Markers Of Insulin Sensitivity Research Articles

Sarcopenic obesity and insulin resistance: Application of novel body composition models.

Sarcopenic obesity (SO) is characterized by the co-occurrence of high adiposity (HA) and low muscle mass (LM) and has been associated with an increased risk for cardiometabolic diseases. The aim of this study was to investigate the association between markers of insulin sensitivity and SO defined by three novel body composition models: body composition phenotypes; truncal fat mass to appendicular skeletal mass (TrFM/ASM) ratio load capacity; and fat mass to fat-free mass (FM/FFM) ratio load capacity. The study included 314 participants 18 to 65 y of age. Body composition was assessed by dual-energy x-ray absorptiometry. The first model includes four phenotypes: low adiposity-high muscle mass (LA-HM), high adiposity-high muscle mass (HA-HM), low adiposity-low muscle mass (LA-LM), and high adiposity-low muscle mass (HA-LM). The second and third load-capacity models stratified participants into three centile groups: <15th, 15th to 84th and ≥85th. A 2-h oral glucose tolerance test was performed and insulin sensitivity was calculated using the Matsuda Index. Glycated hemoglobin and highly sensitive C-reactive protein also were measured. Lower insulin sensitivity was observed in the HA-LM (P < 0.001) and in the ≥85th centile groups of the TrFM/ASM ratio (P < 0.001) and the FM/FFM ratio (P=0.001) compared with the other body composition phenotypes. The HA-LM and ≥85th centile group of the TrFM/ASM ratio model showed significantly higher (P < 0.001) concentrations of glycated hemoglobin compared with the other phenotypes. SO defined by both the four body composition phenotypes and TrFM/ASM definitions was associated with increased impairment of insulin sensitivity and glycemic control.

Caulerpa okamurae extract attenuates inflammatory interaction, regulates glucose metabolism and increases insulin sensitivity in 3T3-L1 adipocytes and RAW 264.7 macrophages

ObjectiveTo examine whether Caulerpa okamurae ethanolic extract (COE) could inhibit obesity-mediated inflammation, improve glucose metabolism and increase insulin sensitivity, using in vitro cell models of RAW 264.7 macrophages and 3T3-L1 adipocytes. MethodsWe cocultured 3T3-L1 adipocytes in direct contact with lipopolysaccharide-stimulated RAW 264.7 macrophages and induced insulin resistance in 3T3-L1 adipocytes with tumor necrosis factor-α (TNF-α) in the presence or absence of 250 µg/mL of COE. We investigated various markers of inflammation, glucose regulation and insulin sensitivity in these models using Griess reagent to measure nitric oxide (NO) production, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose to measure glucose uptake, Western blot analysis to quantify protein expression and reverse transcriptase-polymerase chain reaction to evaluate mRNA expression. ResultsWe found that COE (250 µg/mL) significantly inhibited the lipopolysaccharide-induced inflammatory response in RAW 264.7 macrophages by downregulating NO production, nitric oxide synthase 2 expression and nuclear translocation of nuclear factor-κB. COE also showed similar anti-inflammatory activity in coculture, along with decreased TNF-α, interleukin-6 and monocyte chemoattractant protein mRNA expression. In addition, COE also improved glucose uptake in coculture by upregulating glucose transporter-4 (GLUT-4) and adiponectin and reducing serine phosphorylation of insulin receptor substrate-1 (IRS1). In the TNF-α-induced insulin resistance model of 3T3-L1 adipocytes, COE significantly improved both basal and insulin-stimulated glucose uptake, accompanied by phosphorylation of IRS1 at tyrosine 632, phospho-5′ adenosine monophosphate-activated protein kinase α and glycogen synthase kinase-3β (Ser9) as well as upregulation of GLUT-4. ConclusionTogether, these findings suggest that COE has potential to treat or prevent obesity-induced metabolic disorders.

Antihyperglycemic Effects and Mode of Actions of Musa paradisiaca Leaf and Fruit Peel Hydroethanolic Extracts in Nicotinamide/Streptozotocin-Induced Diabetic Rats

