Triazole GHS-R1a antagonists JMV4208 and JMV3002 attenuate food intake, body weight, and adipose tissue mass in mice.

The only peripherally released orexigenic hormone, ghrelin, plays a key role in food intake and body weight regulation. Antagonizing the ghrelin receptor, GHS-R1a, represents a promising approach for anti-obesity therapy. In our study, two novel GHS-R1a antagonists JMV4208 and JMV3002, which are trisubstituted 1,2,4-triazoles, decreased food intake in fasted lean mice in a dose-dependent manner, with ED50 values of 5.25 and 2.05 mg/kg, respectively. Both compounds were stable in mouse blood, with half-lives of 90 min (JMV4208) and 60 min (JMV3002), and disappeared from the blood 8h after administration. Fourteen days of treatment with the ghrelin antagonists (20 mg/kg twice a day) decreased food intake, body weight and adipose tissue mass in mice with diet-induced obesity (DIO). These results are likely attributable to an impact on food intake reduction and an attenuated expression of the lipogenesis-promoting enzymes (acetyl-CoA carboxylase 1 in subcutaneous fat and fatty acid synthase in subcutaneous and intraperitoneal fat). The decrease in fat mass negatively impacted circulating leptin levels. These data suggest that JMV4208 and JMV3002 could be useful therapeutic agents for the treatment of obesity.

Comparison of dinner with bedtime administration of insulin glargine in type 1 diabetic patients treated with basal-bolus regimen.

OBJECTIVE: To establish the equivalence in efficacy (HbA(1c)) of insulin glargine injected at dinner versus bedtime in a large number of patients with type 1 diabetes using a fast-acting analogue (FAA) or regular human insulin (RHI) as prandial insulin in an insulin glargine-bolus regimen. RESEARCH DESIGN AND METHODS: In a 26-week trial, 1178 patients with type 1 diabetes and treated with different basal-bolus regimens were randomized to receive insulin glargine once daily at dinner (n=589) or at bedtime (n=589) while continuing their previous prandial insulin (FAA: 75%; RHI: 25% of patients). The primary objective was to demonstrate equivalence in terms of HbA(1c) levels at endpoint. RESULTS: Baseline characteristics were similar in the two groups. At endpoint, HbA(1c) (mean+/-standard deviation [S.D.]) had decreased by 0.25+/-0.66% to 7.77+/-0.96% in the dinnertime group (P<0.0001), and by 0.24+/-0.76% to 7.83+/-1.07% in the bedtime group (P<0.0001). The HbA(1c) difference between dinner and bedtime was -0.022% (two-sided 90% confidence interval [CI] -0.09; 0.05), demonstrating statistical equivalence of HbA(1c) at endpoint between the two groups. Equivalence was also demonstrated within prandial groups: HbA(1c) difference between dinner and bedtime was -0.03% (two-sided 90% CI: -0.11; 0.06) for FAAs and -0.04% (two-sided 90% CI: -0.19; 0.11) for RHIs. The incidence of severe hypoglycaemia did not differ between the treatment groups. CONCLUSION: These data confirm that insulin glargine in combination with either FAA or RHI is equally effective and safe, whether it is administered at dinner or bedtime.

Screening and diagnosis of gestational diabetes.

Gestational diabetes mellitus (GDM) is a risk factor for the mother and foetus. The risks increase proportionally to the maternal blood sugar concentration along a glycaemic continuum. However, there is ongoing controversy about the objectives of active screening and diabetic and obstetrical management for GDM. Various screening and diagnostic tests are used. None of them offers the combination of qualities to be expected from a test: simplicity of use, reproducibility, specificity and sensitivity, but each of them provides a basis on which recommendations can be established. The need to screen GDM as a risk factor in the whole population of pregnant women has led us to propose the use of simple, universally applied test, such as the "practical" test constituted by the assay of fasting and post-prandial blood glucose levels. In addition to screening, a classification which will take into account the results of subsequent as well as initial blood glucose levels could be preferable to evaluate the management and results.

Plasma and urine kinetics of erythritol after oral ingestion by healthy humans.

