Measures Of Insulin Sensitivity Research Articles

Abstract PO2-08-10: Effect of 6 months of bazedoxifene + conjugated estrogens on body composition and insulin resistance

Abstract Menopause transition is often marked by an acceleration of visceral fat accumulation. Excess visceral fat is associated with insulin resistance and increased risk for breast cancer as well as heart disease and diabetes. We measured change in body composition (via iDXA), fasting insulin and glucose as part of an ongoing, Phase IIB trial (NCT04821141) of 6 months of bazedoxifene (BZA) + conjugated estrogen (CE) vs control with primary endpoints of change in mammographic density and breast tissue Ki-67. Participants are women ages 45-60 with vasomotor symptoms at increased risk for development of breast cancer. Methods: Visceral and total fat, lean, and total mass, were measured with iDXA (GE CoreScan™). Fasting plasma was assayed same day as drawn for total insulin using a chemiluminescence assay and glucose using a hexokinase method. Values generated were used to calculate HOMA IR (as a measure of insulin resistance) using the formula insulin µl/ml x glucose mg/dl/405. HOMA %S was calculated as 1/HOMA IR X100 as a measure of insulin sensitivity. Optimal HOMA IR is considered as ≤1; HOMA IR >1.5 is considered abnormal with >2.0 as evidence of insulin resistance. Optimal HOMA %S is 100%. Results: 24 women (12 BZA+CE, 12 Control) have completed baseline and 6-month body composition and insulin resistance assessments. Women randomized to BZA+CE were more likely to experience reduction in insulin resistance and improved insulin sensitivity despite a small weight gain over the initial 6 months. 7/12 randomized to BZA+CE had ≥15% reduction in HOMA IR vs only 2/12 controls. Three participants had HOMA IR >2 at baseline. Of these, one was randomized to BZA+CE and had a normal HOMA IR value at 6 months. The remaining two women were in the control group and saw no improvement in HOMA IR at 6 months. In addition, one woman randomized to control with normal HOMA-IR at baseline had HOMA IR > 2 at 6 months. Next Steps: The improvements in insulin resistance parameters with BZA+CE are similar to those observed in our rodent studies, supporting this combination as promising for use in breast cancer risk reduction in women with vasomotor symptoms at high-risk for metabolic disease. Citation Format: Carol Fabian, Adrian Zelenchuk, Kandy Powers, Amy Kreutzjans, Krystal Pittman, Bill Hendry, Christy Altman, Erin Giles, Katherine L. Cook, Stephen Hursting, Bruce Kimler. Effect of 6 months of bazedoxifene + conjugated estrogens on body composition and insulin resistance [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-10.

The Reproducibility and Reliability of Insulin Sensitivity and Secretion Indices in Children and Adolescents

Context. Insulin sensitivity and secretion indices can be useful tools in understanding insulin homeostasis in children at risk for diabetes. There have been few studies examining the reproducibility of these measures in pediatrics. Objective. To determine whether fasting or oral glucose tolerance test (OGTT)-derived insulin measures would be more reproducible and whether there would be differences based on weight, sex, race, and pubertal status. Design. Observational study. Setting. Clinical research unit. Patients or Other Participants. Two hundred fifty-seven overweight/obese (BMI ≥ 85th%, n = 186) and normal weight (BMI < 85th%, n = 71) children without diabetes between ages of 8 and 17 were included in the study. Methods. OGTT tests performed in study participants at two separate visits within a 3-week period. We performed two formal oral glucose tolerance tests within a 3-week period. The reproducibility of fasting measures was compared with OGTT-derived measures by weight categories and compared by weight, sex, race, and pubertal status. Comparisons were made between the correlation coefficients of fasting vs. OGTT-derived measures and between normal weight vs. obese/overweight participants, male vs. female, White vs. Black, and pre- vs. post-midpubertal. Intraclass correlation coefficients were calculated for each comparison as well. Results. For insulin sensitivity, the OGTT-derived measure was more reproducible than the fasting measures. There were no significant differences in reproducibility in the overweight/obese population compared to the normal weight population nor by sex, race, or pubertal status. Conclusions. Nonfasting insulin sensitivity measures are more reproducible than fasting insulin sensitivity measures, regardless of weight category. Insulin secretion measures have poor reproducibility overall. Weight status, sex, race, and midpubertal stage do not impact the reproducibility of insulin sensitivity and secretion measures.

Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance.

Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.

Leveraging continuous glucose monitoring for personalized modeling of insulin-regulated glucose metabolism

Continuous glucose monitoring (CGM) is a promising, minimally invasive alternative to plasma glucose measurements for calibrating physiology-based mathematical models of insulin-regulated glucose metabolism, reducing the reliance on in-clinic measurements. However, the use of CGM glucose, particularly in combination with insulin measurements, to develop personalized models of glucose regulation remains unexplored. Here, we simultaneously measured interstitial glucose concentrations using CGM as well as plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) in individuals with overweight or obesity to calibrate personalized models of glucose-insulin dynamics. We compared the use of interstitial glucose with plasma glucose in model calibration, and evaluated the effects on model fit, identifiability, and model parameters’ association with clinically relevant metabolic indicators. Models calibrated on both plasma and interstitial glucose resulted in good model fit, and the parameter estimates associated with metabolic indicators such as insulin sensitivity measures in both cases. Moreover, practical identifiability of model parameters was improved in models estimated on CGM glucose compared to plasma glucose. Together these results suggest that CGM glucose may be considered as a minimally invasive alternative to plasma glucose measurements in model calibration to quantify the dynamics of glucose regulation.

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Youth-onset type 2 diabetes (T2D) has a more aggressive phenotype than adult-onset T2D, including rapid loss of glycemic control and increased complication risk. To identify associations of growth hormone mediators with glycemic failure, beta cell function, and insulin sensitivity in youth-onset T2D. This post hoc secondary analysis of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomized clinical trial, which enrolled participants from July 2004 to February 2009, included 398 participants from 15 university-affiliated medical centers with available plasma samples from baseline and 36 months. Participants were youths aged 10 to 17 years with a duration of T2D of less than 2 years who were randomized to metformin, metformin plus lifestyle intervention, or metformin plus rosiglitazone. Participants were followed up for a mean (SD) of 3.9 (1.5) years during the trial, ending in 2011. Statistical analysis was performed from August 2022 to November 2023. Plasma insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), and insulin-like growth factor binding protein 1 (IGFBP-1). Main outcomes were (1) loss of glycemic control during the TODAY study, defined as hemoglobin A1c (HbA1c) level of 8% or more for 6 months or inability to wean from insulin therapy, and (2) baseline and 36-month measures of glycemia (fasting glucose, HbA1c), insulin sensitivity (1/fasting C-peptide), high-molecular-weight adiponectin, and beta cell function (C-peptide index, C-peptide oral disposition index). This analysis included 398 participants (mean [SD] age, 13.9 [2.0] years; 248 girls [62%]; 166 Hispanic participants [42%]; 134 non-Hispanic Black participants [34%], and 84 non-Hispanic White participants [21%]). A greater increase in IGF-1 level between baseline and 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995 [95% CI, 0.991-0.997]; P < .001) and higher C-peptide index per 100-ng/mL increase in IGF-1 (β [SE], 0.015 [0.003]; P < .001). A greater increase in log2 GHR level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.75 [95% CI, 1.05-2.99]; P = .04) and lower C-peptide index (β [SE], -0.02 [0.006]; P < .001). A greater increase in log2 IGFBP-1 level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.37 [95% CI, 1.09-1.74]; P = .007) and higher high-molecular-weight adiponectin (β [SE], 431 [156]; P = .007). This study suggests that changes in plasma growth hormone mediators are associated with loss of glycemic control in youth-onset T2D, with IGF-1 associated with lower risk and GHR and IGFBP-1 associated with increased risk. ClinicalTrials.gov Identifier: NCT00081328.