The present study aimed to evaluate the antihyperglycemic effects of Musa paradisiaca (M. paradisiaca) leaf and fruit peel hydroethanolic extracts and to suggest their probable mode of actions in nicotinamide (NA)/streptozotocin (STZ)-induced diabetic rats. The leaf and fruit peel hydroethanolic extracts were analyzed by GC-MS that indicated the presence of phytol, octadecatrienoic acid, hexadecanoic acid, and octadecadienoic acid as major components in the leaf extract and vitamin E, octadecenamide, β-sitosterol, and stigmasterol as major phytochemicals in the fruit peel extract. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (60 mg/kg body weight) dissolved in citrate buffer (pH 4.5), 15 minutes after intraperitoneal injection of NA (120 mg/kg body weight). The NA/STZ-induced diabetic rats were, respectively, treated with M. paradisiaca leaf and fruit peel hydroethanolic extracts at a dose of 100 mg/kg body weight/day by oral administration for 28 days. The treatment of NA/STZ-induced diabetic rats with leaf and fruit peel extracts significantly improved the impaired oral glucose tolerance and significantly increased the lowered serum insulin and C-peptide levels. The HOMA-IR (as the index of insulin resistance) and QUICKI (as a marker for insulin sensitivity), as well as HOMA-β cell function were significantly alleviated as a result of treatment of diabetic rats with leaf and fruit peel extracts. In association, the elevated serum-free fatty acids, TNF-α, and IL-6 levels were significantly decreased. In addition, the suppressed adipose tissue PPARγ, GLUT4, adiponectin, and insulin receptor β-subunit mRNA expressions were upregulated while the elevated adipose tissue resistin expression was downregulated in diabetic rats as a result of treatment with the leaf and peel extract. Based on these results, it can be concluded that M. paradisiaca leaf and fruit peel hydroethanolic extracts have antihyperglycemic effects which may be mediated via their insulinotropic and insulin-sensitizing effects.

Creatinine/(cystatin C × body weight) ratio is associated with skeletal muscle mass index.

We have previously reported that the creatinine (Cre) to cystatin C (CysC) ratio is associated with height-adjusted skeletal muscle mass index (SMI). However, weight-adjusted SMI is reported to be a more useful marker of insulin sensitivity than height-adjusted SMI. Thus, we hypothesized that the creatinine to (cystatin C × body weight [BW]) relationship (Cre/[CysC × BW]) might be associated with weight-adjusted SMI. In this cross-sectional study of 169 males and 132 females, a body composition analyzer was used and the weight-adjusted SMI was calculated as (absolute muscle mass [kg]/BW [kg]) × 100. The cut-off of low muscle mass was defined as weight-adjusted SMI <37.0% for males and <28.0% for females. The Cre/(CysC × BW) was correlated with weight-adjusted SMI in both males (r = 0.484, p < 0.001) and females (r = 0.538, p < 0.001). In addition, Cre/(CysC × BW) was associated with weight-adjusted SMI in both males (standardized β = 0.493, p < 0.001) and females (standardized β = 0.570, p < 0.001) after adjusting for covariates. According to the receiver operator characteristic (ROC) curve analysis, the optimal cut-off point of Cre/(CysC × BW) for low muscle mass was 0.0145 (area under the ROC curve [AUC] 0.756 [95% confidence interval {95% CI} 0.644-0.842], sensitivity = 0.96, specificity = 0.47, p < 0.001) in males and 0.0090 (AUC 0.976 [95% CI 0.894-0.995], sensitivity = 1.00, specificity = 0.93, p < 0.001) in females. There is a correlation between Cre/(CysC × BW) and weight-adjusted SMI. The Cre/(CysC × BW) could be a practical screening marker for low muscle mass.

Gender diversity of insulin sensitivity markers among patients of type 2 diabetes mellitus in northern India: A cross-sectional analytical study.

Background:Diabetes mellitus is a worldwide health problem with more than 80% diabetics living in LMIC. Biological and psychosocial factors are also responsible for gender diversity in T2DM which highlights the need for action to combat T2DM in India. The current study was undertaken to evaluate the gender diversity of insulin sensitivity markers among patients of T2DM in northern India and secondly, to assess and compare the quality of life among T2DM patients in northern India.Material and Methods:It was a cross-sectional analytical study enrolling 78 patients from tertiary care teaching hospital, India. Inclusion criteria was patients within the age group of 18–60 years, diagnosed with T2DM and on insulin therapy. Case reporting form, anthropometric measures, laboratory investigations, and diabetes quality of life (DQoL) instruments were used for data collection for the period of 3 months.Results:The mean age of T2DM patients for males was 48.00 ± 9.92 years and for females was 49.96 ± 10.39 years. Male and female patients were 50% and 50%, respectively. WHR (P = 0.032), DBP (P = 0.000), body fat % (P = 0.04), and duration of diabetes (P = 0.001) had statistically significant association with insulin resistance (binary logistic regression analysis (P-value <0.05). Results show the statistically significant difference between means of WHR (t value = 4.702, P = 0.000) and body fat % (t value = 3.035, P = 0.000) in male and female T2DM patients (Independent’t’-test) (P-value <0.05).Conclusions:The study concludes that WHR, DBP, body fat %, and duration of diabetes were significant markers of insulin sensitivity. WHR and body fat % were the differential insulin sensitivity markers in male and female patients of T2DM in northern India. Diabetes adversely affects the quality of life in a nearly similar pattern in both male and female patients.

