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Many aging men experience reduced energy and libido related to non-optimal testosterone levels. We conducted a randomized double-blind trial with TrigozimR fenugreek extract to assess impact on plasma and saliva testosterone, and some subjective effects. 95 men (40-80y) completed a 12-week intervention, taking 3 tablets daily with 0 mg (placebo; n = 22), 600 mg (n = 21), 1200 mg (n = 25) and1800 mg (n = 27) fenugreek extract and essential nutrients. Samples were collected at weeks 0, 2, 6, and 12. Participants answered a pre- and post-intervention questionnaire on lifestyle and libido. We measured total testosterone (HPLC-MS/MS) and sex hormone binding globulin (ELISA), calculated free testosterone index (FTI), and measured saliva testosterone. Plasma total testosterone and FTI increased after any dose of TrigozimR vs. baseline (13.0%, p = 1.0x10-4 and 16.3%, p = 6.2x10-6), but not vs. placebo (9.0%, p = 0.122 and 11.3% p = 0.059). 1800 mg TrigozimR resulted in 12.2% increased FTI (p = 0.025). Saliva testosterone concentration increased after any dose of TrigozimR vs. baseline (31.1%, p = 2.3x10-4) and vs. placebo (37.2%, p = 0.042). 1800 mg TrigozimR for 12 weeks resulted in 19.6% (p = 0.006) increased saliva testosterone. Compliance was confirmed by enhanced plasma concentration of 25-hydroxy vitamin D3. We observed no subjective effects or side-effects of TrigozimR. TrigozimR increased saliva and plasma testosterone concentration during intervention but only for saliva vs. placebo. Saliva may be preferred for measuring free testosterone due to no protein-bound testosterone. [ABSTRACT FROM AUTHOR]

Background: Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. Methods: We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models. Results: Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice. Conclusions: Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that the administration of zoledronic acid (ZOL) once yearly for 3 years or once over 3 years, yields similar antifracture efficacy. Bone turnover markers can predict the antifracture efficacy of antiresorptive agents, with procollagen type 1 N-terminal propeptide (P1NP) being the most useful marker. In this retrospective cohort study, we explored the effects of intravenous dosing of ZOL guided by serum (S)-P1NP assessment on bone mineral density (BMD) and fractures. Consenting patients (N  = 202, mean age 68.2 years) with osteoporosis were treated with ZOL for an average of 4.4 (range 2-8) years. S-P1NP and BMD were measured at baseline and every 1-2 years. We assessed the number of subsequent vertebral and nonvertebral fractures in the 2-year time periods. The number of patients assessed was 202, 147, 69, and 29 at years 1-2, 3-4, 5-6, and 7-8, respectively. A new ZOL infusion was given if S-P1NP exhibited values above 35 μg/L. BMD increased by 6.2% (SD 4.0) over the first 2 years and stabilized in years 2-8 (P  <.05). Median S-P1NP exhibited an initial reduction from 58.0 to 31.3 μg/L at year 2 and then increased to 39.0 μg/L at years 7-8. Compared with fractures observed in the last 2 years before baseline, fracture rates exhibited consistent reductions, for vertebral fractures odds ratio (OR) [95% confidence interval] = 0.61 [0.47, 0.80], P  <.001 and for nonvertebral fractures OR = 0.23 [0.18, 0.31], P  <.001. In conclusion, intermittent dosing of intravenous ZOL based on the assessment of S-P1NP with cut-off at 35 μg/L resulted in an initial increase followed by a stable BMD, suppression of S-P1NP, and stable reduction of fractures for 8 years. Only 39% of patients needed more than one infusion. This approach reduces healthcare costs and might also reduce the risk of rare side effects such as osteonecrosis of the jaw and atypical femoral fracture. [ABSTRACT FROM AUTHOR]

Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise ("non-responders"). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40–65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO2max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO2max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes. [ABSTRACT FROM AUTHOR]

South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This study aimed to assess markers of adipose tissue (AT) IR and liver fat in SA and Nordic women post-GDM. A total of 179 SA and 108 Nordic women in Norway underwent oral glucose tolerance tests 1–3 years post-GDM. We measured metabolic markers and calculated the AT IR index and non-alcoholic fatty liver disease liver fat (NAFLD-LFS) scores. Results showed that normoglycaemic SAs had less non-esterified fatty acid (NEFA) suppression during the test, resembling prediabetes/T2D responses, and higher levels of plasma fetuin-A, CRP, and IL-6 but lower adiponectin, indicating AT inflammation. Furthermore, normoglycaemic SAs had higher NAFLD-LFS scores, lower insulin clearance, and higher peripheral insulin than Nordics, indicating increased AT IR, inflammation, and liver fat in SAs. Higher liver fat markers significantly contributed to the ethnic disparities in glucose metabolism, suggesting a key area for intervention to reduce T2D risk post-GDM in SAs. [ABSTRACT FROM AUTHOR]

