Detection of ECG effects of (2R,4R)-monatin, a sweet flavored isomer of a component first identified in the root bark of the Sclerochitin ilicifolius plant.

Enzymatically-synthesized (2R,4R)-monatin has, due to its pure sweet taste, been evaluated for potential use in foods. Non-clinical studies have shown that (2R,4R)-monatin is well tolerated at high dietary concentrations, is not genotoxic/mutagenic, carcinogenic, or overtly toxic. In a pharmacokinetic and metabolism study involving 12 healthy males, consumption of a single oral dose (2 mg/kg) of (2R,4R)-monatin resulted in a small reduction of heart rate and prolongation of the QTcF interval of 20-24 ms, corresponding to the time of peak plasma levels (t(max)). These findings were evaluated in a cross-over thorough QT/QTc study with single doses of 150 mg (2R,4R)-monatin, placebo and positive control (moxifloxacin) in 56 healthy males. Peak (2R,4R)-monatin plasma concentration (1720 ± 538 ng/mL) was reached at 3.1 h (mean tmax). The placebo-corrected, change-from-baseline QTcF (ΔΔQTcF) reached 25 ms three hours after dosing, with ΔΔQTcF of 23 ms at two and four hours. Using exposure response (QTc) analysis, a significant slope of the relationship between (2R,4R)-monatin plasma levels and ΔΔQTcF was demonstrated with a predicted mean QT effect of 0.016 ms per ng/mL. While similarly high plasma levels are unlikely to be achieved by consumption of (2R,4R)-monatin in foods, QTc prolongation at this level is a significant finding.

Dose-response characteristics of high-viscosity hydroxypropylmethylcellulose in subjects at risk for the development of type 2 diabetes mellitus.

BACKGROUND: Hydroxypropylmethylcellulose (HPMC) is a modified cellulose fiber that creates a viscous solution in the gastrointestinal tract. The present study examined the dose-response characteristics of high-viscosity (HV)-HPMC consumption on postprandial glucose and insulin levels in men and women at increased risk for type 2 diabetes mellitus. METHODS: Subjects were a subset of participants in two trials with elevated peak postprandial glucose [>or=7.8 mmol/L (>or=140 mg/dL)] and body mass index (BMI) >or=27 kg/m(2). Subjects (n = 39) consumed breakfast meals containing 75 g of carbohydrate, each of which contained 1, 2, 4, or 8 g of HV-HPMC or a cellulose control in a randomized, double-blind manner. Each subject completed tests with control and two HV-HPMC doses. RESULTS: Peak glucose concentration was lower than control (all P < 0.01) following 2 g (10%), 4 g (18%), and 8 g (20%) of HV-HPMC. Peak insulin was also reduced (P < 0.01) following 2 g (32%), 4 g (35%), and 8 g (46%) of HV-HPMC doses versus control. Incremental areas for glucose from 0 to 120 min were reduced by 8-40% versus control but only reached significance for the 4-g and 8-g conditions, whereas incremental areas under the insulin curves were reduced by 14-53% (P < 0.01 for 2, 4, and 8 g of HV-HPMC). CONCLUSIONS: Among subjects at risk for type 2 diabetes mellitus, 1.0-8.0 g of HV-HPMC blunted postprandial glucose and insulin responses in a dose-dependent manner. Additional research is warranted to assess whether chronic consumption might retard the development or progression of glucose intolerance.

Hydroxypropylmethylcellulose and methylcellulose consumption reduce postprandial insulinemia in overweight and obese men and women.

Hydroxypropylmethylcellulose (HPMC) and methylcellulose (MC) are modified cellulose dietary fibers that generate viscous solutions in the gastrointestinal (GI) tract. This study assessed the effects of high viscosity (HV) HPMC, ultra-HV (UHV) HPMC, and medium viscosity MC on postprandial glucose and insulin responses in overweight and obese men and women (n = 50). After overnight fasts, subjects consumed 5 breakfast meals containing 75 g carbohydrate, each of which contained 1 of the following: 1 g HV-HPMC, 2 g HV-HPMC, 2 g UHV-HPMC, 4 g medium-viscosity MC or control (2 g cellulose). Test sequence was randomized and double-blind, except the MC test, which was last and single-blind (46 subjects completed all 5 tests). Glucose and insulin responses were determined pre-meal and for 120 min postprandially. Median (interquartile limits) peak glucose concentration was lower (P = 0.001) after the meal containing 2.0 g UHV-HPMC (7.1, 6.3-8.2 mmol/L) compared with the control meal (7.7, 6.6-8.7 mmol/L). The control did not differ from the other conditions for peak glucose or for any of the HPMC/MC conditions for glucose incremental areas under the curves (IAUC). Peak insulin was reduced (P < 0.05) for all HPMC/MC conditions compared with control. Insulin IAUC was lower than control (P < 0.001) after meals containing 2 g HV-HPMC, 2 g UHV-HPMC, and 4 g MC. GI symptoms did not differ among treatments. These findings indicate that HV-HPMC (1 and 2 g), UHV-HPMC (2 g), and MC (4 g) consumption reduced postprandial insulin excursions consistent with delayed glucose absorption.

High-viscosity hydroxypropylmethylcellulose blunts postprandial glucose and insulin responses.

OBJECTIVE: High-viscosity hydroxypropylmethylcellulose (HV-HPMC) is a modified cellulose fiber that produces a viscous gel in the gastrointestinal tract. Clinical trials demonstrate that consumption of HV-HPMC significantly lowers cholesterol, but limited information has been available on the influence of HV-HPMC on postprandial insulin and glucose responses. The objective of this investigation was to assess the influence of HV-HPMC on postprandial glucose and insulin responses in overweight and obese men and women. RESEARCH DESIGN AND METHODS: Participants were 31 overweight or obese men and women without diabetes who underwent three breakfast meal tests in random order, separated by > or = 72 h. Test meals containing 75 g carbohydrate plus 4 or 8 g HV-HPMC or control meals containing 8 g cellulose were delivered in a double-blind fashion. RESULTS: Peak glucose was significantly lower (P < 0.001) after both HV-HPMC-containing meals (7.4 mmol/l [4 g] and 7.4 mmol/l [8 g]) compared with the control meal (8.6 mmol/l). Peak insulin concentrations and the incremental areas for glucose and insulin from 0 to 120 min were also significantly reduced after both HV-HPMC doses versus control (all P < 0.01). CONCLUSIONS: These findings indicate that HV-HPMC consumption reduces postprandial glucose and insulin excursions, which may favorably alter risks for diabetes and cardiovascular disease.