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Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects., Author(s): Hao Wu [1]; Eduardo Esteve [2, 3, 4]; Valentina Tremaroli [1]; Muhammad Tanweer Khan [1]; Robert Caesar [1]; Louise Mannerås-Holm [1]; Marcus Ståhlman [1]; Lisa M Olsson [1]; Matteo [...]

OBJECTIVE This study sought to identify the pro le of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity. RESEARCH DESIGN AND METHODS The circulating miRNA pro le was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross-sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion. RESULTS Cross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR-423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of fourmiRNAs (miR-140-5p,miR-423-5p,miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (- 15.8%; P = 0.004), and miR-222 (- 47.2%; P = 0.03),in parallel to decreased fasting glucose and HbA1c. Furthermore, while insulin infusion during clamp decreased miR-222 (- 62%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05) . CONCLUSIONS This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity. [ABSTRACT FROM AUTHOR]

Background: The CGMS Gold continuous glucose monitor presents a problem of lack of accuracy, especially in the lower range, sometimes leading to missed or false alarms. The new algorithm aims to improve the measurement accuracy and hypoglycemia detection., Material/methods: Twenty-one patients with type 1 diabetes were monitored for 3 days (1 day at the hospital and 2 at home) using the CGMS Gold. For these patients, blood glucose samples were taken every 15 minutes for 2 hours after meals and every half hour otherwise during the first day. A new calibration algorithm was developed and implemented using CGMS Gold intensity readings and capillary glucose., Results: After 1 day, a comparison of results from either the CGMS Gold algorithm and the proposed algorithm, compared with results from blood (2450 points), showed an increase of data in zone A with the proposed algorithm (4.4% in the Clarke error grid analysis (EGA) and 5.0% in the Consensus EGA). After comparing for 3 days, a reduction of 24.7%, p<0.05, in the overall median relative absolute difference (RAD) was also obtained. In the hypoglycemic range, a significant decrease in median RAD was observed (64.4%, p<0.05). Furthermore, the undetected hypoglycemia events in capillary samples by the proposed algorithm were reduced by 59.8% compared to the CGMS Gold algorithm., Conclusions: The performance as measured with clinical and numerical accuracy criteria illustrates the improved accuracy of the proposed algorithm in comparison with the CGMS Gold algorithm. A significant improvement in hypoglycemia detection was observed.

Background: Continuous glucose monitors (CGMs) present a problem of lack of accuracy, especially in the lower range, sometimes leading to missed or false hypoglycemia. A new algorithm is presented here aimed at improving the measurement accuracy and hypoglycemia detection. Its core is the estimation of blood glucose (BG) in real time (RT) from CGM intensity readings using autoregressive (AR) models., Methods: Eighteen patients with type 1 diabetes were monitored for three days (one at the hospital and two at home) using the CGMS Gold. For these patients, BG samples were taken every 15 min for 2 h after meals and every half hour otherwise during the first day. The relationship between the current measured by the CGMS Gold and BG was learned by an AR model, allowing its RT estimation. New capillary glucose measurements were used to correct the model BG estimations., Results: A total of 563 paired points were obtained from BG and monitor readings to validate the new algorithm. 98.5% of paired points fell in zones A+B of the Clarke error grid analysis with the proposed algorithm. The overall mean and median relative absolute differences (RADs) were 9.6% and 6.7%. Measurements meeting International Organization for Standardization (ISO) criteria were 88.7%. In the hypoglycemic range, the mean and median RADs were 8.1% and 6.0%, and measurements meeting ISO criteria were 86.7%. The sensitivity and specificity with respect to hypoglycemia detection were 91.5% and 95.0%., Conclusions: The performance measured with both clinical and numerical accuracy metrics illustrates the improved accuracy of the proposed algorithm compared with values presented in the literature. A significant improvement in hypoglycemia detection was also observed., ((c) 2010 Diabetes Technology Society.)

The aims of this work were to evaluate thyroid hormone receptor-alpha (TR alpha), TR alpha 1, and TR alpha 2 mRNA gene expression and TR alpha 1:TR alpha 2 ratio, identified as candidate factors for explaining regional differences between human adipose tissue depots. TR alpha, TR alpha 1, and TR alpha 2 mRNA levels, and the gene expressions of arginine-serine-rich, splicing factor 2 (SF2), heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1), heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), and Spot 14 (S14) were evaluated in 76 paired adipose tissue samples obtained from a population of 38 women who varied widely in terms of obesity and body fat distribution. Gene expression for these factors was also studied in stromal-vascular cells (SVCs) and mature adipocytes (MAs) from eight paired fat depots. TR alpha gene and TR alpha 1 mRNA expression were increased 1.46-fold (P = 0.006) and 1.80-fold (P < 0.0001), respectively, in subcutaneous (SC) vs. visceral fat. These differences in gene expression levels were most significant in the obese group, in which the TR alpha 1:TR alpha 2 ratio was 2.24-fold (P < 0.0001) higher in SC vs. visceral fat. S14 gene expression was also increased by 2.42-fold (P < 0.0001) and correlated significantly with TR alpha and TR alpha 1 gene expression and with the TR alpha 1:TR alpha 2 ratio. In agreement with these findings, hnRNP A1:SF2 ratio was decreased by 1.39-fold (P = 0.001). TR alpha and S14 levels were 2.1-fold (P < 0.0001) and 112.4-fold (P < 0.0001), respectively, higher in MAs than in SVCs from both fat depots. In summary, genes for TR-alpha, their upstream regulators, and downstream effectors were differentially expressed in SC vs. omental (OM) adipose tissue. Our findings suggest that TR alpha1 could contribute to SC adipose tissue expandability in obese subjects.