Measures Of Glucose Homeostasis Research Articles

Increased Plasma Branched Short-Chain Fatty Acids and Improved Glucose Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Short chain fatty acids (SCFA) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched short chain fatty acids (BSCFA), isobutyrate, isovalerate, and methylbutyrate, is largely unknown. In a cohort of 219 non-Hispanic Whites and 126 African Americans, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, lipid traits, and other SCFA. We observed a bimodal distribution of BSCFA, with 25 individuals having high levels (HBSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared to the L-BSCFA group (16% versus 49%, P=0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFA. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose were lower and disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial Cpeptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.

Abstract 18928: Phenotypic Manifestations of Polygenic Risk for Ischemic Stroke in Adults Free From Disease

Introduction: Ischemic stroke is a complex heritable disease with a substantial proportion of risk attributable to polygenic factors. Little is known about how polygenic risk for stroke may manifest as intermediate phenotypes. Hypothesis: Polygenic liability for ischemic stroke will be associated with cardiometabolic phenotypes even in young adults free from disease. Methods: Polygenic risk derived from a multi ancestry population (GIGASTROKE ~1.2 million SNPs) was applied to 454 White adults from the HERITAGE Family Study with imputed whole genome data available. Participants (mean age = 31.5 ±14.5 years, 51% female) underwent robust cardiometabolic profiling including deeply phenotyped cardiopulmonary exercise tests, body composition, lipid panels, inflammatory markers, and measures of glucose homeostasis. General linear models adjusted for age and sex were used to test the association between z-scored polygenic risk of stroke (SPRS) and 130 phenotypes. A false discovery rate of <5% was used to determine significance. Results: SPRS did not associate with demographic traits or measures of body composition. SPRS was positively associated with several blood pressure related phenotypes with the strongest association between SPRS and systolic blood pressure response to acute exercise (β=0.01, p=2.86e-05), which persisted after adjustment for resting systolic blood pressure. Additionally, 19 total phenotypes were nominally associated (p<0.05) with SPRS including multiple apoB related plasma lipid traits ( Table 1 ). Interestingly, SPRS was also inversely associated with hematocrit (β= -0.06, FDR=0.004). Conclusions: Genetic risk of ischemic stroke is associated with hemodynamic traits even in a cohort of relatively young adults free from overt cardiometabolic disease. Additionally, blood pressure response to acute exercise may represent an early manifestation of genetic liability to stroke.

Associations between avocado intake and measures of glucose and insulin homeostasis in Hispanic individuals with and without type 2 diabetes: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Background and AimsTo investigate associations between avocado intake and glycemia in adults with Hispanic/Latino ancestry. Methods and ResultsThe associations of avocado intake with measures of insulin and glucose homeostasis were evaluated in a cross-sectional analysis of up to 14,591 Hispanic/Latino adults, using measures of: average glucose levels (hemoglobin A1c; HbA1c), fasting glucose and insulin, glucose and insulin levels after an oral glucose tolerance test (OGTT), and calculated measures of insulin resistance (HOMA-IR, and HOMA-%β), and insulinogenic index. Associations were assessed using multivariable linear regression models, which controlled for sociodemographic factors and health behaviors, and which were stratified by dysglycemia status.In those with normoglycemia, avocado intake was associated with a higher insulinogenic index (β = 0.17 ± 0.07, P = 0.02). In those with T2D (treated and untreated), avocado intake was associated with lower hemoglobin A1c (HbA1c; β = −0.36 ± 0.21, P = 0.02), and lower fasting glucose (β = −0.27 ± 0.12, P = 0.02). In the those with untreated T2D, avocado intake was additionally associated with HOMA-%β (β = 0.39 ± 0.19, P = 0.04), higher insulin values 2-h after an oral glucose load (β = 0.62 ± 0.23, P = 0.01), and a higher insulinogenic index (β = 0.42 ± 0.18, P = 0.02). No associations were observed in participants with prediabetes. ConclusionsWe observed an association of avocado intake with better glucose/insulin homeostasis, especially in those with T2D.

