Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals

Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a mitochondrial-derived peptide that attenuates weight gain and hyperinsulinemia when administered to high fat-fed mice. MOTS-c is therefore a potential regulator of metabolic homeostasis under conditions of high-energy supply. However, the effect of insulin resistance and obesity on plasma MOTS-c concentration in humans is unknown. To gain insight into MOTS-c regulation, we measured plasma MOTS-c concentration and analyzed its relationship with insulin sensitivity surrogates, in lean and obese humans (n=10 per group). Obese individuals had impaired insulin sensitivity as indicated by low Matsuda and high Homeostatic Model Assessment (HOMA) indexes. Although plasma MOTS-c concentration was similar in lean and obese individuals (0.48±0.16 and 0.52±0.15 ng/mL; p=0.60), it was correlated with HOMA (r=0.53; p<0.05) and Matsuda index (r=−0.46; p<0.05). Notably, when the groups were analyzed separately, the associations remained only in lean individuals. We conclude that plasma MOTS-c concentration is unaltered in human obesity. However, MOTS-c associates positively with insulin resistance mostly in lean individuals, indicating that plasma MOTS-c concentration depends on the metabolic status in this population. Such dependence seems altered when obesity settles. The implications of plasma MOTS-c for human metabolic homeostasis deserve future examination.

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The Relationship between Circulating Acetate and Human Insulin Resistance before and after Weight Loss in the DiOGenes Study

Nutrients ◽

10.3390/nu12020339 ◽

2020 ◽

Vol 12 (2) ◽

pp. 339

Author(s):

Manuel A. González Hernández ◽

Emanuel E. Canfora ◽

Kenneth Pasmans ◽

A. Astrup ◽

W. H. M. Saris ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Loss ◽

Insulin Sensitivity ◽

Positive Association ◽

Fat Free Mass ◽

Model Assessment ◽

Random Factor ◽

Before And After ◽

Homeostatic Model Assessment ◽

Matsuda Index

Microbially-produced acetate has been reported to beneficially affect metabolic health through effects on satiety, energy expenditure, insulin sensitivity, and substrate utilization. Here, we investigate the association between sex-specific concentrations of acetate and insulin sensitivity/resistance indices (Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), circulating insulin and Matsuda Index) in the Diet, Obesity and Genes (DiOGenes) Dietary study at baseline and after a low-calorie diet (LCD, 800 kcal/d). In this analysis, 692 subjects (Body Mass Index >27 kg/m2) were included, who underwent an LCD for 8 weeks. Linear mixed models were performed, which were adjusted for mean acetate concentration, center (random factor), age, weight loss, and fat-free mass (FFM). At baseline, no associations between plasma acetate and insulin sensitivity/resistance indices were found. We found a slight positive association between changes in acetate and changes in HOMA-IR (stdβ 0.130, p = 0.033) in women, but not in men (stdβ −0.072, p = 0.310) independently of age, weight loss and FFM. We were not able to confirm previously reported associations between acetate and insulin sensitivity in this large European cohort. The mechanisms behind the sex-specific relationship between LCD-induced changes in acetate and insulin sensitivity require further study.

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The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

Clinical Chemistry ◽

10.1373/clinchem.2010.153726 ◽

2011 ◽

Vol 57 (2) ◽

pp. 309-316 ◽

Cited By ~ 73

Author(s):

Greisa Vila ◽

Michaela Riedl ◽

Christian Anderwald ◽

Michael Resl ◽

Ammon Handisurya ◽

...

Keyword(s):

Insulin Resistance ◽

Gastric Bypass ◽

Insulin Sensitivity ◽

Oral Glucose ◽

Model Assessment ◽

Obese Patients ◽

Growth Differentiation Factor 15 ◽

Homeostatic Model Assessment ◽

Homeostatic Model ◽

The Relationship

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

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Melatonin Treatment Improves Insulin Resistance and Pigmentation in Obese Patients with Acanthosis Nigricans

International Journal of Endocrinology ◽

10.1155/2018/2304746 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Hang Sun ◽

Xingchun Wang ◽

Jiaqi Chen ◽

Aaron M. Gusdon ◽

Kexiu Song ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Acanthosis Nigricans ◽