Interactive calculator to estimate insulin sensitivity in type 1 diabetes.

The gold standard for measuring insulin sensitivity (IS) is the hyperinsulinemic-euglycemic clamp, a time, costly, and labor-intensive research tool. A low insulin sensitivity is associated with a complication-risk in type 1 diabetes. Various formulae using clinical data have been developed and correlated with measured IS in type 1 diabetes. We consolidated multiple formulae into an online calculator (bit.ly/estimated-GDR), enabling comparison of IS and its probability of IS <4.45 mg/kg/min (low) or >6.50 mg/kg/min (high), as measured in a validation set of clamps in 104 adults with type 1 diabetes. Insulin sensitivity calculations using different formulae varied significantly, with correlations (R2 ) ranging 0.005-0.87 with agreement in detecting low and high glucose disposal rates in the range 49-93% and 89-100%, respectively. We demonstrate that although the calculated IS varies between formulae, their interpretation remains consistent. Our free online calculator offers a user-friendly tool for individual IS calculations and also offers efficient batch processing of data for research.

Adipose knockout of H-ferritin improves energy metabolism in mice

ObjectiveFerritin, the principal iron storage protein, is essential to iron homeostasis. How iron homeostasis affects the adipose tissue is not well understood. We investigated the role of ferritin heavy chain in adipocytes in energy metabolism. MethodsWe generated adipocyte-specific ferritin heavy chain (Fth, also known as Fth1) knockout mice, herein referred to as FthAKO. These mice were analyzed for iron homeostasis, oxidative stress, mitochondrial biogenesis and activity, adaptive thermogenesis, insulin sensitivity, and metabolic measurements. Mouse embryonic fibroblasts and primary mouse adipocytes were used for in vitro experiments. ResultsIn FthAKO mice, the adipose iron homeostasis was disrupted, accompanied by elevated expression of adipokines, dramatically induced heme oxygenase 1(Hmox1) expression, and a notable decrease in the mitochondrial ROS level. Cytosolic ROS elevation in the adipose tissue of FthAKO mice was very mild, and we only observed this in the brown adipose tissue (BAT) but not in the white adipose tissue (WAT). FthAKO mice presented an altered metabolic profile and showed increased insulin sensitivity, glucose tolerance, and improved adaptive thermogenesis. Interestingly, loss of ferritin resulted in enhanced mitochondrial respiration capacity and a preference for lipid metabolism. ConclusionsThese findings indicate that ferritin in adipocytes is indispensable to intracellular iron homeostasis and regulates systemic lipid and glucose metabolism.

Ultra-processed food intake, gut microbiome, and glucose homeostasis in mid-life adults: Background, design, and methods of a controlled feeding trial

BackgroundAging is associated with gut dysbiosis, low-grade inflammation, and increased risk of type 2 diabetes (T2D). Prediabetes, which increases T2D and cardiovascular disease risk, is present in 45–50% of mid-life adults. The gut microbiota may link ultra-processed food (UPF) with inflammation and T2D risk. MethodsFollowing a 2-week standardized lead-in diet (59% UPF), adults aged 40–65 years will be randomly assigned to a 6-week diet emphasizing either UPF (81% total energy) or non-UPF (0% total energy). Measurements of insulin sensitivity, 24-h and postprandial glycemic control, gut microbiota composition/function, fecal short chain fatty acids, intestinal inflammation, inflammatory cytokines, and vascular function will be made before and following the 6-week intervention period. Prior to recruitment, menus were developed in order to match UPF and non-UPF conditions based upon relevant dietary factors. Menus were evaluated for palatability and costs, and the commercial additive content of study diets was quantified to explore potential links with outcomes. ResultsOverall diet palatability ratings were similar (UPF = 7.6 ± 1.0; Non-UPF = 6.8 ± 1.5; Like Moderately = 7, Like Very Much = 8). Cost analysis (food + labor) of the 2000 kcal menu (7-d average) revealed lower costs for UPF compared to non-UPF diets ($20.97/d and $40.23/d, respectively). Additive exposure assessment of the 2000 kcal UPF diet indicated that soy lecithin (16×/week), citric acid (13×/week), sorbic acid (13×/week), and sodium citrate (12×/week) were the most frequently consumed additives. ConclusionsWhether UPF consumption impairs glucose homeostasis in mid-life adults is unknown. Findings will address this research gap and contribute information on how UPF consumption may influence T2D development.