Glycomacropeptide Impacts Amylin-Mediated Satiety, Postprandial Markers of Glucose Homeostasis, and the Fecal Microbiome in Obese Postmenopausal Women

BackgroundObesity with metabolic syndrome is highly prevalent and shortens lifespan. ObjectivesIn a dose-finding crossover study, we evaluated the effect of glycomacropeptide (GMP) on satiety, glucose homeostasis, amino acid concentrations, inflammation, and the fecal microbiome in 13 obese women. MethodsEligible women were ≤10 yr past menopause with a body mass index [BMI (in kg/m2)] of 28 to 35 and no underlying inflammatory condition affecting study outcomes. Participants consumed GMP supplements (15 g GMP + 10 g whey protein) twice daily for 1 wk and thrice daily for 1 wk, with a washout period between the 2 wk. Women completed a meal tolerance test (MTT) on day 1 (soy MTT) and day 7 (GMP MTT) of each week. During each test, subjects underwent measures of glucose homeostasis, satiety, cytokines, and the fecal microbiome compared with that of usual diet, and rated the acceptability of consuming GMP supplements. ResultsThe mean ± SE age of the 13 women was 57 ± 1 yr, with a median of 8 yr (range: 3–9 yr) past menopause and a BMI of 30 (IQR: 29–32). GMP was highly acceptable to participants, permitting high adherence. Metabolic effects were similar for twice or thrice daily GMP supplementation. Glucose, insulin, and cytokine concentrations were no different. The postprandial area under the curve (AUC) for glucagon concentrations was significantly lower, and the insulin-glucagon ratio was significantly higher with GMP than that with the soy MTT. Postprandial AUC amylin concentration was significantly higher with GMP than that with the soy MTT and correlated with C-peptide (P < 0.001; R2 = 0.52) and greater satiety. Ingestion of GMP supplements twice daily reduced members of the genus Streptococcus (P = 0.009) and thrice daily consumption reduced overall α diversity. ConclusionsGMP is shown to increase amylin concentrations, improve glucose homeostasis, and alter the fecal microbiome. GMP can be a helpful nutritional supplement in obese postmenopausal women at risk for metabolic syndrome. Further investigation is warranted.This trial was registered at clinicaltrials.gov as NCT05551091.

Metabolomic profiling of glucose homeostasis in African Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS-FS)

IntroductionAfrican Americans are at increased risk for type 2 diabetes.ObjectivesThis work aimed to examine metabolomic signature of glucose homeostasis in African Americans.MethodsWe used an untargeted liquid chromatography-mass spectrometry metabolomic approach to comprehensively profile 727 plasma metabolites among 571 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) and investigate the associations between these metabolites and both the dynamic (SI, insulin sensitivity; AIR, acute insulin response; DI, disposition index; and SG, glucose effectiveness) and basal (HOMA-IR and HOMA-B) measures of glucose homeostasis using univariate and regularized regression models. We also compared the results with our previous findings in the IRAS-FS Mexican Americans.ResultsWe confirmed increased plasma metabolite levels of branched-chain amino acids and their metabolic derivatives, 2-aminoadipate, 2-hydroxybutyrate, glutamate, arginine and its metabolic derivatives, carbohydrate metabolites, and medium- and long-chain fatty acids were associated with insulin resistance, while increased plasma metabolite levels in the glycine, serine and threonine metabolic pathway were associated with insulin sensitivity. We also observed a differential ancestral effect of glutamate on glucose homeostasis with significantly stronger effects observed in African Americans than those previously observed in Mexican Americans.ConclusionWe extended the observations that metabolites are useful biomarkers in the identification of prediabetes in individuals at risk of type 2 diabetes in African Americans. We revealed, for the first time, differential ancestral effect of certain metabolites (i.e., glutamate) on glucose homeostasis traits. Our study highlights the need for additional comprehensive metabolomic studies in well-characterized multiethnic cohorts.

Cardiovascular correlates of epigenetic aging across the adult lifespan: a population-based study

Individuals with a similar chronological age can exhibit marked differences in cardiovascular risk profiles, but it is unknown whether this variation is related to different rates of biological aging. Therefore, we investigated the relation between nine domains of cardiovascular function and four epigenetic age acceleration estimators (i.e., AgeAccel.Horvath, AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim), derived from DNA methylation profiles. Among 4194 participants (mean age 54.2 years (range 30.0–95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany, epigenetic age acceleration increased by 0.19–1.84 years per standard deviation (SD) increase in cardiovascular risk across multiple domains, including measures of kidney function, adiposity, and a composite cardiovascular risk score. Measures of inflammation and glucose homeostasis were associated with AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim, but not with AgeAccel.Horvath. Moreover, effect sizes were larger for AgeAccelPheno and AgeAccelGrim than for AgeAccel.Horvath and AgeAccel.Hannum. Similarly, epigenetic age acceleration increased by 0.15–0.81 years per SD increase in markers of vascular function (blood pressure, arterial stiffness, and hemodynamic measures), whereas better endothelial function was only associated with lower AgeAccelGrim. Most effects on epigenetic age acceleration were independent, which suggests they independently contribute to different rates of biological aging.

Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis.

Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Shared Activities With Parents During Adolescence Predicts Health Risk Across Multiple Biological Systems 22 Years Later.

Although affectively focused dimensions of social relationships are associated with differences in health risk, less research has considered nonaffective features of relationships, such as engaging in shared activities. This study sought to test whether adolescents who engaged in more shared activities with their parents had lower health risk in early midlife across multiple biological markers. Using data from a nationally representative study ( N = 4801), prospective associations between shared activities with parents during adolescence and health risk classifications for measures of inflammation, renal function, glucose homeostasis, and cholesterol 22 years later were examined, along with the potentially confounding roles of childhood socioeconomic status and parent-child relationship satisfaction. Exploratory analyses considered possible indirect effects of cigarette use, alcohol use, and body mass index in adulthood. Engaging in more shared activities with parents was associated with a reduced likelihood of being classified in a high-risk health category for markers of inflammation ( B = -0.02, standard error [SE] = 0.01, p = .040), renal function ( B = -0.08, SE = 002, p = .001), glucose ( B = -0.06, SE = 0.23, p = .011), and high-density lipoprotein ( B = - 0.03, SE = 0.01, p = .021), and overall allostatic load ( B = - 0.02, SE = 0.02, p = .001), beyond demographic and health covariates. Controlling for parental income and relationship satisfaction largely did not affect observed associations. Exploratory tests of indirect effects imply that health behaviors in adulthood may partially account for observed associations. Engaging in more shared activities predicted more optimal health classifications 22 years later, suggesting that the amount of contact between parents and teenagers may have long-lasting beneficial health effects. Furthermore, consideration of nonaffective dimensions of family relationships may provide additional insight into associations between social relationships and health.

Frequent Cannabis Smoking and Association with Prediabetes and Diabetes in Early Adulthood

Background: Cannabis use in young adulthood has been linked with increased risk of prediabetes later in life. However, many previous studies have only used fasting blood samples to determine risk for type 2 diabetes (T2D), which may not detect early changes in glucose homeostasis. The objective of this study was to determine the association between cannabis use and risk for prediabetes and T2D in young adults using several measures of glucose homeostasis, including an oral glucose tolerance test (OGTT). Methods: The Meta-CHEM study is a subset (N=84) of overweight and obese young adults aged 22–25 years from the Children&amp;#x27;s Health Study (CHS). Participants underwent a single clinical visit which included a 2-hour OGTT and questionnaire about cannabis smoking habits in the past year. Participants were classified as non-smokers, light cannabis smokers (smoke &amp;#x3c;once a week), and heavy cannabis smokers (smoke &amp;#x3e;once a week). Those smoking more than one cigarette in the past week were excluded from the study. Participants were classified as having prediabetes or T2D if they had a HbA1c &amp;#x3e;5.6%, fasting glucose &amp;#x3e;99 mg/dL, and/or 2-hour OGTT glucose &amp;#x3e;139 mg/dL. Logistic regression was used to assess the associations between cannabis smoking habits and metabolic outcomes after adjusting for age, sex, education, body mass index, Hispanic ethnicity, physical activity, and alcohol consumption. Results: 52 (62%) participants were non-diabetic, 28 (33%) had pre-diabetes, and 4 (0.05%) had T2D. 25 (30%) participants were nonsmokers, 47 (56%) were light cannabis smokers, and 12 (14%) were heavy cannabis smokers. The odds of having prediabetes or T2D was 7.3 times higher among heavy smokers (95% CI: 0.94, 7.7), and 1.5 times higher among light smokers (CI: 0.43, 6.0) than nonsmokers (P-value for trend = 0.03). Conclusion: Cannabis use in overweight and obese young adults was significantly associated with risk of having prediabetes or T2D.

