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Aims/hypothesis The objective of this prevention programme was to study whether combining pioglitazone with lifestyle modification would enhance the efficacy of lifestyle modification in preventing type 2 diabetes in Asian Indians with impaired glucose tolerance. Methods In a community-based, placebo-controlled 3 year prospective study, 407 participants with impaired glucose tolerance (mean age 45.3 ± 6.2 years, mean BMI 25.9 ± 3.3 kg/m²) were sequentially grouped to receive either: lifestyle modification plus pioglitazone, 30 mg (n = 204) or lifestyle modification plus placebo (n = 203). The participants and investigators were blinded to the assignment. The primary outcome was development of diabetes. Results At baseline, both groups had similar demographic, anthropometric and biochemical characteristics. At year 3, the response rate was 90.2%. The cumulative incidence of diabetes was 29.8% with pioglitazone and 31.6% with placebo (unadjusted HR 1.084 [95% CI 0.753-1.560], p = 0.665). Normoglycaemia was achieved in 40.9% and 32.3% of participants receiving pioglitazone and placebo, respectively (p = 0.109). In pioglitazone group, two deaths and two non-fatal hospitalisations occurred due to cardiac problems; in the placebo group there were two occurrences of cardiac disease. Conclusions/interpretation Despite good adherence to lifestyle modification and drug therapy, no additional effect of pioglitazone was seen above that achieved with placebo. The effectiveness of the intervention in both groups was comparable with that of lifestyle modification alone, as reported from the Indian Diabetes Prevention Programme-1. The results are at variance with studies that showed significant relative risk reduction in conversion to diabetes with pioglitazone in Americans with IGT. An ethnicity-related difference in the action of pioglitazone in non-diabetic participants may be one explanation. Trial registration: ClinicalTrials.gov NCT00276497 Funding: This study was funded by the India Diabetes Research Foundation

Lifestyle interventions reduce the incidence of type 2 diabetes among individuals with impaired glucose tolerance (IGT). However, it is unknown whether this is due to improved insulin sensitivity or insulin secretion. We investigated at baseline insulin sensitivity and insulin secretion applying frequently sampled intravenous glucose tolerance test (FSIGT) in 87 of 101 obese middle-aged subjects with IGT randomized into an intervention or a control group in the Finnish Diabetes Prevention Study. FSIGT was repeated after 4 years in 52 people. There were no significant differences in any of the baseline anthropometric or metabolic characteristics between the groups. The 4-year weight and waist circumference decreases were greater in the intervention than in the control group (P = 0.043 and P = 0.025, respectively). At 4-year examination, insulin sensitivity (Si) tended to be higher in the intervention group (the difference between the mean values 36%; P = 0.067, and P = 0.136 after adjustment for age, sex, BMI, and baseline Si value). There was strong correlation between the 4-year changes in Si and weight (r = -0.628 and r = -0.710, for intervention and control groups; P < 0.001 for both). In the entire group, Si improved by 64% in the highest tertile of weight loss but deteriorated by 24% in those who gained weight (lowest tertile). Acute insulin response declined significantly in the control group. In conclusion, Si markedly improved by weight reduction during the 4-year follow-up of individuals with IGT. Insulin secretion remained constant for years in individuals with IGT who were able to lose weight.

