title: Predictors of Whole-Body Insulin Sensitivity Across Ages and Adiposity in Adult Humans.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Antigoni Z
authors.initials: AZ
authors.lastname: Lalia
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Surendra
authors.initials: S
authors.lastname: Dasari
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Johnson
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Robinson
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Konopka
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Klaus
authors.initials: K
authors.lastname: Distelmaier
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: John D
authors.initials: JD
authors.lastname: Port
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Glavin
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Raul Ruiz
authors.initials: RR
authors.lastname: Esponda
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: K Sreekumaran
authors.initials: KS
authors.lastname: Nair
authors.affiliation: Divisions of Endocrinology and Metabolism (A.Z.L., M.L.J., M.M.R., A.R.K., K.D., R.R.E., K.S.N., I.R.L.), Biomedical Statistics and Informatics (S.D.), and Radiology (J.D.P., M.T.G.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Lanza
mesh_terms: D050154:Adiposity; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D015308:Anaerobic Threshold; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D015309:Glucose Clamp Technique; D006706:Homeostasis; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D011237:Predictive Value of Tests; D017382:Reactive Oxygen Species / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D017382:Reactive Oxygen Species