The Weak Relationship between Vitamin D Compounds and Glucose Homeostasis Measures in Pregnant Women with Obesity: An Exploratory Sub-Analysis of the DALI Study.

Studies on the relationship between vitamin D (VitD) and glucose homeostasis usually consider either total VitD or 25OHD3 but not 25OHD2 and epimers. We aimed to evaluate the cross-sectional association of VitD compounds with glucose homeostasis measurements in pregnant women with overweight/obesity participating in the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus Prevention study. Methods: The analysis included 912 women. Inclusion criteria: <20 weeks gestation, body mass index ≥29 kg/m2 and information on exposure and outcome variables at baseline. Measurements: A 75 g OGTT at <20, 24–28 and 35–37 weeks gestation (except if previous diabetes diagnosis). Exposure variables: 25OHD2, 25OHD3 and C3-epimer. Outcome variables: fasting and post-challenge insulin sensitivity and secretion indices, corresponding disposition indices (DI), plasma glucose at fasting and 1 and 2 h, hyperglycemia in pregnancy (HiP). Statistics: Multivariate regression analyses with adjustment. Results: Baseline VitD sufficiency was 66.3%. Overall, VitD compounds did not show strong associations with any glucose homeostasis measures. 25OHD3 showed direct significant associations with: FPG at <20 and 24–28 weeks (standardized β coefficient (β) 0.124, p = 0.030 and 0.111, p = 0.026 respectively), 2 h plasma glucose at 24–28 weeks (β 0.120, p = 0.018), and insulin sensitivity (1/HOMA-IR, β 0.127, p = 0.027) at 35–37 weeks; it showed an inverse association with fasting DI (QUCKI*HOMA-β) at <20 and 24–28 weeks (β −0.124, p = 0.045 and β −0.148, p = 0.004 respectively). 25OHD2 showed direct associations with post-challenge insulin sensitivity (Matsuda, β 0.149, p = 0.048) at 24–28 weeks) and post-challenge DI (Matsuda*Stumvoll phase 1) at 24–28 and 35–37 weeks (β 0.168, p = 0.030, β 0.239, p = 0.006). No significant association with C3-epimer was observed at any time period. Conclusions: In these women with average baseline VitD in sufficiency range, VitD compounds did not show clear beneficial associations with glucose homeostasis measures.

Sex-specific differences in metabolic outcomes after sleeve gastrectomy and intermittent fasting in obese middle-aged mice.

Despite the high prevalence of obesity among middle-aged subjects, it is unclear if sex differences in middle age affect the metabolic outcomes of obesity therapies. Accordingly, in this study, middle-aged obese female and male mice were randomized to one of three groups: sleeve gastrectomy (SG), sham surgery ad libitum (SH-AL), or sham surgery with weight matching to SG through intermittent fasting with calorie restriction (SH-IF). Comprehensive measures of energy and glucose homeostasis, including energy intake, body weight, energy expenditure, glucose and insulin tolerance, and interscapular brown adipose tissue (iBAT) sympathetic innervation density were obtained. At the end of 8 wk, SG and SH-IF females had better metabolic outcomes than their male counterparts. SG females had improved weight loss maintenance, preservation of fat-free mass (FFM), higher total energy expenditure (TEE), normal locomotor activity, and reduced plasma insulin and white adipose tissue (WAT) inflammatory markers. SH-IF females also had lower plasma insulin and WAT inflammatory markers, and higher TEE than SH-IF males, despite their lower FFM. In addition, SH-IF females had higher iBAT sympathetic nerve density than SG and SH-AL females, whereas there were no differences among males. Notably, SH-IF mice of both sexes had the most improved glucose tolerance, highlighting the benefits of fasting, irrespective of weight loss. Results from this study demonstrate that in middle-aged obese mice, female sex is associated with better metabolic outcomes after SG or IF with calorie restriction. Clinical studies are needed to determine if sex differences should guide the choice of obesity therapies.NEW & NOTEWORTHY SG or IF with calorie restriction produces better metabolic outcomes in females than in males. IF with calorie restriction prevents metabolic adaptation, even in the face of fat-free mass loss. IF with calorie restriction in females only, is associated with increased iBAT sympathetic innervation, which possibly mitigates reductions in energy expenditure secondary to fat-free mass loss. Lastly, IF leads to better glucose homeostasis than SG, irrespective of sex.