Resistance Index ◽

Inflammatory Factors ◽

Model Assessment ◽

Obese Patients ◽

Inflammatory Status ◽

Before And After ◽

Matsuda Index

Objective. This study aimed to determine the effects of melatonin on insulin resistance in obese patients with acanthosis nigricans (AN). Methods. A total of 17 obese patients with acanthosis nigricans were recruited in a 12-week pilot open trial. Insulin sensitivity, glucose metabolism, inflammatory factors, and other biochemical parameters before and after the administration of melatonin were measured. Results. After 12 weeks of treatment with melatonin (3 mg/day), homeostasis model assessment insulin resistance index (HOMA-IR) (8.99 ± 5.10 versus 7.77 ± 5.21, p<0.05) and fasting insulin (37.09 5 ± 20.26 μU/ml versus 32.10 ± 20.29 μU/ml, p<0.05) were significantly decreased. Matsuda index (2.82 ± 1.54 versus 3.74 ± 2.02, p<0.05) was significantly increased. There were also statistically significant declines in the AN scores of the neck and axilla, body weight, body mass index, body fat, visceral index, neck circumference, waist circumference, and inflammatory markers. Conclusions. It was concluded that melatonin could improve cutaneous symptoms in obese patients with acanthosis nigricans by improving insulin sensitivity and inflammatory status. This trial is registered with ClinicalTrials.gov NCT02604095.

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Significance and role of homeostatic model assessment in the evaluation of glucose regulation mechanisms

Medicinski pregled ◽

10.2298/mpns1706155n ◽

2017 ◽

Vol 70 (5-6) ◽

pp. 155-161

Author(s):

Stanislava Nikolic ◽

Nikola Curic ◽

Romana Mijovic ◽

Branislava Ilincic ◽

Damir Benc

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Glucose Regulation ◽

Oral Glucose ◽

Model Assessment ◽

Oral Glucose Tolerance ◽

Homeostatic Model Assessment ◽

Homeostatic Model

Introduction. Mathematical formulas, such as homeostatic model assessment indexes, proved to be useful for the estimation of insulin resistance. Nevertheless, numerous published results point to a considerable variability of their reference values. The aim of this study was to use homeostatic model assessment indexes and evaluate levels of insulin resistance in nondiabetic patients. Material and Methods. The study included 486 individuals (mean age 36.84 ? 12.86; 17% of males and 83% of females). Blood sampling was performed in order to determine glucose and insulin plasma levels, at the 0th and 120th minute of the oral glucose tolerance test. The indexes were calculated by the use of homeostatic model assessment 2 calculator, homeostatic model assessment of insulin resistance, homeostatic model assessment of insulin sensitivity, and homeostatic model assessment of ?-cells function. The results were statistically analyzed using a Data Analysis programme. Results. In the examined population, the average glycemic values of the oral glucose tolerance test were within the euglycemic scope (Gluc 0 = 4.76 ? 0.45 mmol/L; Gluc 120 = 5.24 ? 1.17 mmol/L), while the average values of calculated homeostatic model assessment indexes were: insulin resistance - 1.41 ? 0.82; ?-cells function - 131.54 ? 49.41%, and insulin sensitivity - 91.94 ? 47.32%. According to study cut-off values, homeostatic model assessment of insulin resistance was less than 2. We found 84 (17.28%) individuals with increased insulin resistance. Also, we set the lowest reference value for homeostatic model assessment of insulin sensitivity at less than 50%. With the probability of 66.67% (x? ? 1SD), basal insulin level under 11.9 mIU/L can be considered to correspond to physiologic level of insulin resistance. Conclusion. The follow-up of increased insulin resistance and altered secretion of pancreatic ?-cells, at early stages of glucose regulation disturbances, may be useful in assessing dynamics and level of glucose regulation disturbances and their appropriate treatment. This article has been corrected. Link to the correction <a href="http://dx.doi.org/10.2298/MPNS1708202E">10.2298/MPNS1708202E</a>

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The Insulin Sensitivity Mcauley Index (Mcai) is Associated with 40-Year Cancer Mortality in a Cohort of Men and Women Free of Diabetes at Baseline

10.21203/rs.3.rs-1011207/v1 ◽

2021 ◽

Author(s):