Body composition of New Zealand European and Pacific women is associated with lower dietary fibre intake and gut microbiota diversity

AbstractDiet is considered one of the key drivers of the world-wide obesity epidemic, and the gut microbiota may play a role in this multifaceted disease due to their mutualistic relationship. This study investigated relationships between habitual dietary intake of New Zealand European and Pacific women and their gut microbiota and body fat content. Pacific (44%) and NZ European (NZE; 56%) women (n = 287) aged 18–45 years were recruited based on body mass index (normal versus obese) and stratified as low (&lt; 35%) or high (≥ 35%) body fat percentage (BF%). Dietary intake was assessed with a 5-day estimated food record and a semi-quantitative food frequency questionnaire, which were used to calculate habitual dietary intake using the National Cancer Institute (NCI) method. BF% was assessed by dual-energy x-ray absorptiometry (DXA). Fasting blood samples were analysed for markers of insulin sensitivity. The DNA from faecal samples was analysed following shotgun sequencing. There were no significant differences in BF% between Pacific and NZE women (p = 0.498). Significant differences in homeostasis model assessment of insulin resistance (HOMA-IR) index were observed between Pacific (3.4 [2.3, 5.9]) and NZE (2.1 [1.5, 3.1], p ≤ 0.001) women, and between; low-BF% (1.9 [1.3, 2.7]) and high-BF% (3.4 [2.5, 5.9], p ≤ 0.001) groups. The highest (27.6g/d [24.9, 30.6]) compared to the lowest tertile (16g/d [13.3, 17.6]) of habitual total dietary fibre (DF) intake was associated with a significantly lower HOMA-IR (2.1 [1.3, 3.1] versus 3.3 [2.1, 5.3] p ≤ 0.001) respectively. Higher DF intake was also associated with significantly lower BF% (β -0.35, p ≤ 0.001), and this relationship became stronger when considering the intake of other macronutrients (β -0.47, p ≤ 0.001). Alpha diversity; observed taxonomic units (OTU's; rs = -0.15, p = 0.011), Pielou's evenness (rs = -0.20, p = 0.001), and Shannon index (rs = -0.22, p ≤ 0.001), were all negatively correlated with BF%. In contrast BF% was positively correlated with the Firmicutes:Bacteroidetes ratio (rs = 0.26, p ≤ 0.001). HOMA-IR index was significantly higher in Pacific and women in the higher BF% group, indicating an increased metabolic disease risk. Higher habitual DF intake was associated with lower BF% and HOMA-IR, suggesting a potential metabolically protective effect. The positive effects of higher DF intake may be associated with microbiota diversity, as higher BF% was associated with reduced alpha diversity and an increased Firmicutes:Bacteroidetes ratio. Further analysis will explore which foods contributed to the higher DF intake, and associations with body composition, microbiota and biomarkers of metabolic health.

Effects of a whole diet approach on metabolic flexibility, insulin sensitivity and postprandial glucose responses in overweight and obese adults - A randomized controlled trial.

Metabolic flexibility is the ability to adapt fuel oxidation to fuel availability. Metabolic inflexibility has been associated with obesity, the metabolic syndrome and insulin resistance, and can be improved by exercise or weight loss. Dietary changes can modulate metabolic flexibility; however, the effect of a whole diet approach on metabolic flexibility has never been studied. Therefore, our objective was to assess the effect of a healthy diet (HD), as compared to a typical Western diet (WD), on several fasting and postprandial markers of metabolic flexibility and insulin sensitivity. In this parallel randomized trial, overweight or obese men and women (50-70 years; BMI 25-35kg/m2) consumed a healthy diet (HD; high in fruits and vegetables, pulses, fibers, nuts, fatty fish, and low in high-glycemic carbohydrates; n=19) or a typical Western diet (WD; n=21) for six weeks, following a two-week run-in period. The change in respiratory quotient upon insulin stimulation (ΔRQ), and insulin sensitivity, expressed as the M-value, were both determined with a hyperinsulinemic euglycemic clamp. Additionally, other fasting and postprandial markers of metabolic flexibility were assessed during a 5-h high-fat high-glycemic mixed meal challenge. ΔRQ (p=0.730) and insulin sensitivity (p=0.802) were not significantly affected by diet. Postprandial RQ did also not show significant differences (p=0.610), whereas postprandial glucose excursions were significantly higher in the HD group at T30 (p=0.014) and T45 (p=0.026) after mixed meal ingestion (p=0.037). Fasting glucose (p=0.530) and HbA1c (p=0.124) remained unchanged, whereas decreases in fasting insulin (p=0.038) and the HOMA-IR (p=0.050) were significantly more pronounced with the HD. A healthy diet for six weeks, without further life-style changes, did not improve metabolic flexibility and whole-body insulin sensitivity, when compared to a Western-style diet. It remains to be determined whether the short time increase in postprandial glucose is physiologically relevant or detrimental to metabolic health. This trial was registered at clinicaltrials.gov as NCT02519127.