Measures of glucose homeostasis during and after duodenal exclusion using a duodenal-jejunal bypass liner in a normoglycemic, nonobese canine model.

Discovering the role duodenal exclusion plays in weight loss and resolution of type 2 diabetes (T2D) may help refine the surgical and nonsurgical treatment of obesity and T2D. To assess changes in glucose homeostasis due to duodenal exclusion using a duodenal-jejunal bypass liner (DJBL) in a nonobese canine model. Academic laboratory setting. An intravenous glucose tolerance test (IVGTT), and a mixed-meal tolerance test (MMTT) at baseline, 1, and 6 weeks post DJBL implantation (I1 and I6, respectively), and 1 and 6 weeks post DJBL removal (R1 and R6, respectively) were done in canines (n = 7) fed a normal chow diet. Placement of the DJBL induced weight loss that was maintained until 4 weeks post removal (R4), despite normal food intake. Total bile acids (TBA) and glucagon-like peptide-1 (GLP-1) during the MMTT were significantly increased at I1 and were associated with increased lactate and free fatty acids. Hypoglycemia counter-regulation was blunted during the IVGTT at I1 and I6, returning to baseline at R1. While there were no changes to insulin sensitivity during the experiment, glucose tolerance was significantly increased following the removal of the DJBL at R1. These data show that in a normoglycemic, nonobese canine model, duodenal exclusion induces energy intake-independent weight loss and negative metabolic effects that are reversed following re-exposure of the small intestine to nutrients.

Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion

ObjectiveIL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice. MethodsTransgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre+/- mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups. ResultsIL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre+/- mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre+/- controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre+/- controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia. ConclusionsThis study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress.

Relationships Between Urinary Metals and Diabetes Traits Among Mexican Americans in Starr County, Texas, USA.

Hispanics/Latinos have higher rates of type 2 diabetes (T2D), and the origins of these disparities are poorly understood. Environmental endocrine-disrupting chemicals (EDCs), including some metals and metalloids, are implicated as diabetes risk factors. Data indicate that Hispanics/Latinos may be disproportionately exposed to EDCs, yet they remain understudied with respect to environmental exposures and diabetes. The objective of this study is to determine how metal exposures contribute to T2D progression by evaluating the associations between 8 urinary metals and measures of glycemic status in 414 normoglycemic or prediabetic adults living in Starr County, Texas, a Hispanic/Latino community with high rates of diabetes and diabetes-associated mortality. We used multivariable linear regression to quantify the differences in homeostatic model assessments for pancreatic β-cell function, insulin resistance, and insulin sensitivity (HOMA-β, HOMA-IR, HOMA-S, respectively), plasma insulin, plasma glucose, and hemoglobin A1c (HbA1c) associated with increasing urinary metal concentrations. Quantile-based g-computation was utilized to assess mixture effects. After multivariable adjustment, urinary arsenic and molybdenum were associated with lower HOMA-β, HOMA-IR, and plasma insulin levels and higher HOMA-S. Additionally, higher urinary copper levels were associated with a reduced HOMA-β. Lastly, a higher concentration of the 8 metal mixtures was associated with lower HOMA-β, HOMA-IR, and plasma insulin levels as well as higher HOMA-S. Our data indicate that arsenic, molybdenum, copper, and this metal mixture are associated with alterations in measures of glucose homeostasis among non-diabetics in Starr County. This study is one of the first to comprehensively evaluate associations of urinary metals with glycemic measures in a high-risk Mexican American population.

Habitual Intake of Marine-Derived n-3 PUFAs is Inversely Associated with a Cardiometabolic Inflammatory Profile in Yup'ik Alaska Native People

