The Brain Matures with Stronger Functional Connectivity and Decreased Randomness of Its Network

We investigated the development of the brain's functional connectivity throughout the life span (ages 5 through 71 years) by measuring EEG activity in a large population-based sample. Connectivity was established with Synchronization Likelihood. Relative randomness of the connectivity patterns was established with Watts and Strogatz' (1998) graph parameters C (local clustering) and L (global path length) for alpha (∼10 Hz), beta (∼20 Hz), and theta (∼4 Hz) oscillation networks. From childhood to adolescence large increases in connectivity in alpha, theta and beta frequency bands were found that continued at a slower pace into adulthood (peaking at ∼50 yrs). Connectivity changes were accompanied by increases in L and C reflecting decreases in network randomness or increased order (peak levels reached at ∼18 yrs). Older age (55+) was associated with weakened connectivity. Semi-automatically segmented T1 weighted MRI images of 104 young adults revealed that connectivity was significantly correlated to cerebral white matter volume (alpha oscillations: r = 33, p<01; theta: r = 22, p<05), while path length was related to both white matter (alpha: max. r = 38, p<001) and gray matter (alpha: max. r = 36, p<001; theta: max. r = 36, p<001) volumes. In conclusion, EEG connectivity and graph theoretical network analysis may be used to trace structural and functional development of the brain

Long-term metformin adherence in the Diabetes Prevention Program Outcomes Study

Introduction To investigate long-term metformin adherence in the Diabetes Prevention Program Outcomes Study (DPPOS) by examining: (1) predictors of long-term adherence to study metformin and (2) whether metformin adherence was associated with incident type 2 diabetes.Research design and methods DPPOS was an open-label continuation of the randomized clinical trial (Diabetes Prevention Program (DPP)) in which eligible participants randomized to the metformin group were offered study metformin and followed over 11 years. A brief structured adherence interview was administered semiannually. Metformin adherence was assessed by pill counts. Predictors of metformin adherence were examined in multivariate regression models. Incident diabetes associated with metformin adherence and other variables was assessed in Cox proportional hazards models.Results Of 868 participants eligible to continue taking study metformin, 664 (76%) took at least some metformin over 11 years, with 478 of them reporting problems with adherence. DPPOS cumulative adherence showed significant associations of higher adherence (≥80%) with early adherence at 3 months in DPP (p&lt;0.001) and lower depression scores during DPPOS (p&lt;0.001); significant differences were also seen by race/ethnicity (p&lt;0.004). Predicting adherence by multivariate modeling showed odds of adherence significantly lower for Black participants and for participants reporting more than one barrier. Odds for adherence were significantly higher for those adherent early in DPP and those reporting at least one planned strategy to improve adherence. Higher metformin adherence was significantly associated with a lower diabetes risk (p=0.04), even after adjustment for demographic variables, depression, and anxiety scores.Conclusions In this long-term diabetes prevention study, early metformin adherence and planned strategies to promote adherence improved long-term adherence over 11 years; higher adherence to metformin was related to lower diabetes incidence. Incorporating strategies to promote adherence when initially prescribing metformin and counseling to support adherence over time are warranted

Pre-impaired fasting glucose state is a risk factor for endothelial dysfunction: Flow-mediated Dilation Japan (FMD-J) study

Introduction Diabetes mellitus is associated with endothelial dysfunction. However, there is little information on the relationships of fasting blood glucose (FBG), including high normal blood glucose and impaired fasting glucose (IFG) with endothelial function. The purpose of this study was to evaluate the relationship between FBG level and flow-mediated vasodilation (FMD) using a large sample size.Research design and methods This study was a cross-sectional study. We measured FMD in 7265 subjects at 31 general hospitals. The subjects were divided into four groups based on FBG levels: &lt;100, 100–109, 110–125, and ≥126 mg/dL or known diabetes. The subjects were also divided into six groups based on FBG levels: &lt;90, 90–94, 95–99, 100–109, 110–125, and ≥126 mg/dL or known diabetes.Results FMD decreased in relation to increase in FBG level. There was a significant difference in FMD between the FBG of &lt;100 mg/dL group and the other three groups (6.7±3.1% vs 5.9±2.8%, 5.7±3.1%, and 5.1±2.6%, respectively; p&lt;0.001). After adjustment for confounding factors, the odds of having the lowest quartile of FMD were significantly higher in the FBG of 95–99, 100–104, 105–109, 110–125, and ≥126 mg/dL or known diabetes groups than in the FBG of the &lt;90 mg/dL group.Conclusions These findings suggest that FBG of 100–109 mg/dL and FBG of 110–125 mg/dL are similarly associated with endothelial dysfunction and that a pre-IFG state (FBG of 95–99 mg/dL) is also a risk for endothelial dysfunction compared with FBG of &lt;90 mg/dL.Trial registration number UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Activity and Sedentary Time 10 Years After a Successful Lifestyle Intervention : The Diabetes Prevention Program