MiRNAs Regulating Insulin Sensitivity Are Dysregulated in Polycystic Ovary Syndrome (PCOS) Ovaries and Are Associated With Markers of Inflammation and Insulin Sensitivity.

Objective: MicroRNAs (miRNAs) are gene expression regulators. Altered miRNA levels are associated with diabetes, insulin resistance, and inflammation. Insulin resistance and inflammation are both features of Polycystic ovary syndrome (PCOS). The aim of this study was first to assess differences in selected miRNAs (miR-146a, miR-155, miR-320, miR-370, miR-486), involved in insulin sensitivity regulation and inflammation, in women with or without PCOS. Second, to investigate relationships among these miRNAs, insulin, High mobility group box 1 (HMGB1), and IL-6 in follicular fluid (FF), serum 17-beta estradiol (E2), and the number of dominant follicles.Methods: Thirty PCOS and thirty-six non-PCOS women undergoing in vitro fertilization were enrolled. RNA from granulosa cells (GC) and FF was extracted and the specific miRNAs were evaluated using qRT-PCR. HMGB1, insulin, and IL-6 in FF, and serum E2 were assayed using specific kits.Results: MiR-146a, miR-155, miR-486 were upregulated and miR-320 and miR-370 were downregulated in GC from the PCOS patients. In FF, miR-146a, miR-155, and miR-486 showed lower levels in PCOS, whereas miR-320 and miR-370 showed an opposite trend but no significant changes were observed. These miRNAs showed relationships with Body Mass Index (BMI), age, E2, number of dominant follicles, insulin, and HMGB1.Conclusion: In conclusion, the miRNAs analyzed showed changes in PCOS ovaries and had relationships with indices of inflammation and insulin sensitivity within the ovary, providing evidence for new regulatory mechanisms.

Maternal Adipose Tissue Expansion, A Missing Link in the Prediction of Birth Weight Centile.

Maternal body mass index (BMI) is associated with increased birth weight but does not explain all the variance in fetal adiposity. To assess the contribution of maternal body fat distribution to offspring birth weight and adiposity. Longitudinal study throughout gestation and at delivery. Women recruited at 12 weeks of gestation and followed up at 26 and 36 weeks. Cord blood was collected at delivery. Pregnant women (n = 45) with BMI 18.0 to 46.3 kg/m2 and healthy pregnancy outcome. Maternal first trimester abdominal subcutaneous and visceral adipose tissue thickness (SAT and VAT) was assessed by ultrasound. Maternal body fat distribution, maternal and cord plasma glucose and lipid concentrations, placental weight, birth weight, and fetal adiposity assessed by cord blood leptin. VAT was the only anthropometric measure independently associated with birth weight centile (r2 adjusted 15.8%, P = .002). BMI was associated with trimester 2 and trimesters 1 through 3 area under the curve (AUC) glucose and insulin resistance (Homeostatic Model Assessment). SAT alone predicted trimester 2 lipoprotein lipase (LPL) mass (a marker of adipocyte insulin sensitivity) (11.3%, P = .017). VAT was associated with fetal triglyceride (9.3%, P = .047). Placental weight was the only independent predictor of fetal adiposity (48%, P < .001). Maternal trimester 2 and AUC LPL were inversely associated with fetal adiposity (r = -0.69, P = .001 and r = -0.58, P = .006, respectively). Maternal VAT provides additional information to BMI for prediction of birth weight. VAT may be a marker of reduced SAT expansion and increased availability of maternal fatty acids for placental transport.