Yonatan Moshkovits ◽

David Rott ◽

Angela Chetrit ◽

Rachel Dankner

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Cancer Mortality ◽

Model Assessment ◽

Cancer Death ◽

Men And Women ◽

Adult Men ◽

Sensitivity Indices ◽

Increased Risk ◽

Homeostatic Model Assessment

Abstract Background:The association between insulin resistance and cancer mortality is not fully explored. We investigated the association between several insulin sensitivity indices (ISIs) and cancer mortality in a cohort of adult men and women free of diabetes. We hypothesized that higher insulin resistance (Q1 of the Mcauley index (MCAi), calculated by fasting insulin and triglycerides, and Q4 of the Homeostatic Model Assessment (HOMA), calculated by fasting plasma glucose and insulin) will be associated with greater cancer mortality risk.Methods: A cohort of 1612 men and women free of diabetes during baseline were followed since 1979 through 2016 for cause specific mortality as part of the Israel study on Glucose Intolerance, Obesity and Hypertension (GOH). Results: Mean age at baseline was 51.5 ± 8.0 years, 804 (49.9%) were males, and 871 (54.0%) had prediabetes. Mean follow-up was 36.7±0.2 years and 47,191 person years were accrued. Cumulative incidence analysis using Cox proportional hazard model and competing risks analysis adjusted for age, sex, country of origin, BMI, blood pressure, total cholesterol, smoking and glycemic status (table 2), revealed an increased risk for cancer death, sub-distribution HR=1.4 (95% CI: 1.1-1.9, p=0.02) for individuals in the lower quartile of MCAi (Q1), denoting higher insulin resistance, compared with the upper quartiles (Q2-4). No statistically significant association was observed between the other insulin resistance surrogates and cancer death.Conclusion: The MCAi was found to independently associate with an increased risk for cancer mortality in adult men and women free of diabetes. The MCAi may be considered as a long-term prognostic biomarker in diabetes-free adults.

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Comparison of Various Indices in Identifying Insulin Resistance and Diabetes in Chronic Spinal Cord Injury

Journal of Clinical Medicine ◽

10.3390/jcm10235591 ◽

2021 ◽

Vol 10 (23) ◽

pp. 5591

Author(s):

Gary J. Farkas ◽

Phillip S. Gordon ◽

Nareka Trewick ◽

Ashraf S. Gorgey ◽

David R. Dolbow ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Diagnostic Study ◽

Model Assessment ◽

Linear Regression Models ◽

Post Injury ◽

Intravenous Glucose ◽

Cord Injury ◽

Matsuda Index

The purpose of this screening and diagnostic study was to examine the accord among indices of glucose metabolism, including the Homeostatic Model Assessment for Insulin Resistance (HOMA), HOMA2, Matsuda Index, Quantitative Insulin-sensitivity Check Index (QUICKI), hemoglobin A1C (HbA1C), and fasting plasma glucose (FPG) against intravenous glucose tolerance test-measured insulin sensitivity (Si) in individuals with chronic motor complete SCI. Persons with chronic (≥12-months post-injury) SCI (n = 29; 79% men; age 42.2 ± 11.4; body mass index 28.6 ± 6.4 kg/m2; C4-T10) were included. Measures were compared using adjusted R2 from linear regression models with Akaike information criterion (AIC, a measure of error). QUCKI had the greatest agreement with Si (adjusted R2 = 0.463, AIC = 91.1, p = 0.0001), followed by HOMA (adjusted R2 = 0.378, AIC = 95.4, p = 0.0008), HOMA2 (adjusted R2 = 0.256, AIC = 99.7, p = 0.0030), and the Matsuda Index (adjusted R2 = 0.356, AIC = 95.5, p = 0.0004). FPG (adjusted R2 = 0.056, AIC = 107.5, p = 0.1799) and HbA1C (adjusted R2 = 0.1, AIC = 106.1, p = 0.0975) had poor agreement with Si. While HbA1C and FPG are commonly used for evaluating disorders of glucose metabolism, QUICKI demonstrates the best accord with Si compared to the other measures.

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Metabolomics Identifies Distinctive Metabolite Signatures for Measures of Glucose Homeostasis: The Insulin Resistance Atherosclerosis Family Study (IRAS-FS)

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02203 ◽

2018 ◽

Vol 103 (5) ◽

pp. 1877-1888 ◽

Cited By ~ 10

Author(s):

Nicholette D Palmer ◽

Hayrettin Okut ◽

Fang-Chi Hsu ◽

Maggie C Y Ng ◽

Yii-Der Ida Chen ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Cell Function ◽