Introduction: This study aims to determine if evidence exists for a lasting effect of the Diabetes Prevention Program (DPP) lifestyle intervention on activity levels by comparing objectively collected activity data between the DPP Outcome Study (DPPOS) cohort and adults from the National Health and Nutrition Examination Survey (NHANES; 2003-2006). Methods: Average minutes/day of light and moderate to vigorous physical activity (MVPA) and sedentary behavior from ActiGraph accelerometers (collected 2010-2012) were examined (2013-2014) for comparable DPPOS and NHANES subgroups by age, sex, and diabetes status. Longitudinal questionnaire data on leisure activity, collected yearly from DPP baseline to the time of accelerometer measurement (1996-2010; 11.9-year mean follow-up), were also examined to provide support for a long-term intervention effect. Results: Average minutes/day of accelerometer-derived MVPA was higher in all DPPOS subgroups versus NHANES subgroups of similar age/sex/diabetes status; with values as much as twice as high in some DPPOS subgroups. Longitudinal questionnaire data from DPP/DPPOS showed a maintained increase of 1.24 MET hours/week (p=0.026) of leisure activity in DPPOS participants from all original study arms between DPP baseline and accelerometer recording. There were no consistent differences between comparable DPPOS and NHANES subgroups for accelerometer-derived sedentary or light-intensity activity minutes/day. Conclusions: More than 10 years after the start of DPP, DPPOS participants performed more accelerometer-measured MVPA than similar adults from NHANES. Longitudinal questionnaire data support the accelerometer-based findings by suggesting that leisure activity levels at the time of accelerometer recording remained higher than DPP baseline levels

Effectiveness and cost-effectiveness of diabetes prevention among adherent participants

OBJECTIVES: We report the 10 year effectiveness and within-trial cost-effectiveness of the The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) interventions among participants who were adherent to the interventions. STUDY DESIGN: DPP was a 3-year randomized clinical trial followed by 7-years of open-label modified intervention followup. METHODS: Data on resource utilization, cost, and quality-of-life were collected prospectively. Economic analyses were performed from health system and societal perspectives. Lifestyle adherence was defined as achieving and maintaining a 5% reduction in initial body weight and metformin adherence as taking metformin at 80% of study visits. RESULTS: The relative risk reduction was 49.4% among adherent lifestyle participants and 20.8% among adherent metformin participants compared to placebo. Over 10 years, the cumulative, undiscounted, per capita direct medical costs of the interventions, as implemented during the DPP, were greater for adherent lifestyle participants ($4,810) than adherent metformin participants ($2,934) or placebo ($768). Over 10 years, the cumulative, per capita non-intervention-related direct medical costs were$4,250 greater for placebo participants compared to adherent lifestyle participants and $3,251 greater compared to adherent metformin participants. The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.80) than metformin (6.74) or placebo (6.67). Without discounting, from both a modified societal perspective (excluding participant time), lifestyle cost <$5,000 per QALY-gained and metformin was cost-saving compared to placebo. CONCLUSIONS: Over 10 years, lifestyle intervention and metformin were cost-saving compared to placebo. These analyses confirm that lifestyle and metformin represent a good value for money

Regression from prediabetes to normal glucose regulation is associated with reduction in cardiovascular risk: results from the Diabetes Prevention Program outcomes study.

OBJECTIVE: Restoration of normal glucose regulation (NGR) in people with prediabetes significantly decreases the risk of future diabetes. We sought to examine whether regression to NGR is also associated with a long-term decrease in cardiovascular disease (CVD) risk. RESEARCH DESIGN AND METHODS: The Framingham (2008) score (as an estimate of the global 10-year CVD risk) and individual CVD risk factors were calculated annually for the Diabetes Prevention Program Outcomes Study years 1–10 among those patients who returned to NGR at least once during the Diabetes Prevention Program (DPP) compared with those who remained with prediabetes or those in whom diabetes developed during DPP (N = 2,775). RESULTS: The Framingham scores by glycemic exposure did not differ among the treatment groups; therefore, pooled estimates were stratified by glycemic status and were adjusted for differences in risk factors at DPP baseline and in the treatment arm. During 10 years of follow-up, the mean Framingham 10-year CVD risk scores were highest in the prediabetes group (16.2%), intermediate in the NGR group (15.5%), and 14.4% in people with diabetes (all pairwise comparisons P < 0.05), but scores decreased over time for those people with prediabetes (18.6% in year 1 vs. 15.9% in year 10, P < 0.01). The lower score in the diabetes group versus other groups, a declining score in the prediabetes group, and favorable changes in each individual risk factor in all groups were explained, in part, by higher or increasing medication use for lipids and blood pressure. CONCLUSIONS: Prediabetes represents a high-risk state for CVD. Restoration of NGR and/or medical treatment of CVD risk factors can significantly reduce the estimated CVD risk in people with prediabetes

The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery

Background/Goals: The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight. Methods: Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype (WT) mice made obese on high-fat diet. Results: Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, insulin resistance (HOMA-IR), and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice. Conclusions: PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as glucagon-like peptide-1 (GLP-1) remain to be investigated