Serum osteopontin predicts glycaemic profile improvement in metabolic syndrome: A pilot study.

Prediabetes is often observed in patients with Metabolic Syndrome (MetS) and might be associated with metabolic and inflammatory alterations. Here, we investigated whether the inflammatory molecule osteopontin (OPN) might have a prognostic impact in a cohort of MetS patients (n = 85) with baseline normal glycaemia or impaired fasting glucose (IFG) over one year of recommended pharmacological treatments and Mediterranean diet. Patients were then followed up for 12 months with intermediate evaluation after 6 months. At all time points, anthropometric and clinical data were recorded, alongside with haematological and biochemical profiles, including serum concentrations of OPN. As expected, Mediterranean diet improves glycaemic profile in patients with IFG. Baseline serum OPN failed to be associated with baseline anthropometric or biochemical variables. At baseline, higher levels of OPN were shown in patients with IFG as compared to normal glycaemia. Two distinct subgroups of patients in whom OPN decreased or remained stable/increased at follow-up were identified. When higher serum OPN levels were observed at baseline, greater reduction was observed at 1-year follow-up. Reduction in circulating OPN levels was associated with metabolic improvement in terms of blood pressure, LDL-c, HDL-c, and glycaemia. At both univariate and adjusted logistic regression analyses, serum OPN emerged as an independent predictor of glycaemic profile improvement at 1-year follow-up (adjOR 1.05 [1.00-1.10]; P = .041). In conclusion, pharmacological and dietetic interventions improved glycaemic profile in patients with MetS. In particular, glycaemic improvement was demonstrated in patients who also reduce circulating OPN levels. Higher OPN levels at baseline predict normalization of glycaemic profile.

Sex-specific effects of ketogenic diet after pre-exposure to a high-fat, high-sugar diet in rats.

BACKGROUND AND AIMS: The objectives were to evaluate the relationship between ketogenic diets, the ketone body beta-hydroxybutyrate (BHB), parameters known to increase risk for cardiovascular and metabolic diseases in both sexes, using a pre-clinical model of obesity. METHODS AND RESULTS: Rats had access to a diet high in fat and sugar (HFS) for 12 weeks. After HFS, they switched to chow (HFS-CH) or ketogenic diet (HFS-KD) for 3 weeks to model a dietary intervention. Body weight, adiposity, and food intake were measured. Glucose tolerance and corticosterone response to stress were measured after HFS, then again after the intervention. Both sexes increased body weight, food intake, and adiposity compared to control (CTL) while on HFS. HFS females showed impaired glucose tolerance. HFS males developed a dampened corticosterone to stress, whereas HFS females developed an exacerbated response. The effects of HFS on adiposity and corticosterone were reversed in HFS-CH males. These same improvements were observed in HFS-CH females, although they still had impaired glucose tolerance. HFS-KD males showed some improvements, however, they still had higher body weight and adiposity than CTL. The same pattern was observed in females. These beneficial effects of KD correlated with plasma BHB levels in females but not in males. CONCLUSIONS: These data model effects reported in clinical literature and serve as a valuable translational tool to further test causal mechanisms that lead to desirable outcomes of KD. These sex-specific relationships are important, as KD could potentially affect endocrine mechanisms differently in males and females.

Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes.

Erythritol Ameliorates Small Intestinal Inflammation Induced by High-Fat Diets and Improves Glucose Tolerance.

BACKGROUND: Erythritol, a sugar alcohol, is widely used as a substitute for sugar in diets for patients with diabetes or obesity. METHODS: In this study, we aimed to investigate the effects of erythritol on metabolic disorders induced by a high-fat diet in C57BL/6J mice, while focusing on changes in innate immunity. RESULTS: Mice that were fed a high-fat diet and administered water containing 5% erythritol (Ery group) had markedly lower body weight, improved glucose tolerance, and markedly higher energy expenditure than the control mice (Ctrl group) (n = 6). Furthermore, compared with the Ctrl group, the Ery group had lesser fat deposition in the liver, smaller adipocytes, and significantly better inflammatory findings in the small intestine. The concentrations of short-chain fatty acids (SCFAs), such as acetic acid, propanoic acid, and butanoic acid, in the serum, feces, and white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. In flow cytometry experiments, group 3 innate lymphoid cell (ILC3) counts in the lamina propria of the small intestine and ILC2 counts in the white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. Quantitative real-time reverse transcription polymerase chain reaction analyses showed that the Il-22 expression in the small intestine of the Ery group was markedly higher than that in the Ctrl group. CONCLUSIONS: Erythritol markedly decreased metabolic disorders such as diet-induced obesity, glucose intolerance, dyslipidemia, and fat accumulation in the mouse liver by increasing SCFAs and modulating innate immunity.