Fibroblast Growth Factor 21: A More Effective Biomarker Than Free Fatty Acids and Other Insulin Sensitivity Measures for Predicting Non-alcoholic Fatty Liver Disease in Saudi Arabian Type 2 Diabetes Patients.

Background Non-alcoholic fatty liver disease (NAFLD) is more prevalent among individuals with type 2 diabetes (T2DM), elevating their risk of cardiovascular diseases (CVDs) and premature mortality. There is a need to modify treatment strategies to prevent or delay these adverse outcomes. Currently, there are no sensitive or specific biomarkers for predicting NAFLD in Saudi T2DM patients. Therefore, we aimed to explore the possibility of using fibroblast growth factor 21 (FGF-21), free fatty acids (FFAs), homeostatic model assessment for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) as possible markers. Methodology In this study, a total of 67 T2DM patients were recruited. NAFLD was detected by ultrasonography in 28 patients. Plasma glucose, FFAs, FGF-21, and serum insulin were measured in fasting blood samples. HOMA-IR and QUICKI were calculated. The means of the two groups with and without NAFLD were statistically compared. The receiver operating characteristics (ROC) curve and the area under the curve (AUC) were used to assess the ability to identify NAFLD. Results The mean levels of FGF-21 and HOMA-IR were significantly higher and that of QUICKI was significantly lower in patients with NAFLD than in those without (p < 0.001, p = 0.023, and p = 0.018, respectively). FGF-21 had the highest AUC to identify NAFLD (AUC = 0.981, 95% confidence interval = 0.954-1, P < 0.001). The AUCs for HOMA-IR, QUICKI, and FFA were <0.7. The highest sensitivity, specificity, positive likelihood ratio, and the lowest negative likelihood ratio were found when FGF-21 was used to predict NAFLD. Conclusions FGF-21 may be used as a biomarker to predict NAFLD in people with T2DM due to its high sensitivity and specificity compared to the other markers.

An extended minimal model of OGTT: estimation of α- and β-cell dysfunction, insulin resistance, and the incretin effect.

Loss of insulin sensitivity, α- and β-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here, we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from eight individuals with T2D and eight weight-matched controls (CS) without diabetes to obtain parameters related to insulin sensitivity, β- and α-cell function. The parameters, i.e., measures of insulin sensitivity, a1, suppression of glucagon secretion, k1, magnitude of glucagon secretion, γ2, and incretin-dependent insulin secretion, γ3, were found to be different between CS and T2D with P values < 0.002, <0.017, <0.009, <0.004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman rank test correlation coefficient of 0.67 (P < 0.012). The average incretin effect was found to be different between CS and T2D (P < 0.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.NEW & NOTEWORTHY A new extended model of oral glucose tolerance test (OGTT) has been developed that includes glucagon dynamics and incretin contribution to insulin secretion. The model allows the estimation of parameters related to α- and β-cell dysfunction, insulin sensitivity, and incretin action. A new function describing the influx of glucose from the gut has been introduced. A new rubric for estimating the incretin effect directly from the OGTT experiment has been developed. The effect of glucose dose was also investigated.

Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes

BackgroundIn vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.MethodsWe used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).ResultsCirculating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β =  − 0.67, P-value = 1.88 × 10−6 and HOMA-B β = 0.59, P-value = 1.88 × 10−5; IL-1RA ~ HOMA-S β =  − 0.51, P-value = 8.49 × 10−5 and HOMA-B β = 0.48, P-value = 5.71 × 10−4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10−6), though these associations were not consistent in all sensitivity analyses.ConclusionsThe findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP’s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.

Associations of plasma sphingolipids with measures of insulin sensitivity, β-cell function, and incident diabetes in Japanese Americans

Background and aimsTo prospectively investigate associations of plasma sphingolipids with insulin sensitivity, β-cell function, and incident diabetes in the Japanese American Community Diabetes Study. Methods and resultsBaseline plasma samples from adults without diabetes (n = 349; mean age 56.7 years, 51 % men) were assayed for circulating ceramide and sphingomyelin species. Adjusted regression models examined cross-sectional and longitudinal associations with insulin sensitivity (HOMA2-%S), β-cell function (oral disposition index: DIo) and with incident diabetes over 5 years follow-up. Concentrations of four species (Ceramide C16:0, C18:0, C20:0, and C22:0) were inversely associated with HOMA2-%S at baseline (all P values < 0.05, Q values < 0.05) and change in HOMA2-%S over 5 years (all P values < 0.05, Q values < 0.05). No sphingolipids were associated with baseline or change in DIo. Of the four species associated with HOMA2-%S, only Ceramide C18:0 was significantly and positively associated with incident diabetes (RR/1SD 1.44, 95 % CI 1.10–1.80, P = 0.006, Q = 0.024). The association of plasma Ceramide C18:0 with the risk of diabetes was partially mediated by change in HOMA2-%S between baseline and 5 years (mediation proportion: 61.5 %, 95 % CI 21.1%–212.5 %). ConclusionPlasma Ceramide C18:0 was associated with higher risk of incident diabetes which was partially mediated through a decrease in insulin sensitivity between baseline and five years. Circulating Ceramide C18:0 could be a potential biomarker for identifying those at risk of developing diabetes.

Relationship between adiponectin and blood pressure in obese Latino adolescent boys with a family history of type 2 diabetes

introductionAdipokines are associated with several pathological states including, metabolic syndrome, obesity, insulin resistance and type 2 diabetes. One of these adipokines, adiponectin is of particular interest as it has been shown to have numerous anti-inflammatory effects, However, the association between adiponectin and blood pressure remains inconclusive especially in the Latino adolescent with obesity.PurposeTo investigate the relationship between plasma adiponectin and blood pressure in Latino adolescents’ boys with obesity and a with a family history of Type 2 diabetes.MethodsThirty two Latino adolescent males with obesity aged 14–17 years with a family history of type 2 diabetes underwent a frequently sampled glucose tolerance test (FSIVGTT) to measure insulin sensitivity. Body composition was assessed using dual energy x-ray absorptiometry. Obesity was defined as having a BMI percentile ≥95. Blood pressure was assessed using the Dinamap automated blood pressure monitor, and the average of three readings was used in the analysis. Fasting plasma adiponectin was determined using radioimmunoassay.ResultsThere were moderate positive significant correlations for adiponectin and Systolic blood pressure(SBP) (rho = 0.436, p < 0.027) and Diastolic blood pressure(DBP) (rho = 0.41,p < 0.028). A multivariate liner regression showed that plasma adiponectin could significantly detect 19% of the variance in SBP (p = 0.017, and 33% for DBP (p = 0.017). In a simple linear regression adiponectin was not related to any of our variables (p < 0.05).ConclusionIn conclusion, adiponectin was positively and significantly correlated to blood pressure in Latino adolescent with obesity. Future studies should investigate this relationship in a large sample of Latino adolescent youth.