Effect of prenatal EPA and DHA on maternal and cord blood insulin sensitivity: a secondary analysis of the mothers, omega 3, and mental health study

BackgroundWe sought to determine whether prenatal supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) would increase markers of insulin sensitivity in maternal or cord blood compared with placebo supplementation. A secondary aim was to evaluate the association of serum EPA and DHA fractions with adiponectin, leptin and the adiponectin:leptin ratio (ALR). We hypothesized that omega-3 fatty acid supplementation would increase markers of insulin sensitivity in maternal and umbilical cord plasma.MethodsWe analyzed stored plasma samples collected from a prior 3-arm prospective, double-blinded, randomized controlled trial in which 126 women with singleton pregnancies between 12- and 20-weeks’ gestation were randomized to receive: 1) an EPA-rich fish oil supplement, 2) a DHA-rich fish oil supplement, or 3) a soy oil placebo. Maternal venous blood samples were collected at 12–20 weeks gestation (before supplementation) and at 34–36 weeks gestation. At delivery, cord blood was collected. Samples were analyzed using sandwich enzyme-linked immunosorbent assay kits to quantify leptin and adiponectin levels which were utilized to calculate the ALR, a proxy measure for insulin sensitivity.ResultsWe found no difference in adiponectin, leptin, and the ALR between the treatment and placebo groups at baseline, after supplementation, or in umbilical cord blood. In regression analyses, higher maternal serum DHA fraction was associated with increased ALR before (p = 0.01) and after (p = 0.04) DHA supplementation. There was no association of EPA fraction with any measure of insulin sensitivity. Cord blood DHA fraction was significantly associated with cord plasma leptin (p = 0.02).Early pregnancy BMI was significantly associated with maternal leptin levels at baseline and in late pregnancy (p < 0.001) and was inversely associated with the ALR (p < 0.001). The ALR decreased significantly between the early and late pregnancy visits (p < 0.001). Pregnancy weight gain was inversely associated with the ALR (P. < 0.02).ConclusionsEPA- and DHA- rich fish oil supplementation had no effect on plasma markers of insulin sensitivity. However, maternal serum DHA fraction was significantly associated with markers of insulin sensitivity.Trial registrationhttps://clinicaltrials.gov/, registration number NCT00711971, 7/7/2008.

Association of Serum Total Osteocalcin Concentrations With Endogenous Glucocorticoids and Insulin Sensitivity Markers in 12-Year-Old Children: A Cross-Sectional Study.

Background: Osteocalcin (OC) is an osteoblast-derived marker of bone turnover that has recently been linked to glucose metabolism, glucocorticoid action, and cardiovascular risk.Objective: We determined whether serum total OC (tOC) is associated with cardiometabolic factors, such as insulin sensitivity (IS) markers and endogenous glucocorticoids in 12-year-old children. In addition, we assessed whether low birth weight or exposure to maternal preeclampsia affect tOC concentrations.Methods: In this cross-sectional study, 192 children (109 girls) were studied at 12 years of age. Seventy of them had been born small (SGA), 78 appropriate for gestational age (AGA), and 44 from preeclamptic pregnancies (PRE) as AGA. Blood pressure was measured, and fasting blood samples were collected for markers of glucose metabolism, osteoblast, adipocyte, and adrenocortical function. IS was estimated by Quantitative Insulin Sensitivity Check Index (QUICKI). Free cortisol index (FCI) was calculated as serum cortisol/corticosteroid binding globulin.Results: The highest tOC concentrations were detected in midpubertal children (Tanner B/G stage 3). The children in the highest tOC quartile (n = 48) had lower body mass index (BMI), waist-to-height ratio, diastolic blood pressure, leptin, cortisol/cortisone ratio and FCI, and higher insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, and alkaline phosphatase (ALP) than those in the lower tOC quartiles (p < 0.02 for all). QUICKI was similar in these subgroups. In logistic regression analysis, pubertal developmental stages 2 and 3, high ALP, IGF-I, and low FCI and BMI (p < 0.02 for all) were associated independently with higher tOC. The means of serum tOC and IS markers were similar in the SGA, AGA, and PRE subgroups.Conclusions: In both sexes, the highest tOC levels were detected in midpubertal children reflecting the fast pubertal growth phase. Higher tOC levels were associated with lower BMI and FCI, whereas no association was found with IS. Birth weight or exposure to preeclampsia had no effect on tOC concentrations.

Roux-en-Y-Bariatric Surgery Reduces Markers of Metabolic Syndrome in Morbidly Obese Patients