Does L-leucine supplementation cause any effect on glucose homeostasis in rodent models of glucose intolerance? A systematic review.

L-Leucine has been used to improve metabolic outcomes in glucose-intolerant rodent models. However, because studies have used different experimental models and conditions it is difficult to establish the best approach for new clinical trials evaluating the potential effects of L-leucine on glucose homeostasis. We performed a systematic review to report the effect of L-leucine supplementation on glucose homeostasis in rodents with glucose intolerance. The search engines MEDLINE and ScienceDirect were applied using MeSH terms. Thirty-four studies were included in this systematic review. Based on the current data, ingestion of 90-140 mg day-1 of isolated L-leucine in diet-induced obesity (DIO) models shows improvement in metabolic markers if offered during the development of the metabolic disorder in almost all the studies, but not after. Branched-chain amino acid supplementation was effective in streptozotocin-induced ß-cells death but not in DIO models. L-Leucine supplementation seems to have an optimal dose and timing for supplementation to improve glucose homeostasis in DIO.

Development of a brief, reliable and valid diet assessment tool for impaired glucose tolerance and diabetes: the UK Diabetes and Diet Questionnaire.

OBJECTIVE: Dietary advice is fundamental in the prevention and management of type 2 diabetes (T2DM). Advice is improved by individual assessment but existing methods are time-consuming and require expertise. We developed a twenty-five-item questionnaire, the UK Diabetes and Diet Questionnaire (UKDDQ), for quick assessment of an individual's diet. The present study examined the UKDDQ's repeatability and relative validity compared with 4 d food diaries. DESIGN: The UKDDQ was completed twice with a median 3 d gap (interquartile range=1-7 d) between tests. A 4 d food diary was completed after the second UKDDQ. Diaries were analysed and food groups were mapped on to the UKDDQ. Absolute agreement between total scores was examined using intra-class correlation (ICC). Agreement for individual items was tested with Cohen's weighted kappa (κ w). SETTING: South West of England. SUBJECTS: Adults (n 177, 50·3 % women) with, or at high risk for, T2DM; mean age 55·8 (sd 8·6) years, mean BMI 34·4 (sd 7·3) kg/m2; participants were 91 % White British. RESULTS: The UKDDQ showed excellent repeatability (ICC=0·90 (0·82, 0·94)). For individual items, κ w ranged from 0·43 ('savoury pastries') to 0·87 ('vegetables'). Total scores from the UKDDQ and food diaries compared well (ICC=0·54 (0·27, 0·70)). Agreement for individual items varied and was good for 'alcohol' (κ w=0·71) and 'breakfast cereals' (κ w=0·70), with no agreement for 'vegetables' (κ w=0·08) or 'savoury pastries' (κ w=0·09). CONCLUSIONS: The UKDDQ is a new British dietary questionnaire with excellent repeatability. Comparisons with food diaries found agreements similar to those for international dietary questionnaires currently in use. It targets foods and habits important in diabetes prevention and management.

Supplementation of Syzygium cumini seed powder prevented obesity, glucose intolerance, hyperlipidemia and oxidative stress in high carbohydrate high fat diet induced obese rats.

