in diabetes. We show in 9 type 2 patients, that the fall in systolic blood pressure is greater in response to intraduodenal glucose infused at 4 kcal/min than 2 kcal/min, implying that strategies to slow gastric emptying may be effective in the management of postprandial hypotension.