BackgroundObesity is closely linked to increased markers of metabolic syndrome and development of diabetes. Roux-en-Y bariatric surgery reduces hyperinsulinemia and improves insulin sensitivity and hence benefits morbidly obese patients.AimTo determine changes in markers of metabolic syndrome, pancreatic function, and hepatic insulin sensitivity in patients before and 1 year after undergoing Roux-en-Y gastric bypass surgery.MethodsWe enrolled 43 consecutive patients in a single center. Markers for metabolic syndrome included proinsulin, insulin, C-peptide, liver enzymes, and serum levels of selected microRNAs hsa-miR-122, hsa-miR-130, hsa-miR-132, and hsa-miR-375.ResultsAfter surgery, all patients showed a significant 37% drop of body mass index (p < 0.001). Furthermore, proinsulin (59% reduction, p < 0.001), insulin (76% reduction, p < 0.001), and C-peptide (56% reduction, p < 0.001) were all reduced 1 year after surgery. Using the hepatic insulin clearance score, we determined a significant increase in hepatic insulin clearance after surgery (76% increase, p < 0.001). Especially diabetic patients showed a marked 2.1-fold increase after surgery. Hepatic enzymes ALT (35% reduction, p = 0.002) and γGT (48% reduction, p < 0.001) were significantly reduced in all patients with similar improvement in diabetic and non-diabetic patients. miRNAs hsa-miR-122, hsa-miR-130, and hsa-miR-132 were all significantly reduced whereas hsa-miR-375 was increased after gastric bypass surgery (p < 0.001 for all miRNAs).ConclusionBoth liver and pancreatic stress parameters were reduced significantly 1 year after Roux-en-Y gastric bypass surgery suggesting an overall amelioration of the metabolic syndrome in all patients regardless of previous health status.

Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans

Aims/hypothesisInsulin resistance in skeletal muscle and liver plays a major role in the pathophysiology of type 2 diabetes. The hyperinsulinaemic–euglycaemic clamp is considered the gold standard for assessing peripheral and hepatic insulin sensitivity, yet it is a costly and labour-intensive procedure. Therefore, easy-to-measure, cost-effective approaches to determine insulin sensitivity are needed to enable organ-specific interventions. Recently, evidence emerged that plasma cathepsin D (CTSD) is associated with insulin sensitivity and hepatic inflammation. Here, we aimed to investigate whether plasma CTSD is associated with hepatic and/or peripheral insulin sensitivity in humans.MethodsAs part of two large clinical trials (one designed to investigate the effects of antibiotics, and the other to investigate polyphenol supplementation, on insulin sensitivity), 94 overweight and obese adults (BMI 25–35 kg/m2) previously underwent a two-step hyperinsulinaemic–euglycaemic clamp (using [6,6-2H2]glucose) to assess hepatic and peripheral insulin sensitivity (per cent suppression of endogenous glucose output during the low-insulin-infusion step, and the rate of glucose disappearance during high-insulin infusion [40 mU/(m2 × min)], respectively). In this secondary analysis, plasma CTSD levels, CTSD activity and plasma inflammatory cytokines were measured.ResultsPlasma CTSD levels were positively associated with the proinflammatory cytokines IL-8 and TNF-α (IL-8: standardised β = 0.495, p < 0.001; TNF-α: standardised β = 0.264, p = 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised β = −0.206, p = 0.043), independent of age, sex, BMI and waist circumference, but it was not associated with peripheral insulin sensitivity. However, plasma IL-8 and TNF-α were not significantly correlated with hepatic insulin sensitivity.Conclusions/interpretationWe demonstrate that plasma CTSD activity, but not systemic inflammation, is inversely related to hepatic insulin sensitivity, suggesting that plasma CTSD activity may be used as a non-invasive marker for hepatic insulin sensitivity in humans.

Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study

MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis. Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12 months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers. Patients were randomly assigned to placebo (n = 94), or 62.5 mg (n = 99), 125 mg (n = 98), or 250 mg (n = 101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4 ± 1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5 mg, 125 mg and 250 mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44-1.81), 1.22 (95% CI 0.60-2.48), and 1.64 (95% CI 0.83-3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups. MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive measures of liver cell injury and glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444]. First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects.

Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health

ObjectiveThe gut microbiota has been implicated in the aetiology of obesity and associated comorbidities. Patients with Prader-Willi syndrome (PWS) are obese but partly protected against insulin resistance. We hypothesised that...

Effects of Consuming Almonds on Insulin Sensitivity and Other Cardiometabolic Health Markers in Adults With Prediabetes