Insulin Response ◽

Model Assessment ◽

Homeostatic Model Assessment ◽

Β Cell Function ◽

Homeostatic Model

Abstract Context Metabolomics provides a biochemical fingerprint that, when coupled with clinical phenotypes, can provide insight into physiological processes. Objective Survey metabolites associated with dynamic and basal measures of glucose homeostasis. Design Analysis of 733 plasma metabolites from the Insulin Resistance Atherosclerosis Family Study. Setting Community based. Participants One thousand one hundred eleven Mexican Americans. Main Outcome Dynamic measures were obtained from the frequently sampled intravenous glucose tolerance test and included insulin sensitivity and acute insulin response to glucose. Basal measures included homeostatic model assessment of insulin resistance and β-cell function. Results Insulin sensitivity was associated with 99 metabolites (P < 6.82 × 10−5) explaining 28% of the variance (R2adj) beyond 28% by body mass index. Beyond branched chain amino acids (BCAAs; P = 1.85 × 10−18 to 1.70 × 10−5, R2adj = 8.1%) and phospholipids (P = 3.51 × 10−17 to 3.00 × 10−5, R2adj = 14%), novel signatures of long-chain fatty acids (LCFAs; P = 4.49 × 10−23 to 4.14 × 10−7, R2adj = 11%) were observed. Conditional analysis suggested that BCAA and LCFA signatures were independent. LCFAs were not associated with homeostatic model assessment of insulin resistance (P > 0.024). Acute insulin response to glucose was associated with six metabolites; glucose had the strongest association (P = 5.68 × 10−16). Homeostatic model assessment of β-cell function had significant signatures from the urea cycle (P = 9.64 × 10−14 to 7.27 × 10−6, R2adj = 11%). Novel associations of polyunsaturated fatty acids (P = 2.58 × 10−13 to 6.70 × 10−5, R2adj = 10%) and LCFAs (P = 9.06 × 10−15 to 3.93 × 10−7, R2adj = 10%) were observed with glucose effectiveness. Assessment of the hyperbolic relationship between insulin sensitivity and secretion through the disposition index revealed a distinctive signature of polyunsaturated fatty acids (P = 1.55 × 10−12 to 5.81 × 10−6; R2adj = 3.8%) beyond that of its component measures. Conclusions Metabolomics reveals distinct signatures that differentiate dynamic and basal measures of glucose homeostasis and further identifies new metabolite classes associated with dynamic measures, providing expanded insight into the metabolic basis of insulin resistance.

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The Relationship between Abdominal Fat Phenotypes and Insulin Resistance in Non-Obese Individuals after Acute Pancreatitis

Nutrients ◽

10.3390/nu12092883 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2883 ◽

Cited By ~ 1

Author(s):

Juyeon Ko ◽

Loren Skudder-Hill ◽

Jaelim Cho ◽

Sakina H. Bharmal ◽

Maxim S. Petrov

Keyword(s):

Insulin Resistance ◽

Acute Pancreatitis ◽

Insulin Sensitivity ◽

Visceral Fat ◽

Abdominal Fat ◽

Model Assessment ◽

Healthy Controls ◽

Tyg Index ◽

Pancreatic Fat ◽

Matsuda Index

Both type 2 prediabetes/diabetes (T2DM) and new-onset prediabetes/diabetes after acute pancreatitis (NODAP) are characterized by impaired tissue sensitivity to insulin action. Although the outcomes of NODAP and T2DM are different, it is unknown whether drivers of insulin resistance are different in the two types of diabetes. This study aimed to investigate the associations between abdominal fat phenotypes and indices of insulin sensitivity in non-obese individuals with NODAP, T2DM, and healthy controls. Indices of insulin sensitivity (homeostasis model assessment of insulin sensitivity (HOMA-IS), Raynaud index, triglyceride and glucose (TyG) index, Matsuda index) were calculated in fasting and postprandial states. Fat phenotypes (intra-pancreatic fat, intra-hepatic fat, skeletal muscle fat, visceral fat, and subcutaneous fat) were determined using magnetic resonance imaging and spectroscopy. Linear regression and relative importance analyses were conducted. Age, sex, and glycated hemoglobin A1c were adjusted for. A total of 78 non-obese individuals (26 NODAP, 20 T2DM, and 32 healthy controls) were included. Intra-pancreatic fat was significantly associated with all the indices of insulin sensitivity in the NODAP group, consistently in both the unadjusted and adjusted models. Intra-pancreatic fat was not significantly associated with any index of insulin sensitivity in the T2DM and healthy controls groups. The variance in HOMA-IS was explained the most by intra-pancreatic fat (R2 = 29%) in the NODAP group and by visceral fat (R2 = 21%) in the T2DM group. The variance in the Raynaud index was explained the most by intra-pancreatic fat (R2 = 18%) in the NODAP group and by visceral fat (R2 = 15%) in the T2DM group. The variance in the TyG index was explained the most by visceral fat in both the NODAP group (R2 = 49%) and in the T2DM group (R2 = 25%). The variance in the Matsuda index was explained the most by intra-pancreatic fat (R2 = 48%) in the NODAP group and by visceral fat (R2 = 38%) in the T2DM group. The differing association between intra-pancreatic fat and insulin resistance can be used to differentiate NODAP from T2DM. Insulin resistance in NODAP appears to be predominantly driven by increased intra-pancreatic fat deposition.