BackgroundThe relationship between dietary n-3 PUFAs and the prevention of cardiometabolic diseases, including type 2 diabetes, is unresolved. Examination of the association between n-3 PUFAs and chronic low-grade inflammation in a population where many individuals have had an extremely high intake of marine mammals and fish throughout their lifespan may provide important clues regarding the impact of n-3 PUFAs on health. ObjectivesThe aim of this study was to explore associations between concentrations of n-3 PUFAs resulting from habitual intake of natural food sources high in fish and marine mammals with immune biomarkers of metabolic inflammation and parameters of glucose regulation. MethodsA total of 569 Yup'ik Alaska Native adults (18–87 years old) were enrolled in this cross-sectional study between December 2016 and November 2019. The RBC nitrogen isotope ratio (NIR; 15N/14N) was used as a validated measure of n-3 PUFA intake to select 165 participant samples from the first and fourth quartiles of n-3 PUFA intakes. Outcomes included 38 pro- and anti-inflammatory cytokines and 8 measures of glucose homeostasis associated with type 2 diabetes risks. These outcomes were evaluated for their associations with direct measurements of EPA, DHA, and arachidonic acid in RBCs. AnalysisLinear regression was used to detect significant relationships with cytokines and n-3 PUFAs, adiposity, and glucose-related variables. ResultsThe DHA concentration in RBC membranes was inversely associated with IL-6 (β = –0.0066; P < 0.001); EPA was inversely associated with TNFα (β = –0.4925; P < 0.001); and the NIR was inversely associated with Monocyte chemoattractant protein-1 (MCP-1) (β = –0.8345; P < 0.001) and IL-10 (β = –1.2868; P < 0.001). ConclusionsHabitual intake of marine mammals and fish rich in n-3 PUFAs in this study population of Yup'ik Alaska Native adults is associated with reduced systemic inflammation, which may contribute to the low prevalence of diseases in which inflammation plays an important role.

Life-course Exposure to Perfluoroalkyl Substances in Relation to Markers of Glucose Homeostasis in Early Adulthood.

To investigate the prospective associations of life-course perfluoroalkyl substances (PFASs) exposure with glucose homeostasis at adulthood. We calculated insulin sensitivity and beta-cell function indices based on 2-h oral glucose tolerance tests at age 28 in 699 Faroese born in 1986-1987. Five major PFASs were measured in cord whole blood and in serum from ages 7, 14, 22, and 28 years. We evaluated the associations with glucose homeostasis measures by PFAS exposures at different ages using multiple informant models fitting generalized estimating equations and by life-course PFAS exposures using structural equation models. Associations were stronger for perfluorooctane sulfonate (PFOS) and suggested decreased insulin sensitivity and increased beta-cell function-for example, β (95% CI) for log-insulinogenic index per PFOS doubling = 0.12 (0.02, 0.22) for prenatal exposures, 0.04 (-0.10, 0.19) at age 7, 0.07 (-0.07, 0.21) at age 14, 0.05 (-0.04, 0.15) at age 22, and 0.04 (-0.03, 0.11) at age 28. Associations were consistent across ages (P for age interaction > 0.10 for all PFASs) and sex (P for sex interaction > 0.10 for all PFASs, except perfluorodecanoic acid). The overall life-course PFOS exposure was also associated with altered glucose homeostasis (P = 0.04). Associations for other life-course PFAS exposures were nonsignificant. Life-course PFAS exposure is associated with decreased insulin sensitivity and increased pancreatic beta-cell function in young adults.

The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial.

The effect of oral glutathione (GSH) supplementation was studied in obese subjects with and without type 2 diabetes (T2DM) on measures of glucose homeostasis and markers of oxidative stress. Twenty subjects (10 patients with T2DM and 10 obese subjects) were recruited for the study, and randomized in a double-blinded placebo-controlled manner to consume either 1000 mg GSH per day or placebo for 3 weeks. Before and after the 3 weeks insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp and a muscle biopsy was obtained to measure GSH and skeletal muscle mitochondrial hydrogen peroxide (H2O2) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (∼19%) in the GSH group; no change was seen in GSH to glutathione disulfide ratio. Skeletal muscle mitochondrial H2O2 emission rate did not change in response to the intervention and neither did the urinary excretion of the RNA oxidation product 8-oxo-7,8-dihydroguanosine or the DNA oxidation product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), although 8-oxodG decreased as a main effect of time. Oral GSH supplementation improves insulin sensitivity in obese subjects with and without T2DM, although it does not alter markers of oxidative stress. The study has been registered in clinicaltrials.gov (NCT02948673). Novelty: Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without T2DM. H2O2 emission rate from skeletal muscle mitochondria was not affected by GSH supplementation.