Objective: This study examined the effect of acarbose therapy on carotid intima-media thickness (IMT) in patients with established coronary artery disease (CAD) who had been newly diagnosed with impaired glucose tolerance (IGT) or mild type 2 diabetes mellitus (T2DM). Methods: This was a 1-year, prospective, randomized, open-label, parallel-group study in patients with established CAD (≥50% stenosis on quantitative coronary angiography) who were newly diagnosed with IGT or mild T2DM. IGT was defined as 2-hour glucose concentrations of 140 to 199 mg/dL on the 75-g oral glucose tolerance test (OGTT). Mild T2DM was defined as a fasting plasma glucose concentration <126 mg/dL, 2-hour plasma glucose concentration on OGTT >200 mg/dL, and glycosylated hemoglobin (HbA 1c) <6.5%. On the day after undergoing coronary angiography, patients were randomly allocated to receive either acarbose 150 mg/d or control (no treatment). Carotid IMT was measured by ultrasonography at baseline and at 12 months of follow-up. The changes in glucose profiles (75-g OGTT), HbA 1c, and lipid profiles were also compared between baseline and follow-up. At visits every 2 months, data on adverse events, drug adherence, and changes in medication were collected. Adverse events were recorded based on spontaneous reports and questioning by the investigator. Clinical follow-up data on outcomes of interest were obtained from patients' hospital charts or from telephone interviews; these outcomes were the incidence of mortality, nonfatal myocardial infarction, repeat percutaneous coronary intervention for a treated coronary artery, and stroke. Results: Ninety Japanese patients were enrolled in the study (45 in each group). Two patients in the acarbose group discontinued therapy due to drug-related diarrhea, and 1 patient in each group was discontinued because of a newly diagnosed malignancy. Three patients in the control group were discontinued because they initiated treatment with fibrates, and 2 patients in the control group were lost to follow-up. Thus, complete baseline and follow-up data were available for 42 patients in the acarbose group and 39 in the control group. These 81 patients were predominantly male (74 [91.4%]), with a mean (SD) age of 66.3 (9.0) years, mean body weight of 65.9 (10.5) kg, and mean HbA 1c of 5.57% (0.38%). Baseline characteristics appeared to be comparable between the 2 groups. In the acarbose group, IMT increased from a mean of 1.28 (0.53) mm at baseline to 1.30 (0.52) mm at 12-month follow-up (mean change, 0.02 [0.29] mm; P = NS), whereas in the control group, it increased from a mean of 1.15 (0.37) mm to 1.32 (0.46) mm (mean change, 0.17 [0.25] mm; P < 0.001 ). The difference between groups was statistically significant ( P = 0.01). In addition, the acarbose group had significant reductions from baseline in 2-hour glucose concentrations on the 75-g OGTT (mean change, −24.8 [45.2] mg/dL; P = 0.001), fasting total cholesterol (mean change, −11.26 [26.1] mg/dL; P = 0.009), and fasting triglyceride concentrations (mean change, −30.4 [62.7] mg/dL; P = 0.003), whereas the corresponding changes were not significant in the control group (mean change, −8.5 [39.4], −6.22 [26.7], and −1.05 [74.2] mg/dL, respectively). Cardiovascular events requiring hospitalization occurred in 4 patients (9.5%) in the acarbose group and 4 patients (10.3%) in the control group. No deaths, nonfatal myocardial infarctions, or strokes occurred in either group over the follow-up period. Conclusion: In this small, open-label study in patients with established CAD who were newly diagnosed with IGT or mild T2DM, 12 months of treatment with acarbose was associated with a beneficial effect in terms of preventing the progression of carotid IMT compared with control, although it was not associated with a significant decrease in IMT from baseline. UMIN (University Hospital Medical Information Network) Clinical Trials Registry identifier: UMIN000000544.

Alzheimer disease (AD) is a major cause of age-related dementia. We do not fully understand AD aetiology and pathogenesis, but oxidative damage is a key component. The brain mostly uses glucose for energy, but in AD and amnestic mild cognitive impairment glucose metabolism is dramatically decreased, probably owing, at least in part, to oxidative damage to enzymes involved in glycolysis, the tricarboxylic acid cycle and ATP biosynthesis. Consequently, ATP-requiring processes for cognitive function are impaired, and synaptic dysfunction and neuronal death result, with ensuing thinning of key brain areas. We summarize current research on the interplay and sequence of these processes and suggest potential pharmacological interventions to retard AD progression.Oxidative damage plays a key role in the development of Alzheimer disease. In this Review, Butterfield and Halliwell discuss how this damage relates to impaired brain glucose metabolism and proteostasis defects and how knowledge of it may suggest potential therapies.

Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance.

Periodontitis has been implicated as a risk factor for metabolic disorders such as type 2 diabetes, atherosclerotic vascular diseases and non-alcoholic fatty liver disease. Although bacteremias from dental plaque and/or elevated circulating inflammatory cytokines emanating from the inflamed gingiva are suspected mechanisms linking periodontitis and these diseases, direct evidence is lacking. We hypothesize that disturbances of the gut microbiota by swallowed bacteria induce a metabolic endotoxemia leading metabolic disorders. To investigate this hypothesis, changes in the gut microbiota, insulin and glucose intolerance and levels of tissue inflammation were analysed in mice after oral administration of Porphyromonas gingivalis , a representative periodontopathogens. Pyrosequencing revealed that the population belonging to Bacteroidales was significantly elevated in P. gingivalis -administered mice which coincided with increases in insulin resistance and systemic inflammation. In P. gingivalis -administered mice blood endotoxin levels tended to be higher, whereas gene expression of tight junction proteins in the ileum was significantly decreased. These results provide a new paradigm for the interrelationship between periodontitis and systemic diseases.