Chromium propionate in turkeys: effects on insulin sensitivity

The objective of this study was to evaluate the effects of dietary chromium (Cr), as Cr propionate (Cr Prop), on measures of insulin sensitivity in turkeys. Plasma glucose and nonesterified fatty acid (NEFA), and liver glycogen concentrations were used as indicators of insulin sensitivity. One-day-old Nicholas Large White female poults (n=336) were randomly assigned to dietary treatments consisting of 0 (control), 0.2, 0.4, or 0.6 mg supplemental Cr/kg diet. Each treatment consisted of 12 replicate cages with 7 turkeys per cage. Final BW were taken on d 34, and on d 35 two birds from each cage were sampled for plasma glucose and NEFA, and liver glycogen determination at the initiation (fed state) and termination (fasted state) of a 24-h fast. Following a 24-h fast, 2 turkeys per cage were refed (refed state) their treatment diet for 4 h, and then harvested. Feed/gain and ADG did not differ between control and Cr-supplemented turkeys over the 34-d study, but feed intake tended (P=0.071) to be greater for controls than turkeys receiving 0.4 mg Cr/kg diet. Fed turkeys had greater plasma glucose (P=0.002) and liver glycogen (P=0.001) concentrations, and lower (P=0.001) NEFA concentrations than fasted birds. Turkeys refed after fasting had greater (P=0.001) plasma glucose and liver glycogen concentrations, and lower (P=0.001) plasma NEFA levels than fed turkeys. Liver glycogen and plasma NEFA concentrations did not differ among control and Cr-supplemented birds in the fed, fasted, or refed state. Plasma glucose concentrations were not affected by treatment in fed or fasted turkeys. Turkeys supplemented with 0.2 or 0.4 mg Cr/kg and refed after fasting had lower (quadratic, P=0.038) plasma glucose concentrations than controls. Plasma glucose concentrations in refed birds did not differ among Cr-supplemented turkeys. The lower plasma glucose concentration in Cr-supplemented turkeys following refeeding is consistent with Cr enhancing insulin sensitivity.

NEFA Dynamics in Adults With Severe Obesity and Insulin Resistance: No Coupling to the rs9939609 FTO Risk Allele.

The FTO gene is highly expressed in adipose tissues; however, whether nonesterified fatty acids (NEFA) dynamics are impacted by FTO has not been rigorously tested for in a uniformly obese study population comprising both sexes. To test for associations of the rs9939609 FTO risk allele with NEFA suppression. We investigated 97 subjects with severe obesity but without diabetes, having genotype TT (n = 32), AT (n = 31), or AA (n = 34) in a cross-sectional observation study. NEFA suppression was assessed from a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer as well as from the response to a standardized meal. Insulin sensitivity was assessed by hepatic and total insulin sensitivity measurements in the clamp and by the Matsuda index during the meal. Variables of possible importance for NEFA dynamics were primarily assessed by linear regression. No genotype associations with fasting or suppressed NEFA were found, whether in the clamp or meal situation (P > .7 for all comparisons). Independent of genotype, higher fasting concentrations of NEFA and larger NEFA suppression were found in female compared with male subjects. Fasting NEFA or degree of suppression were not associated with total fat mass or body mass index. The respiratory quotient was negatively associated with NEFA suppression. In a gender-mixed adult population of obese individuals, an FTO obesity-risk allele did not affect fasting NEFA nor suppression thereof. These negative results on NEFA dynamics appear strengthened by the documentation of gender influence and associations with parameters reflective of insulin resistance.