BACKGROUND: Obesity and related complications have now became epidemic both in developed and developing countries. Cafeteria type diet mainly composed of high fat high carbohydrate components which plays a significant role in the development of obesity and metabolic syndrome. This study investigated the effect of Syzygium cumini seed powder on fat accumulation and dyslipidemia in high carbohydrate high fat diet (HCHF) induced obese rats. METHOD: Male Wistar rats were fed with HCHF diet ad libitum, and the rats on HCHF diet were supplemented with Syzygium cumini seed powder for 56 days (2.5% w/w of diet). Oral glucose tolerance test, lipid parameters, liver marker enzymes (AST, ALT and ALP) and lipid peroxidation products were analyzed at the end of 56 days. Moreover, antioxidant enzyme activities were also measured in all groups of rats. RESULTS: Supplementation with Syzygium cumini seed powder significantly reduced body weight gain, white adipose tissue (WAT) weights, blood glucose, serum insulin, and plasma lipids such as total cholesterol, triglyceride, LDL and HDL concentration. Syzygium cumini seed powder supplementation in HCHF rats improved serum aspartate amino transferase (AST), alanine amino transferase (ALT), and alkaline phosphatase (ALP) activities. Syzygium cumini seed powder supplementation also reduced the hepatic thiobarbituric acid reactive substances (TBARS) and elevated the antioxidant enzyme superoxide dismutase (SOD) and catalase (CAT) activities as well as increased glutathione (GSH) concentration. In addition, histological assessment showed that Syzygium cumini seed powder supplementation prevented inflammatory cell infiltration; fatty droplet deposition and fibrosis in liver of HCHFD fed rats. CONCLUSION: Our investigation suggests that Syzygium cumini seed powder supplementation prevents oxidative stress and showed anti-inflammatory and antifibrotic activity in liver of HCHF diet fed rats. In addition, Syzygium cumini seed powder may be beneficial in ameliorating insulin resistance and dyslipidemia probably by increasing lipid metabolism in liver of HCHF diet fed rats.

Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia.

OBJECTIVE: We evaluated whether patients with histologically verified nonalcoholic fatty liver disease (NAFLD) have an impaired incretin effect and hyperglucagonaemia. METHODS: Four groups matched for age, sex and body mass index were studied: (i) 10 patients with normal glucose tolerance and NAFLD; (ii) 10 patients with type 2 diabetes and NAFLD; (iii) eight patients with type 2 diabetes and no liver disease; and (iv) 10 controls. All participants underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycaemic intravenous glucose infusion (IIGI). We determined the incretin effect by relating the beta cell secretory responses during the OGTT and IIGI. Data are presented as medians (interquartile range), and the groups were compared by using the Kruskal-Wallis test. RESULTS: Controls exhibited a higher incretin effect [55% (43-73%)] compared with the remaining three groups (P < 0.001): 39% (44-71%) in the nondiabetic NAFLD patients, 20% (-5-50%) in NAFLD patients with type 2 diabetes, and 2% (-8-6%) in patients with type 2 diabetes and no liver disease. We found fasting hyperglucagonaemia in NAFLD patients with [7.5 pmol L(-1) (6.8-15 pmol L(-1))] and without diabetes [7.5 pmol L(-1) (5.0-8.0 pmol L(-1))]. Fasting glucagon levels were lower but similar in patients with type 2 diabetes and no liver disease [4.5 pmol L(-1) (3.0-6.0 pmol L(-1))] and controls [3.4 pmol L(-1) (1.8-6.0 pmol L(-1) )]. All groups had similar glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide responses. CONCLUSIONS: Patients with NAFLD have a reduced incretin effect and fasting hyperglucagonaemia, with the latter occurring independently of glucose (in)tolerance.

Dietary supplementation with Lactobacillus plantarum dy-1 fermented barley suppresses body weight gain in high-fat diet-induced obese rats.

BACKGROUND: Cereal fermentations have shown significant potential in improvement and design of the nutritional quality and health effects of foods and ingredients. In the present study, the effect of supplementary Lactobacillus plantarum dy-1 fermented barley (LFB) on obesity in high-fat diet (HFD)-induced obese rats was investigated. RESULTS: LFB treatment showed a lower rate of increase in body weight and percentage of body fat and a reversal of HFD-induced glucose intolerance, with ameliorated hyperinsulinemia, decreased levels of triglycerides and total cholesterol, and inhibited concentration of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α. Moreover, LFB treatment also showed the strongest inhibition of nuclear factor (NF)-kB activation and exhibited the greatest effects in blocking the degradation of the inhibitor of NF-kB and inhibiting p38 and JNK1 phosphorylation compared with HFD and raw barley treatment. CONCLUSIONS: It was clear that Lactobacillus plantarum dy-1 fermentation significantly improves the anti-obesity properties of barley. The results establish the foundation for ameliorating diet-induced obesity of product with LFB as nutritional supplements. © 2016 Society of Chemical Industry.