Context: The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity. Objective: We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites. Methods: In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts. Results: SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB. Conclusion: Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB. [ABSTRACT FROM AUTHOR]

Context: Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. Objective: This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. Methods: We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n= 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. Results: In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] −0.19 [−0.21 to −0.17]), body fat (−0.12 [−0.14 to −0.10), and fasting C-peptide (−2.04 [−2.46 to −1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (−0.5 [−0.7 to −0.4] and −0.5 [−0.6 to −0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, −1.72 [−2.86 to −0.58], and −0.20 [−0.36 to −0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. Conclusion: BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sObR. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling. [ABSTRACT FROM AUTHOR]

Although there are some epigenome-wide association studies (EWAS) of insulin resistance, for most of them authors did not replicate their findings, and most are focused on populations of European ancestry, limiting the generalizability. In the Epigenetics in Pregnancy (EPIPREG; n = 294 Europeans and 162 South Asians) study, we conducted an EWAS of insulin resistance in maternal peripheral blood leukocytes, with replication in the Born in Bradford (n = 879; n = 430 Europeans and 449 South Asians), Methyl Epigenome Network Association (MENA) (n = 320), and Botnia (n = 56) cohorts. In EPIPREG, we identified six CpG sites inversely associated with insulin resistance across ancestry, of which five were replicated in independent cohorts (cg02988288, cg19693031, and cg26974062 in TXNIP; cg06690548 in SLC7A11; and cg04861640 in ZSCAN26). From methylation quantitative trait loci analysis in EPIPREG, we identified gene variants related to all five replicated cross-ancestry CpG sites, which were associated with several cardiometabolic phenotypes. Mediation analyses suggested that the gene variants regulate insulin resistance through DNA methylation. To conclude, our cross-ancestry EWAS identified five CpG sites related to lower insulin resistance. [ABSTRACT FROM AUTHOR]

South Asian women have a higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however, the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, β-cell function, and hepatic insulin clearance in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years, BMI 29.1 kg/m2) by oral glucose tolerance test using deconvolution of C-peptide kinetics. Thirty-one percent of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher areas under the curve (AUCs) for glucose, prehepatic insulin, and peripheral insulin and lower insulin sensitivity, disposition index, and fasting hepatic insulin clearance than Nordic women. In the group with prediabetes or diabetes, South Asian women had similar AUCs for glucose and prehepatic insulin but a higher AUC for peripheral insulin, lower disposition index, and lower fasting hepatic insulin clearance than Nordic women. The waist-to-height ratio mediated ∼25-40% of the ethnic differences in insulin sensitivity in participants with normoglycemia. Overall, our novel data revealed that South Asian women with normoglycemia after GDM showed lower insulin secretion for a given insulin resistance and lower hepatic insulin clearance than Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized. [ABSTRACT FROM AUTHOR]

Background. Levels of thyroid-stimulating hormone (TSH) are believed to reflect degree of disease in patients with hypothyroidism, and normalization of levels is the treatment goal. However, despite adequate levels of TSH after starting levothyroxine (LT4) therapy, 5–10% of hypothyroid patients complain of persisting symptoms with a significant negative impact on quality of life. This indicates that TSH is not an optimal indicator of intracellular thyroid hormone effects in all patients. Our aim was to investigate different effects of LT3 and LT4 monotherapy on other biomarkers of the thyroid signaling pathway, in addition to adverse effects, in patients with residual hypothyroid symptoms. Methods. Fifty-nine female hypothyroid patients, with residual symptoms on LT4 monotherapy or LT4/liothyronine (LT3) combination therapy, were randomly assigned in a non-blinded crossover study and received LT4 or LT3 monotherapy for 12 weeks each. Measurements, including serum analysis of a number of biochemical and hormonal parameters, were obtained at the baseline visit and after both treatment periods. Results. Free thyroxine (FT4) was higher in the LT4 group, while free triiodothyronine (FT3) was higher in the LT3 group. The levels of reverse triiodothyronine (rT3) decreased after LT3 treatment compared with LT4 treatment. Both low-density lipoprotein (LDL) and total cholesterol levels were reduced, while sex hormone-binding globulin (SHBG) increased after LT3 treatment compared with LT4 treatment. The median TSH levels for both treatment groups were within the reference range, however, lower in the LT4 group than in the LT3 group. We did not find any differences in pro-B-type natriuretic peptide (NT pro-BNP), handgrip strength, bone turnover markers, or adverse events between the two treatment groups. Conclusion. We have demonstrated that FT4, FT3, rT3, cholesterol, and SHBG show significantly different values on LT4 treatment compared with LT3 treatment in women with hypothyroidism and residual symptoms despite normal TSH levels. No differences in general or bone-specific adverse effects were demonstrated. This trial is registered with NCT03627611 in May 2018. [ABSTRACT FROM AUTHOR]