Aims/hypothesis Metabolic disorders are commonly investigated using knockout and transgenic mouse models. A variety of mouse strains have been used for this purpose. However, mouse strains can differ in their inherent propensities to develop metabolic disease, which may affect the experimental outcomes of metabolic studies. We have investigated strain-dependent differences in the susceptibility to diet-induced obesity and insulin resistance in five commonly used inbred mouse strains (C57BL/6J, 129X1/SvJ, BALB/c, DBA/2 and FVB/N). Methods Mice were fed either a low-fat or a high-fat diet (HFD) for 8 weeks. Whole-body energy expenditure and body composition were then determined. Tissues were used to measure markers of mitochondrial metabolism, inflammation, oxidative stress and lipid accumulation. Results BL6, 129X1, DBA/2 and FVB/N mice were all susceptible to varying degrees to HFD-induced obesity, glucose intolerance and insulin resistance, but BALB/c mice exhibited some protection from these detrimental effects. This protection could not be explained by differences in mitochondrial metabolism or oxidative stress in liver or muscle, or inflammation in adipose tissue. Interestingly, in contrast with the other strains, BALB/c mice did not accumulate excess lipid (triacylglycerols and diacylglycerols) in the liver; this is potentially related to lower fatty acid uptake rather than differences in lipogenesis or lipid oxidation. Conclusions/interpretation Collectively, our findings indicate that most mouse strains develop metabolic defects on an HFD. However, there are inherent differences between strains, and thus the genetic background needs to be considered carefully in metabolic studies.

Blueberries are a rich source of polyphenols, widely studied for the prevention or attenuation of metabolic diseases. However, the health contribution and mechanisms of action of polyphenols depend on their type and structure. Here, we evaluated the effects of a wild blueberry polyphenolic extract (WBE) ( Vaccinium angustifolium Aiton) on cardiometabolic parameters, gut microbiota composition and gut epithelium histology of high-fat high-sucrose (HFHS) diet-induced obese mice and determined which constitutive polyphenolic fractions (BPF) was responsible for the observed effects. To do so, the whole extract was separated in three fractions, F1) Anthocyanins and phenolic acids, F2) oligomeric proanthocyanidins (PACs), phenolic acids and flavonols (PACs degree of polymerization DP < 4), and F3) PACs polymers (PACs DP > 4) and supplied at their respective concentration in the whole extract. After 8 weeks, WBE reduced OGTT AUC by 18.3% compared to the HFHS treated rodents and the F3 fraction  contributed the most to this effect. The anthocyanin rich F1 fraction did not reproduce this response. WBE and the BPF restored the colonic mucus layer. Particularly, the polymeric PACs-rich F3 fraction increased the mucin-secreting goblet cells number. WBE caused a significant 2-fold higher proportion of Adlercreutzia equolifaciens whereas oligomeric PACs-rich F2 fraction increased by 2.5-fold the proportion of Akkermansia muciniphila . This study reveals the key role of WBE PACs in modulating the gut microbiota and restoring colonic epithelial mucus layer, providing a suitable ecological niche for mucosa-associated symbiotic bacteria, which may be crucial in triggering health effects of blueberry polyphenols.

Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.

To explore the relationship of gut microbiota with the development of type 2 diabetes (T2DM), we analyzed 121 subjects who were divided into 3 groups based on their glucose intolerance status: normal glucose tolerance (NGT; n = 44), prediabetes (Pre-DM; n = 64), or newly diagnosed T2DM (n = 13). Gut microbiota characterizations were determined with 16S rDNA-based high-throughput sequencing. T2DM-related dysbiosis was observed, including the separation of microbial communities and a change of alpha diversity between the different glucose intolerance statuses. To assess the correlation between metabolic parameters and microbiota diversity, clinical characteristics were also measured and a significant association between metabolic parameters (FPG, CRP) and gut microbiota was found. In addition, a total of 28 operational taxonomic units (OTUs) were found to be related to T2DM status by the Kruskal-Wallis H test, most of which were enriched in the T2DM group. Butyrate-producing bacteria (e.g. Akkermansia muciniphila ATCCBAA-835, and Faecalibacterium prausnitzii L2-6) had a higher abundance in the NGT group than in the pre-DM group. At genus level, the abundance of Bacteroides in the T2DM group was only half that of the NGT and Pre-DM groups. Previously reported T2DM-related markers were also compared with the data in this study, and some inconsistencies were noted. We found that Verrucomicrobiae may be a potential marker of T2DM as it had a significantly lower abundance in both the pre-DM and T2DM groups. In conclusion, this research provides further evidence of the structural modulation of gut microbiota in the pathogenesis of diabetes.