The plasma and urine kinetics of erythritol and the effect of erythritol on plasma glucose and insulin levels were studied in human volunteers administered a single oral dose of 1 g erythritol/kg body wt. The plasma level of erythritol increased during the first 30 to 40 min, reaching a maximum value of approximately 2.2 mg/ml after 90 min. Plasma levels of erythritol then declined gradually to approximately 1.5 to 1.7 mg/ml at the end of the 3-hr sampling period. An average of 30% of the ingested amount of erythritol was excreted unchanged in the urine during the first 3 hr. Total urinary excretion increased to 78% after 24 hr. Renal clearance of erythritol was approximately half that of creatinine, indicating tubular reabsorption of erythritol by the kidney. Mean plasma glucose and insulin levels, measured for up to 3 hr after ingestion, were unaffected by erythritol. The results of this study indicate that erythritol was readily absorbed following oral administration and was excreted unchanged in the urine. Less than 20% of erythritol remained unabsorbed and was available for colonic fermentation and potential production of short-chain fatty acids. Its caloric value was estimated to be < or = 0.4 kcal/g.

Gastrointestinal response and plasma and urine determinations in human subjects given erythritol.

This study was undertaken to examine the influence of erythritol on certain plasma and urinary parameters and to assess the gastrointestinal response of humans given erythritol at single oral doses of 0.4 or 0.8 g/kg body wt/day. Three groups of six healthy volunteers each received a midmorning snack containing the equivalent of 0.4 or 0.8 g erythritol/kg body wt or 0.8 g sucrose/kg body wt. A fourth group received no snack and served as a negative control group. Consumption of erythritol did not affect plasma osmolarity, water consumption, or diuresis, and no significant variations in plasma or urine electrolyte balance were observed. Plasma glucose and insulin concentrations also were not affected by erythritol. Gastrointestinal responses to erythritol were comparable to those of sucrose. Plasma and urine erythritol concentrations increased within 2 hr of ingestion in proportion to the amount ingested. Approximately 60% of the erythritol dose was eliminated in the urine within 22 hr. The results of this study demonstrate that ingestion of erythritol at doses of up to 0.8 g/kg body wt does not alter plasma or urine osmolarity or electrolyte balance and is well tolerated by the digestive tract.

Chronic consumption of short-chain fructooligosaccharides by healthy subjects decreased basal hepatic glucose production but had no effect on insulin-stimulated glucose metabolism.

We aimed to study the effects of chronic ingestion of short-chain fructooligosaccharides (FOS), an indigestible carbohydrate, on hepatic glucose production, insulin-mediated glucose metabolism, erythrocyte insulin binding, and blood lipids in healthy subjects. Twelve healthy volunteers received either 20 g FOS/d or sucrose for 4 wk in a double-blind crossover design. FOS did not modify fasting plasma glucose and insulin concentrations. Mean (+/- SEM) basal hepatic glucose production was lower after FOS than after sucrose consumption (2.18 +/- 0.10 compared with 2.32 +/- 0.09 mg.kg-1, min-1, respectively; P < 0.02, paired Student's t test). However, neither insulin suppression of hepatic glucose production nor insulin stimulation of glucose uptake measured by hyperinsulinemic clamp was significantly different between the two dietary periods. Erythrocyte insulin binding was also comparable. Serum triacylglycerols, total and high-density- lipoprotein cholesterol, apolipoproteins A-I and B, and lipoprotein(a) were not modified by FOS. To try to understand why FOS did not increase serum lipids, the in vitro production of short-chain fatty acids from FOS was evaluated by using human fecal inoculum and compared with that from lactulose, which was found to increase serum lipids. FOS produced an acetate-propionate ratio two times lower than that of lactulose. We conclude that 4 wk of 20 g FOS/d decreased basal hepatic glucose production but had no detectable effect on insulin-stimulated glucose metabolism in healthy subjects. The colonic fermentation pattern of undigestible carbohydrates may be relevant to predicting their metabolic effects.

Insulin and glycemic responses in healthy humans to native starches processed in different ways: correlation with in vitro alpha-amylase hydrolysis.