Objective: This study was designed to assess the effects of replacing high-carbohydrate (CHO) foods with raw almonds on insulin sensitivity and cardiometabolic health markers in overweight or obese adults with prediabetes.Method: This randomized crossover study consisted of two 6-week dietary intervention periods, separated by a ≥ 4-week washout. Subjects incorporated 1.5 oz of raw almonds twice daily or isocaloric CHO-based foods into their diets, with instructions to maintain body weight. Dietary intakes as well as insulin sensitivity, CHO metabolism indices, lipoprotein lipids and particles, and inflammatory markers were assessed.Results: Thirty-three subjects (17 male, 16 female), mean age 48.3 ± 2.2 years and body mass index 30.5 ± 0.7 kg/m2, provided evaluable data. Compared to CHO, almonds resulted in significantly (p < 0.01) higher intakes of protein, fat (unsaturated fatty acids), fiber, and magnesium and significantly (p < 0.001) lower intakes of CHO and sugars. No differences were observed between diet conditions for changes from baseline in the insulin sensitivity index from a short intravenous glucose tolerance test or other indices of glucose homeostasis. No significant differences were observed in biomarkers of cardiovascular risk except that the CHO intervention led to a shift toward a higher concentration of cholesterol in small, dense low-density lipoprotein subfraction 3+4 (LDL3 + 4) particles (p = 0.024 vs almonds).Conclusions: Intake of 3.0 oz/d raw almonds, vs energy-matched CHO foods, improved the dietary nutrient profile, but did not significantly affect insulin sensitivity and most markers of cardiometabolic health in overweight and obese men and women with prediabetes.

Synergistic effect of nano-selenium and metformin on type 2 diabetic rat model: Diabetic complications alleviation through insulin sensitivity, oxidative mediators and inflammatory markers.

In the present article, we explore a novel strategy of selenium nanoparticles (Se-NPs) for the treatment of type 2 diabetes mellitus (T2DM) by investigating the effect of Se-NPs alone and in combination with standard anti-diabetic drug metformin (MET) in high-fat diet/streptozotocin (HFD/STZ)-induced T2DM. HFD was supplemented daily to experimental rats for 8 weeks, followed by a single low dose injection of 35 mg/kg of STZ to induce T2DM. The synergistic effect of the different therapeutic strategies on diabetic complications was evaluated after the Se-NPs and MET administration for 8 weeks. Molecular and biochemical analyses were conducted to figure out the effectiveness of our treatment on insulin sensitivity, oxidative mediators and inflammatory markers. Our observations demonstrated that HFD/STZ-induced rats have a toxic effect on serum and hepatic tissues resulted in inducing remarkable oxidative damage and hyper-inflammation with a significant disturbance in the insulin signaling pathway. Experimental animals either treated with mono-therapeutic-two doses Se-NPs (0.1 and 0.4 mg/kg) and/or MET (100 mg/kg) alone as well as the combined therapy resulted in a remarkable protective anti-diabetic effect illustrated by significant decreases in fasting blood glucose and insulin levels after 8 weeks treatment. At the same time, the levels of active insulin signaling proteins pIRS1/pAKT/pGSK-3β/pAMPK were significantly improved. Moreover, Se-NPs exhibited an anti-inflammatory effect by the mitigation of cytokine expression and a balance between oxidative stress and antioxidant status was restored. Furthermore, the anti-diabetic drug MET administration also exhibited a significant improvement in diabetic complications after the treatment period. This study provides mightily the mechanism of action of combined Se-NPs and MET as a promising therapeutic alternative that synergistically alleviates most of diabetic complications and insulin resistance.

Rising Glucagon-Like Peptide 1 Concentrations After Parathyroidectomy in Patients With Primary Hyperparathyroidism

BackgroundAlthough primary hyperparathyroidism has been associated with insulin resistance, potential optimal effects of parathyroidectomy (PTX) on glucose homeostasis remain controversial. Accordingly, the impact of PTX on glucose-stimulated incretin (glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide) secretion has not been evaluated. The aim of this pilot study was to compare glucose-stimulated incretin secretion (GSIS) in patients with asymptomatic primary hyperparathyroidism with normal glucose homeostasis, before and after PTX. MethodsFourteen patients were included in the study. Fasting calcium, parathyroid hormone, glucose, insulin, GLP-1, and gastric inhibitory peptide were measured pre- and post-operatively. Homeostasis Model Assessment 2, QUICKI, and Matsuda indexes were used as markers of insulin sensitivity and resistance before and after PTX. Preoperatively, a 75 g oral glucose tolerance test (OGTT) was performed to evaluate the response of glucose, insulin, and GSIS. OGTT measurements were repeated 6 ± 2 wk post-PTX. ResultsPatients had a mean age of 52.93 ± 9.96 y, and female-to-male ratio was 12:2. Pre- and post-operatively, a positive correlation between parathyroid hormone and Homeostasis Model Assessment 2 for β-cell function was evident (r = 0.74, P = 0.002 and r = 0.55, P = 0.04, respectively). After PTX, a significant increase in GSIS for GLP-1 during OGTT was observed (in 60 min: 63.06 ± 44.78 versus 102.64 ± 40.19 pg/mL, P = 0.02; and in 120 min: 71.20 ± 35.90 versus 102.49 ± 40.02 pg/mL, P = 0.03). ConclusionsThe increase of GLP-1 response following oral glucose load after PTX may reflect an initial recovery phase of glucose homeostasis. Long-term studies are required to elucidate the physiological interplay between the normalization of calciotropic axis and the rising GLP-1 concentrations post-PTX.