Changes in glucose metabolism in people with different glucose metabolism disorders at baseline: follow-up results of a Finnish national diabetes prevention programme.

AIM: To examine changes in glucose metabolism (fasting and 2-h glucose) during follow-up in people with impaired fasting glucose in comparison with changes in people with isolated impaired glucose tolerance, people with impaired fasting glucose and impaired glucose tolerance combined and people with screening-detected Type 2 diabetes at baseline, among those who participated in a diabetes prevention programme conducted in Finland. METHODS: A total of 10 149 people at high risk of Type 2 diabetes took part in baseline examination. Of 5351 individuals with follow-up ≥ 9 months, 1727 had impaired glucose metabolism at baseline and completed at least one lifestyle intervention visit. Most of them (94.6%) were overweight/ obese. RESULTS: Fasting glucose decreased during follow-up among overweight/obese people in the combined impaired fasting glucose and impaired glucose tolerance group (P = 0.044), as did 2-h glucose in people in the isolated impaired glucose tolerance group (P = 0.0014) after adjustment for age, sex, medication and weight at baseline, follow-up time and changes in weight, physical activity and diet. When comparing changes in glucose metabolism among people with different degrees of glucose metabolism impairment, fasting glucose concentration was found to have increased in those with isolated impaired glucose tolerance (0.12 mmol/l, 95% Cl 0.05 to 0.19) and it decreased to a greater extent in those with screening-detected Type 2 diabetes (-0.54 mmol/l, 95% Cl -0.69 to -0.39) compared with those with impaired fasting glucose (-0.21 mmol/l, 95% Cl -0.27 to -0.15). Furthermore, 2-h glucose concentration decreased in the isolated impaired glucose tolerance group (-0.82 mmol/l, 95% Cl -1.04 to -0.60), in the combined impaired fasting glucose and impaired glucose tolerance group (-0.82 mmol/l, 95% Cl -1.07 to -0.58) and in the screening-detected Type 2 diabetes group (-1.52, 95% Cl -1.96 to -1.08) compared with those in the impaired fasting glucose group (0.26 mmol/l, 95% Cl 0.10 to 0.43). Results were statistically significant even after adjustment for covariates (P < 0.001 in all models). CONCLUSIONS: Changes in glucose metabolism differ in people with impaired fasting glucose from those in people with isolated impaired glucose tolerance, people with impaired fasting glucose and impaired glucose tolerance combined and people with screening-detected Type 2 diabetes.

The efficacy and safety of probiotics intervention in preventing conversion of impaired glucose tolerance to diabetes: study protocol for a randomized, double-blinded, placebo controlled trial of the Probiotics Prevention Diabetes Programme (PPDP).

BACKGROUND: Alterations in intestinal microbiota correlate with risk of development of obesity and type 2 diabetes. Probiotics have been suggested to play an important role in the management of dysglycemia, although the evidence is limited. In this study, we aim to explore the efficacy and safety of probiotics intervention in preventing type 2 diabetes in Chinese patients with impaired glucose tolerance. METHODS/DESIGN: A 24-month randomized intervention is conducted from January 2014 to December 2016. The target sample size for intervention is 200 middle-aged men and women aged 30-65 year-old with impaired glucose tolerance. Participants with persistent impaired glucose tolerance were assigned to group A (tablet A) and B (tablet B) in sequential order. The participants and investigators were blinded to the assignment. The primary outcome is development of diabetes. The secondary outcome measures include body composition, biochemical variables and the safety of the probiotics. DISCUSSION: The results from this trial will provide the evidence on the efficacy and safety of probiotics administration in preventing conversion of impaired glucose tolerance to diabetes in a Chinese context. TRIAL REGISTRATION: ChiCTRTRC13004024.

Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes.

