Association between changes in oestradiol and follicleâ stimulating hormone levels during the menopausal transition and risk of diabetes

AimTo investigate the association between changes in oestradiol and follicleâ stimulating hormone levels during the menopausal transition and incident diabetes.MethodsWe followed 1407 preâ menopausal women, aged 42â 52 years at baseline, who experienced natural menopause, from baseline to the 12th annual followâ up visit in the Study of Women’s Health Across the Nation (SWAN). Diabetes was defined based on fasting glucose level, medication use and selfâ report of physician diagnosis. Cox proportional hazards regression was used to evaluate the associations of incident diabetes with three components of the rate of change in hormones: the intercept (preâ menopausal levels) and two pieceâ wise slopes representing change during the early and late transition, respectively.ResultsDuring 15 years of followâ up, 132 women developed diabetes. After adjusting for potential confounders, a higher oestradiol intercept, but not its rate of change, was borderline significantly associated with lower risk of diabetes [hazard ratio for an interquartile range increase (75.2 pmol/L) 0.53, 95% CI 0.27â 1.06]. For follicleâ stimulating hormone, a greater rate of increase in the early transition, but not the intercept or late transition, was significantly associated with lower risk of diabetes [hazard ratio for an interquartile range increase (5.9 IU/L/year) 0.31, 95% CI 0.10â 0.94].ConclusionsLower preâ menopausal oestradiol levels and a slower rate of follicleâ stimulating hormone change during the early transition were associated with higher risk of developing diabetes. Given that obesity plays an important role in diabetes risk and in the levels and changes in oestradiol and follicleâ stimulating hormone over the menopausal transition, weight control in earlier midâ life is important to prevent future diabetes development.What’s new?This is the first study to examine prospectively the associations between levels of and change in oestradiol and follicleâ stimulating hormone (FSH) during the menopausal transition and incident diabetes in a cohort of women.The study shows that, independent of age and other important risk factors of diabetes, women with lower preâ menopausal oestradiol levels and a slower rate of FSH change during the early menopause transition had a higher risk of developing diabetes.Given that obesity plays an important role in diabetes risk as well as in the levels and changes in oestradiol and FSH over the menopausal transition, weight control in earlier midâ life is important to prevent future diabetes development.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136511/1/dme13301_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136511/2/dme13301.pd

Cardiometabolic risk factor clustering in patients with deficient branched‐chain amino acid catabolism: A case‐control study

AbstractClassical organic acidemias (OAs) result from defective mitochondrial catabolism of branched‐chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case‐control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31P/1H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome‐like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA

4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue.

Therapeutic increase of brown adipose tissue (BAT) thermogenesis is of great interest as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, which is synthesized by HA synthases (Has1/Has2/Has3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here, we show that the inhibition of HA-synthesis by 4-MU or genetic deletion of Has2/Has3 improves BAT`s thermogenic capacity, reduces body weight gain, and improves glucose homeostasis independently from adrenergic stimulation in mice on diabetogenic diet, as shown by a magnetic resonance T2 mapping approach. Inhibition of HA synthesis increases glycolysis, BAT respiration and uncoupling protein 1 expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved prescription-free drug, could be repurposed to treat obesity and diabetes

Viscerotropic disease: case definition and guidelines for collection, analysis, and presentation of immunization safety data

Viscerotropic disease (VTD) is defined as acute multiple organ system dysfunction that occurs following vaccination. The severity of VTD ranges from relatively mild multisystem disease to severe multiple organ system failure and death. The term VTD was first used shortly after the initial published reports in 2001 of febrile multiple organ system failure following yellow fever (YF) vaccination. To date, VTD has been reported only in association with YF vaccine and has been thus referred to as YF vaccine-associated viscerotropic disease (YEL-AVD)

Metabolic Effects of n-3 PUFA as Phospholipids Are Superior to Triglycerides in Mice Fed a High-Fat Diet: Possible Role of Endocannabinoids

Background n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides. Methodology/Principal Findings In a ‘prevention study’, C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ~35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine. Conclusions/Significance Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WA