Free Vitamin D: Relationship to Insulin Sensitivity and Vascular Health in Youth

To evaluate the relationship of free 25 hydroxy vitamin D [free 25(OH)D] or bioavailable vitamin D (BioD) concentrations to insulin sensitivity and cardiovascular disease risk markers in normal weight and overweight youth. Cross-sectional study of 79 adolescents 15.4±0.2years, 18 normal weight, 30 overweight, and 31 overweight with prediabetes who underwent peripheral arterial tonometry, dual-energy x-ray absorptiometry, and hyperinsulinemic-euglycemic clamp in subset (n=71) for determination of reactive hyperemia index (RHI), body composition, and insulin sensitivity. 25(OH)D and vitamin D binding protein were measured; free 25(OH)D and BioD were calculated. Across tertiles of free 25(OH)D concentrations (4.0±0.2, 7.5±0.3, and 17.0±2.1 pg/mL, P<.001), the group in the lowest tertile had significantly higher percent body fat (37.8±1.1, 35.2±1.5 and 25.3±2.1%, P<.001), lower insulin sensitivity (4.4±0.4, 6.7±1.2, and 8.2±0.9mg/kg fat-free mass/minute per μu/mL, P=.03), lower RHI (1.42±0.06, 1.54±0.06, and 1.77±0.09, P=.002), higher high-sensitivity C-reactive protein (3.4±0.6, 1.7±0.3, and 1.6±0.4mg/L, P=.015) compared with the second and third tertiles, respectively. Free 25(OH)D levels were inversely related to percent body fat and high-sensitivity C-reactive protein, and positively related to RHI and insulin sensitivity. The relationships of free 25(OH)D to RHI and to insulin sensitivity were no longer significant after adjusting for %body fat. Similar relationships were observed for BioD. Youth with low free 25(OH)D or BioD concentrations have lower insulin sensitivity and worse endothelial function and inflammatory biomarkers compared with those with more sufficient 25(OH)D. However, the effects of vitamin D on these biomarkers may not be independent of the effect of adiposity.

Effects of Lean Beef Intake, as Part of a Healthful Dietary Pattern, on Cardiometabolic Risk Markers in Subjects at Risk for Diabetes Mellitus: a Controlled Feeding Trial (FS18-02-19)

Abstract Objectives To assess and compare the effects of two diets low in saturated fatty acids (SFA): a United States Department of Agriculture (USDA) healthy US-style eating pattern (USDA diet) and a similar diet containing 150 g/d of lean beef in place of refined starches and added sugars (USDA-LB), on insulin sensitivity and other cardiometabolic markers in adults at-risk for type 2 diabetes (T2D). Methods This randomized, controlled crossover trial included two screening visits, a baseline visit, and two 28-d diet periods, separated by a 2-week washout. Thirty-three subjects (7 men, 26 women) provided evaluable data for this analysis. All foods were provided for each 28-d period. At baseline and at the end of each diet condition, insulin sensitivity and pancreatic beta-cell function were assessed with a 50-min intravenous glucose tolerance test. Other risk markers evaluated included fasting lipoprotein lipids, particles and subfractions, apolipoproteins A1 and B, homeostasis model assessment of fasting insulin sensitivity and beta-cell function, and high-sensitivity C-reactive protein. Results Baseline values and responses for selected variables are shown in the Table. Neither the USDA nor the USDA-LB diets had significant effects on insulin sensitivity or pancreatic beta-cell function; however, both produced a significant (P &lt; 0.05) decrease in mean high-density lipoprotein cholesterol (HDL-C) versus baseline. The USDA diet also significantly (P &lt; 0.05) reduced median non-HDL-C and mean total cholesterol (total-C) compared to baseline, but the response did not differ significantly from that of the USDA-LB diet. A shift toward larger and more buoyant LDL subfractions compared to the USDA diet (P = 0.007) and baseline (P &lt; 0.05) occurred with the USDA-LB diet. No other significant differences were observed in carbohydrate or lipid metabolism and assessed parameters. Conclusions Intake of a low-SFA, USDA healthy US-style diet lowered total-C, non-HDL-C, and HDL-C compared with baseline. Inclusion of 150 g/d of lean beef did not adversely affect insulin sensitivity and related cardiometabolic markers compared with the USDA healthy diet and produced a shift toward larger, more buoyant LDL subfractions. Funding Sources Funded by The Beef Checkoff. Supporting Tables, Images and/or Graphs