Effect of low-fat dairy products fortified with 1500IU nano encapsulated vitamin D3 on cardiometabolic indicators in adults with abdominal obesity: a total blinded randomized controlled trial

Background & aims Vitamin D deficiency is widespread worldwide. In this study, we aimed to evaluate the effect of a nano encapsulated form of vitamin D used for fortifying low-fat dairy products (milk and yogurt) on anthropometric indices, glycemic status, and lipid profile in subjects with abdominal obesity. Methods In a totally (quadruple) blinded, randomized, and parallel-controlled trial, 306 individuals with abdominal obesity were randomly allocated to one of four groups: fortified low-fat yogurt (FY, 1500 IU nano encapsulated vitamin D3 per 150 g/d), non-fortified low-fat yogurt (nFY), fortified low-fat milk (FM, 1500 IU nano encapsulated vitamin D3 per 200 g/d), non-fortified low-fat milk (nFM), for 10 weeks (nFM and nFY, were considered as the control groups). Anthropometric and biochemical parameters were measured at baseline and after a ten-week trial in Mashhad, Iran. Results After the ten-week intervention, we found a significant increase in serum concentration of 25(OH)D in both the FM and FY groups compared to the respective control groups (19.10 ± 5.69 ng/mL and 20.88 ± 5.76 ng/mL respectively, p < .001). We observed a significant reduction in weight to hip ratio (p = .04) and a significant improvement in triglyceride (p < .001) and HDL-C (p = .01) only in FM group compared to nFM group. Also, we found a significant reduction in fasting serum insulin (p < .001), and a significant improvement of HOMA-IR (p < .001) and QUICKI (p < .001) in both intervention groups compared to their placebos. Conclusions An intake of fortified dairy products containing nano-encapsulated vitamin D3 was associated with an improvement in some measures of anthropometric indices, glucose homeostasis, and lipid profiles, particularly in individuals receiving fortified milk. Hence, along with other benefits, fortification of dairy products with vitamin D may be an effective approach to improve some cardiometabolic indicators, such as insulin resistance. Trial registration number IRCT20101130005280N27

Urinary oxidized, but not enzymatic vitamin E metabolites are inversely associated with measures of glucose homeostasis in middle-aged healthy individuals

Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (α-tocopherol, α-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between α-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. α-TOH metabolites in blood (α-TOH and α-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both α-TLHQ (oxidized) and α-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of α-TOH metabolites and measures of glucose homeostasis. We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood α-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (α-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher α-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary α-TLHQ to α-CEHC ratio as a measure of oxidized-over-enzymatic conversion of α-TOH. Higher urinary levels of oxidized α-TOH metabolites as well as higher oxidized-to-enzymatic α-TOH metabolite ratio, but not circulating α-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating α-TOH, estimates of the conversion of α-TOH might be informative in relation to health and disease.

The role of a traditional and western diet on glucose homeostasis in Greenlandic Inuit carriers and non-carriers of type 2 diabetes variant in the TBC1D4 gene: A protocol for a randomized clinical trial

IntroductionThe lifestyle of Inuit in Greenland and worldwide is undergoing a transition from a fisher-hunter to a westernized society and meanwhile the prevalence of type-2 diabetes (T2D) has increased dramatically. Studies have shown that a common nonsense p.Arg684Ter variant in TBC1D4, which is frequent in Greenland, confers genetic susceptibility towards high risk of T2D. The aim of the study is to investigate whether a traditional marine diet, with high fat and low carbohydrate, will improve glycemic control in Greenland Inuit compared to a western diet. Moreover, we want to examine if the response is more pronounced in carriers of the p.Arg684Ter variant. Materials and methodsWe will conduct a randomized, clinical cross-over trial with two dietary intervention periods of four weeks duration. The diet intervention comprise provision of >20E% and instruction for the remaining part of the diet. We expect to include 30 homozygous carriers and 30 homozygous non-carriers of the p.Arg684Ter variant, aged 18–80 years, across three Greenlandic towns. The primary outcome is plasma (p)-glucose 2 h post an oral glucose tolerance test and we aim to have 80% power, at α = 0.05, to detect a difference of 1.1 mmol/L. We will also include supporting measures of glucose homeostasis, assess other markers of the metabolic syndrome and perform metabolome and microbiome profiling. The statistical analysis will be performed as complete case analyses using linear mixed models. Ethics and disseminationThe study received approval by the Ethics Committee of Greenland (KVUG 2018-26) and will be disseminated via international peer-reviewed journal articles and conferences. Trial registration numberClinicaltrials.gov identifier no. NCT04011904.