To examine the role of intramyocellular lipid (IMCL) accumulation as well as circulating cytokines, branched-chain amino acids and acylcarnitines in the pathogenesis of muscle insulin resistance in healthy, young, lean insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured these factors in plasma and used (1)H magnetic resonance spectroscopy to assess IMCL content and hyperinsulinemic-euglycemic clamps using [6,6-(2)H(2)] glucose to assess rates of insulin-stimulated peripheral glucose metabolism before and after weight reduction. Seven lean (body mass index < 25 kg/m(2)), young, sedentary IR offspring were studied before and after weight stabilization following a hypocaloric (1,200 Kcal) diet for ∼9 wks. This diet resulted in an average weight loss of 4.1 ± 0.6 kg (P < 0.0005), which was associated with an ∼30% reduction of IMCL from 1.1 ± 0.2% to 0.8 ± 0.1% (P = 0.045) and an ∼30% improvement in insulin-stimulated muscle glucose uptake [3.7 ± 0.3 vs. 4.8 ± 0.1 mg/(kg-min), P = 0.01]. This marked improvement in insulin-stimulated peripheral insulin responsiveness occurred independently of changes in plasma concentrations of TNF-α, IL-6, total adiponectin, C-reactive protein, acylcarnitines, and branched-chain amino acids. In conclusion, these data support the hypothesis that IMCL accumulation plays an important role in causing muscle insulin resistance in young, lean IR offspring, and that both are reversible with modest weight loss.

Probiotic Lactobacillus casei Zhang ameliorates high-fructose-induced impaired glucose tolerance in hyperinsulinemia rats.

AIM: To evaluate the preventive and therapeutic effects of Lactobacilluscasei Zhang on impaired glucose tolerance (IGT) by using fructose-induced hyperinsulinemia rats. METHODS: Rats were fed 25 % fructose solution for hyperinsulinemia with L.casei Zhang for prevention or therapy. Serum levels of insulin, glucagon-like peptide-2 (GLP-2), osteocalcin, malondialdehyde (MDA), total intestinal bile acids and hepatic glycogen contents were determined by assay kits. The major bacteria from feces and liver expression of adiponectin receptor 2 (AdipoR2), liver X receptor-α (LXR-α), peroxisome proliferator-activated receptor gamma (PPAR-γ) and vitamin K epoxide reductase complex subunit 1 mRNA were assessed by RT-PCR. Pancreas injury was evaluated by histological analysis. RESULTS: Lactobacilluscasei Zhang significantly increased numbers of Lactobacillus and Bifidobacterium and decreased Clostridium in the intestine (p < 0.01). Meanwhile, liver glycogen contents were significantly decreased (p < 0.05). In preventive group, accompanied by significantly lower insulin and GLP-2 levels (p < 0.05), L.casei Zhang prevented rats from an increase in oral glucose tolerance area under curve (AUC) which was significant in hyperinsulinemia group (p < 0.05). In therapeutic group, L.casei Zhang administration possessed improved glucose tolerance (p < 0.05), which were associated with increased osteocalcin level (p < 0.01), improved intestinal bile acids secretion (p = 0.060), decreased serum MDA levels (p < 0.05) and upregulation of LXR-α, PPAR-γ and AdipoR2 gene expression, as well as an increase in Bacteroides fragilis (p < 0.05). CONCLUSIONS: Lactobacilluscasei Zhang administration exert both preventive and ameliorative effect on oral glucose tolerance AUC in IGT rats but may be via different mechanisms. L.casei Zhang could prevent rats from increased AUC through GLP-2 lowering, while the ameliorative effect in high-fructose-fed post-adolescent rats may be via B. fragilis enriched vitamin K2-dependent osteocalcin mechanism in which AdipoR2, LXR-α and PPAR-γ signaling were involved.

A low glycaemic load breakfast can attenuate cognitive impairments observed in middle aged obese females with impaired glucose tolerance.

BACKGROUND AND AIMS: There has been no systematic investigation of the individual and combined effects of impaired glucose tolerance (IGT) and obesity on cognitive function in the absence of ageing. The aims were to examine the effects of IGT and increased waist circumference on cognitive function in ostensibly healthy adults, and to investigate whether a low glycaemic load (GL) breakfast can attenuate cognitive impairments in these populations. METHODS AND RESULTS: Sixty five females aged 30-50 years were classified into one of four groups following waist circumference (WC) measurements and an oral glucose tolerance test: NGT/low WC (n = 25), NGT/high WC (n = 22), IGT/low WC (n = 9), IGT/high WC (n = 9). Memory, psychomotor and executive functions were examined 30 and 120 min after consuming low GL, high GL and water breakfasts according to a randomised, crossover, counterbalanced design. IGT was associated with impairment of verbal and spatial memory, and psychomotor function relative to females with NGT, independent of waist circumference. Increased waist circumference was associated with impairment of verbal memory and executive function relative to females with low WC, independent of IGT. Consumption of the LGL breakfast attenuated verbal memory impairment in the IGT/high WC group relative to the HGL breakfast and no energy control. CONCLUSION: Increased central adiposity and abnormalities in glucose tolerance preceding type 2 diabetes can have demonstrable negative effects on cognitive function, even in ostensibly healthy, middle-aged females. The potential for GL manipulations to modulate glycaemic response and cognitive function in type 2 diabetes and obesity merits further investigation.

Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects.

The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 104 min⁻¹·pM⁻¹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 106, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.

Effect of nateglinide on the incidence of diabetes and cardiovascular events.

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of valsartan on the incidence of diabetes and cardiovascular events.

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Prevention of the metabolic syndrome in IGT subjects in a lifestyle intervention: results from the SLIM study.

BACKGROUND AND AIMS: The Study on Lifestyle intervention and Impaired glucose tolerance Maastricht (SLIM), a randomized controlled trial, directed at diet and physical activity in impaired glucose tolerant subjects was effective to improve glucose tolerance and prevent type 2 diabetes. The aim of this study was to determine the effects of the SLIM lifestyle intervention on the incidence and prevalence of the metabolic syndrome (MetS) during the active intervention and four years thereafter. METHODS AND RESULTS: MetS was diagnosed according to the NCEP ATP III criteria. At baseline, 66.4% of all participants (n = 146, age 57 ± 7 years, BMI 29.7 ± 3.6, 51.3% female) fulfilled the criteria for MetS. No significant difference in MetS prevalence was observed between the intervention (63.9%) and control group (68.9%). At the end of active intervention (average duration 4.2 ± 2.0 years), prevalence of MetS was significantly lower in the intervention group (52.6%, n = 57) compared to the control group (74.6%, n = 59) (p = 0.014). Furthermore, in participants without MetS at baseline, cumulative incidence of MetS was 18.2% in the intervention group at the end of active intervention, compared to 73.7% in the control group (Log-rank test, p = 0.011). Four years after stopping active intervention, the reduced incidence of MetS was maintained (Log-rank test, p = 0.002). CONCLUSION: In conclusion, a combined diet-and-exercise intervention to improve glucose tolerance, not only prevented type 2 diabetes, but also reduced the prevalence of MetS and prevented MetS development, showing the long-term impact of lifestyle intervention on cardiovascular risk reduction.

Reduced glycaemic and insulinaemic responses following trehalose and isomaltulose ingestion: implications for postprandial substrate use in impaired glucose-tolerant subjects.

The impact of slowly digestible sugars in reducing the risk of developing obesity and related metabolic disorders remains unclear. We hypothesised that such carbohydrates (CHO), resulting in a lower glycaemic and insulinaemic response, may lead to greater postprandial fat oxidation rates in subjects with impaired glucose tolerance (IGT). The present study intends to compare the postprandial metabolic responses to the ingestion of glucose (GLUC) v. trehalose (TRE) and sucrose (SUC) v. isomaltulose (IMU). In a randomised, single-blind, cross-over design, ten overweight IGT subjects were studied four times, following ingestion of different CHO drinks either at breakfast or in combination with a mixed meal at lunch. Before and 3 h after CHO ingestion, energy expenditure, substrate utilisation and circulating metabolite concentrations were determined. Ingestion of CHO drinks with a meal resulted in an attenuated rise in GLUC (-33 %) and insulin (-14 %) concentrations following TRE when compared with GLUC and following IMU, an attenuation of 43 and 34 % when compared with SUC ingestion, respectively. Additionally, there was less inhibition of the rise in NEFA concentrations and less decline in postprandial fat oxidation (22 %) after IMU when compared with SUC, whereas TRE did not differ from GLUC. The attenuated rise in GLUC and insulin concentrations following IMU ingestion attenuated the postprandial inhibition of fat oxidation compared with SUC when co-ingested with a meal. This suggests that exchange of SUC in the diet for IMU may result in a more favourable metabolic response and may help to reduce the risks associated with obesity and type 2 diabetes.