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Dietary Protein Intake during Pregnancy Is Not Associated with Offspring Insulin Sensitivity during the First Two Years of Life

Nutrients ◽

10.3390/nu12051338 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1338

Author(s):

Brittany R. Allman ◽

D. Keith Williams ◽

Elisabet Børsheim ◽

Aline Andres

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Dietary Protein ◽

Protein Intake ◽

Late Pregnancy ◽

Model Assessment ◽

Dietary Protein Intake ◽

Fat Percentage ◽

Homeostatic Model Assessment ◽

The Relationship

Literature describing a relationship between dietary protein intake during pregnancy and offspring insulin resistance are equivocal perhaps because of the lapse between maternal and offspring measurements (~9–40 years). Thus, we evaluated protein intake in healthy women [n = 182, mean ± SD; body mass index (BMI): 26.2 ± 4.2 kg/m2] in early pregnancy (8.4 ± 1.6 weeks, EP), late pregnancy (30.1 ± 0.4 weeks, LP), and averaged throughout pregnancy, and determined the relationship between protein intake and offspring homeostatic model assessment of insulin resistance (HOMA2-IR) at 12 (12mo) and 24 (24mo) months. EP protein (g·kg−1·day−1) did not associate with HOMA2-IR at 12mo (β = 0.153, p = 0.429) or 24mo (β = −0.349, p = 0.098). LP protein did not associate with HOMA2-IR at 12mo (β = 0.023, p = 0.916) or 24mo (β = −0.442, p = 0.085). Finally, average protein did not associate with HOMA2-IR at 12mo (β = 0.711, p = 0.05) or 24mo (β = −0.445, p = 0.294). Results remained unchanged after adjusting for plant protein intake quartiles during pregnancy, maternal BMI, and offspring sex and body fat percentage. Additionally, these relationships did not change after quartile analysis of average protein intake, even after considering offspring fasting time and HOMA2-IR outliers, and maternal under-reporters of energy intake. Protein intake during pregnancy is not associated with indirect measurements of insulin sensitivity in offspring during the first two years of life.

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Predictors of Whole-Body Insulin Sensitivity Across Ages and Adiposity in Adult Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-2892 ◽

2016 ◽

Vol 101 (2) ◽

pp. 626-634 ◽

Cited By ~ 30

Author(s):

Antigoni Z. Lalia ◽

Surendra Dasari ◽

Matthew L. Johnson ◽

Matthew M. Robinson ◽

Adam R. Konopka ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Whole Body ◽

Model Assessment ◽

Hepatic Insulin Sensitivity ◽

Homeostatic Model Assessment ◽

Homeostatic Model ◽

Intrahepatic Lipid

Context: Numerous factors are purported to influence insulin sensitivity including age, adiposity, mitochondrial function, and physical fitness. Univariate associations cannot address the complexity of insulin resistance or the interrelationship among potential determinants. Objective: The objective of the study was to identify significant independent predictors of insulin sensitivity across a range of age and adiposity in humans. Design, Setting, and Participants: Peripheral and hepatic insulin sensitivity were measured by two stage hyperinsulinemic-euglycemic clamps in 116 men and women (aged 19–78 y). Insulin-stimulated glucose disposal, the suppression of endogenous glucose production during hyperinsulinemia, and homeostatic model assessment of insulin resistance were tested for associations with 11 potential predictors. Abdominal subcutaneous fat, visceral fat (AFVISC), intrahepatic lipid, and intramyocellular lipid (IMCL) were quantified by magnetic resonance imaging and spectroscopy. Skeletal muscle mitochondrial respiratory capacity (state 3), coupling efficiency, and reactive oxygen species production were evaluated from muscle biopsies. Aerobic fitness was measured from whole-body maximum oxygen uptake (VO2 peak), and metabolic flexibility was determined using indirect calorimetry. Results: Multiple regression analysis revealed that AFVISC (P < .0001) and intrahepatic lipid (P = .002) were independent negative predictors of peripheral insulin sensitivity, whereas VO2 peak (P = .0007) and IMCL (P = .023) were positive predictors. Mitochondrial capacity and efficiency were not independent determinants of peripheral insulin sensitivity. The suppression of endogenous glucose production during hyperinsulinemia model of hepatic insulin sensitivity revealed percentage fat (P < .0001) and AFVISC (P = .001) as significant negative predictors. Modeling homeostatic model assessment of insulin resistance identified AFVISC (P < .0001), VO2 peak (P = .001), and IMCL (P = .01) as independent predictors. Conclusion: The reduction in insulin sensitivity observed with aging is driven primarily by age-related changes in the content and distribution of adipose tissue and is independent of muscle mitochondrial function or chronological age.

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