The aim of the study was to elucidate how extracted starches submitted to food processing (or not) can influence plasma insulin and glucose responses in healthy subjects. Native starches from wheat, manihot, smooth peas, or mung beans were tested either raw, as starch gels (boiled and cooled), or cooked and cooled after a preliminary industrial processing: extrusion cooking for wheat, tapioca for manihot, and noodles for mung beans. Eighteen healthy subjects randomly assigned received three different starches under one form of conditioning. All products were submitted to in vitro alpha-amylolysis. Raw manihot starch produced the lowest (p less than 0.05) metabolic responses. Cooking significantly (p less than 0.01) increased plasma responses. However, cooked mung bean noodles gave metabolic responses similar to those of raw products. Close correlations were found between percentages of in vitro starch hydrolysis at 30 min and mean areas under the glycemic curves and the insulinemic curves (r = 0.95, p less than 0.001).

Insulinemic and glycemic indexes of six starch-rich foods taken alone and in a mixed meal by type 2 diabetics.

The glycemic index concept neglects the insulin secretion factor and has not been systematically studied during mixed meals. Six starch-rich foods were tested alone and in an isoglucido-lipido-protidic meal in 18 NIDDs and compared with a glucose challenge. These test meals were randomly assigned using a three factor experiment design. All three tests contained 50 g carbohydrate; mixed meals were adjusted to bring the same amount of fat (20 g), protein (24 g), water (300 mL), and calories (475 kcal) but not the same amount of fiber. Whatever the tested meals, foods elicited a growing glycemic index hierarchy from beans to lentils, rice, spaghetti, potato, and bread (mean range: 0.21 +/- 0.12-92 +/- 0.12, p less than 0.001). Mixing the meals significantly increased the insulinemic indexes (p less than 0.05) and introduced a positive correlation between glycemic and insulinemic indexes (n = 6, r = 0.903; p less than 0.05). The glycemic index concept remains discriminating, even in the context of an iso-glucido-lipido-protidic meal. Insulinemic indexes do not improve discrimination between foods taken alone in type 2 diabetics: they only discriminate between foods during mixed meals, similarly to glycemic indexes.

Sucrose or honey at breakfast have no additional acute hyperglycaemic effect over an isoglucidic amount of bread in type 2 diabetic patients.

Exclusion of simple sugars from the diabetic diet is not always followed by patients and may not even be as crucial as was hitherto thought. We tested three types of mixed breakfasts (400 kcal, 50 g HCO) including an isoglucidic amount either of white bread (30 g), honey (20 g) or sucrose (15 g), at the critical morning period i.e. for breakfast, in a group of 21 Type 2 (non-insulin-dependent) diabetic patients (6 well- and 15 badly controlled). Mean plasma glucose and insulin levels were comparable on the three occasions: respectively with bread, sucrose and honey, peak glucose values were 18 mmol/l, 17.7 mmol/l and 17.5 mmol/l in the uncontrolled group versus 13.9 mmol/l, 12.8 mmol/l and 12.7 mmol/l in the well-controlled group. Peak insulin values were 33.6 mU/1,34.0 mU/l and 36.3 mU/l (p greater than 0.05) in uncontrolled patients against 57.5 mU/l, 54.8 mU/l and 52.5 mU/l in well-controlled subjects (p greater than 0.05). The mean increment in peak plasma glucose values for the three breakfasts was as follows: 6.9 mmol/l, 6.3 mmol/l and 6.2 mmol/l for the uncontrolled group against 7.2 mmol/l, 5.9 mmol/l and 6.2 mmol/l in well-controlled subjects; the mean increment in peak plasma insulin levels was 21.8 mU/l,22.0 mU/l and 24.2 mU/l in the controlled group versus 38.2 mU/l, 32.0 mU/l and 34.7 mU/l in the well-controlled subjects, all values being non-significantly different (p greater than 0.05). We conclude that, in acute conditions, simple sugars have no additional hyperglycaemic effect over an isoglucidic amount of bread in well-and in badly controlled Type 2 diabetic patients, even at breakfast.