Duodenal mucosal resurfacing with photodynamic therapy using methylene blue in a mouse model

BackgroundThe duodenum has emerged as a key player in metabolic diseases. The objective was to evaluate the safety and efficacy of intra-duodenal PDT using methylene blue in managing glycemic control and weight reduction. MethodsOptimal concentration of methylene blue and conditions for intra-duodenal PDT were determined through in vitro experiments. After injecting methylene blue into the duodenum, we performed intra-duodenal PDT. High-fat diet rats were used to assess the efficacy of intra-duodenal PDT through measures of oral glucose tolerance, insulin sensitivity, and weight change. Immunohistochemical staining was also conducted to examine GLP-1 and GIP-producing cells in the ileum and duodenum, respectively. ResultsIntroduodenal PDT reduced villous height of duodenum at 48 h, which was fully recovered at 30 days without complications. Rats treated with PDT showed significantly lower blood glucose levels with glucose loading and improved insulin sensitivity than rats in the sham-treatment group. The PDT group also had a significant reduction in body weight compared to the sham-treatment group at 30 days after intervention, although food intake was not significantly different between the two groups. Numbers of GLP-1 and GIP producing cells in the ileum and irradiated area were significantly higher in the PDT group than in the sham-treatment group. ConclusionsIntra-duodenal PDT using methylene blue showed a feasible therapeutic modality in improving metabolic parameters. However, large animal experiments and mechanism studies are needed to determine the clinical relevance. The possibility of repeating this treatment every 30 days and its accompanying complications should be further studied.

Glycemic and metabolic sub-classification of prediabetes and risk factors for cardiovascular disease in the D2d cohort

ObjectivesPrediabetes represents a spectrum of metabolic abnormalities, including insulin resistance and secretory impairment, that carries increased cardiovascular disease (CVD) risk. It is unclear whether specific glycemic and metabolic sub-classifications are associated with CVD risk. This cross-sectional analysis of 3946 participants from the Vitamin D and Type 2 Diabetes (D2d) study cohort aimed to determine the associations between various baseline CVD risk factors, glycemic sub-classifications of prediabetes (FPG, 2hPG, and HbA1c), and measures of insulin sensitivity and secretion from an OGTT. MethodsThe metabolic syndrome and atherosclerotic cardiovascular disease (ASCVD) risk scores were determined for tertiles of insulin sensitivity (HOMA2S) and insulinogenic index (IGI). Unadjusted analyses showed elevated CVD risk factors in the lowest tertile for both IGI and HOMA2S. ResultsAfter adjustment for age, gender, race, obesity, and smoking status, the association remained between HOMA2S and ASCVD score (r = -0.11, p< 0.001) but not for IGI. Those who met at least 2 diagnosic criteria for prediabetes had the largest proportion (> 40%) of participants with high ASCVD risk score >20. A higher percentage of individuals that met all 3 criteria for prediabetes had metabolic syndrome and ASCVD risk score >20 (87.2% and 15.3%, respectively) than those who only met 1 prediabetes criterion (51.6% and 7.1%, respectively). ConclusionsIn conclusion, multiple metabolic (HOMA2S, IGI) and glycemic criteria of prediabetes (FPG, 2hPG, & HbA1c) are needed to fully recognize the elevated CVD risk profile that can manifest in prediabetes.

Mets-IR as a predictor of cardiovascular events in the middle-aged and elderly population and mediator role of blood lipids.