Insulin became available for the treatment of patients with diabetes 100 years ago, and soon thereafter it became evident that the biological response to its actions differed markedly between individuals. This prompted extensive research into insulin action and resistance (IR), resulting in the universally agreed fact that IR is a core finding in patients with type 2 diabetes mellitus (T2DM). T2DM is the most prevalent form of diabetes, reaching epidemic proportions worldwide. Physical activity (PA) has the potential of improving IR and is, therefore, a cornerstone in the prevention and treatment of T2DM. Whereas most research has focused on the acute effects of PA, less is known about the effects of long-term PA on IR. Here, we describe a model of potential mechanisms behind reduced IR after long-term PA to guide further mechanistic investigations and to tailor PA interventions in the therapy of T2DM. The development of such interventions requires knowledge of normal glucose metabolism, and we briefly summarize an integrated physiological perspective on IR. We then describe the effects of long-term PA on signaling molecules involved in cellular responses to insulin, tissue-specific functions, and whole-body IR. [ABSTRACT FROM AUTHOR]

Objective: The effects of levothyroxine (LT4)/liothyronine (LT3) combination therapy on quality of life (QoL) in hypothyroid patients former on LT4 monotherapy have been disappointing. We therefore wanted to test the effects of LT3 monotherapy on QoL in hypothyroid patients with residual symptoms despite thyroid stimulating hormone (TSH) values within the reference range. Design: Female hypothyroid patients with residual symptoms on LT4 monotherapy or combination LT4/LT3 therapy received LT3 and LT4 monotherapy, respectively for 12 weeks in a non-blinded randomized crossover study. Methods: Fifty-nine patients aged 18-65 years were included. QoL was assessed using one disease-specific questionnaire (ThyPRO) and two generic questionnaires (Fatigue Questionnaire and SF-36) at baseline and at the end of the two treatment periods. Clinical indices of cardiovascular health (resting heart rate and blood pressure), as well as thyroid tests, were assessed at baseline and at the end of the two treatment periods. Results: After 12 weeks of LT3 treatment, 12 of the 13 domains of the ThyPRO questionnaire (physical, mental and social domains) showed significant improvements. The most pronounced improvements were less tiredness (mean -21 ± 26; P <0.0001) and cognitive complaints (mean -20 ± 20; P <0.0001). LT4 monotherapy exerted minor effects on two domains only (cognitive complaints and impaired daily life). All three dimensions' scores in the Fatigue Questionnaire (physical, mental and total fatigue) improved after LT3 treatment compared to baseline (P <0.001), and in the SF-36 questionnaire 7 of 8 scales showed significantly better scores after LT3 treatment compared to baseline. There were no differences in blood pressure or resting heart rate between the two treatment groups. TSH in patients on LT3 was slightly higher (median 1.33 mU/L (interquartile range (IQR) 0.47-2.26)) than in patients on LT4 (median 0.61 mU/L (IQR 0.25-1.20; P <0.018). Five patients on LT3 dropped out of the study due to subjectively reported side effects, compared to only one on LT4. Conclusions: LT3 treatment improved QoL in women with residual hypothyroid symptoms on LT4 monotherapy or LT4/LT3 combination therapy. Short-term LT3 treatment did not induce biochemical or clinical hyperthyroidism, and no cardiovascular adverse effects were recorded. Further studies are needed to assess the long-term safety and efficacy of LT3 monotherapy. Clinical Trial Registration: ClinicalTrials.gov , identifier NCT03627611. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution. Materials and Methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome. Results: Cold stimulated skin temperatures decreased less with LT3 vs. LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P <0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P <0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation. Clinical Trial Registration: ClinicalTrials.gov , identifier NCT03627611 [ABSTRACT FROM AUTHOR]

Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother's and child's health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes. [ABSTRACT FROM AUTHOR]