Cardiovascular disease (CVD) is a global health concern, with a significant impact on morbidity and mortality rates. Using fasting glucose, fasting triglycerides, body mass index (BMI), and high-density lipoprotein cholesterol (HDL-C), the metabolic score of insulin resistance (Mets-IR), a novel index created by Mexican researchers to assess insulin sensitivity, is a more precise way to measure insulin sensitivity. This study aimes to explore the association between Mets-IR and CVD, as well as investigate the potential mediating role of of low-density lipoprotein cholesterol (LDL-C). The study's data came from the 2011 and 2018 China Health and Retirement Longitudinal Studies (CHARLS). We used three logistic regression models to account for the potential effects of ten factors on cardiovascular disease/stroke/heart disease. Moreover, We performed mediation analyses to evaluate the role of LDL-C in the association between Mets-IR and incident CVD. This study comprised 4,540 participants, of whom 494 (10.88%) were found to develop disease (CVD). Each interquartile range (IQR) increased in Mets-IR raised the risk of developing CVD by 38% (OR=1.38; 95% CI, 1.21-1.56) and there was a linear dose-response relationship between Mets-IR and the risk of new-onset cardiovascular disease, stroke, and heart disease (P overall<0.05, P non-linear>0.05). Approximately 5% (indirect effect/total effect) of the significant association of Mets-IR with stroke was mediated by LDL-C, respectively. With the addition of Mets-IR to the base model, the continuous net reclassification improvement and integrated discrimination improvement for predicting cardiovascular disease increased by 0.175 (P <0.001) and 0.006 (P <0.001), respectively. ets-IR is associated with an increased risk of cardiovascular disease/stroke/cardiac issues, with LDL-C mediating these relationships. Improving insulin sensitivity and lipid regulation may be essential and effective preventive measures for cardiovascular events.

Arsenic metabolism, diabetes prevalence, and insulin resistance among Mexican Americans: A mendelian randomization approach.

Differences in arsenic metabolism capacity may influence risk for type 2 diabetes, but the mechanistic drivers are unclear. We evaluated the associations between arsenic metabolism with overall diabetes prevalence and with static and dynamic measures of insulin resistance among Mexican Americans living in Starr County, Texas. We utilized data from cross-sectional studies conducted in Starr County, Texas, from 2010-2014. A Mendelian randomization approach was utilized to evaluate the associations between arsenic metabolism and type 2 diabetes prevalence using the intronic variant in the arsenic methylating gene, rs9527, as the instrumental variable for arsenic metabolism. To further assess mechanisms for diabetes pathogenesis, proportions of the urinary arsenic metabolites were employed to assess the association between arsenic metabolism and insulin resistance among participants without diabetes. Urinary biomarkers of arsenic metabolites were modeled as individual proportions of the total. Arsenic metabolism was evaluated both with a static outcome of insulin resistance, homeostatic measure of assessment (HOMA-IR), and a dynamic measure of insulin sensitivity, Matsuda Index. Among 475 Mexican American participants from Starr County, higher metabolism capacity for arsenic is associated with higher diabetes prevalence driven by worse insulin resistance. Presence of the minor T allele of rs9527 is independently associated with an increase in the proportion of monomethylated arsenic (MMA%) and is associated with an odds ratio of 0.50 (95% CI: 0.24, 0.90) for type 2 diabetes. This association was conserved after potential covariate adjustment. Furthermore, among participants without type 2 diabetes, the highest quartile of MMA% was associated with 22% (95% CI: -33.5%, -9.07%) lower HOMA-IR and 56% (95% CI: 28.3%, 91.3%) higher Matsuda Index for insulin sensitivity. Arsenic metabolism capacity, indicated by a lower proportion of monomethylated arsenic, is associated with increased diabetes prevalence driven by an insulin resistant phenotype among Mexican Americans living in Starr County, Texas.

BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study.

This study exploredthe association of BMI and insulin sensitivity with cognitive performance in type 2 diabetes. A cross-sectional analysis of data from the baseline assessment of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE) was conducted. BMI was used as a surrogate of adiposity and the Matsuda index as the measure of insulin sensitivity. Cognitive tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and the letter and animal fluency tests. Cognitive assessments were completed by 5018 (99.4%) of 5047 participants aged 56.7 ± 10.0 years, of whom 36.4% were female. Higher BMI and lower insulin sensitivity were related to better performance on memory and verbal fluency tests. In models including BMI and insulin sensitivity simultaneously, only higher BMI was related to better cognitive performance. In this study, higher BMI and lower insulin sensitivity in type 2 diabetes were cross-sectionally associated with better cognitive performance. However, only higher BMI was related to cognitive performance when both BMI and insulin sensitivity were considered simultaneously. The causality and mechanisms for this association need to be determined in future studies.