TY - JOUR
T1 - Predictors of whole-body insulin sensitivity across ages and adiposity in adult humans
AU - Lalia, Antigoni Z.
AU - Dasari, Surendra
AU - Johnson, Matthew L.
AU - Robinson, Matthew M.
AU - Konopka, Adam R.
AU - DIstelmaier, Klaus
AU - Port, John D.
AU - Glavin, Maria T.
AU - Esponda, Raul Ruiz
AU - Nair, K. Sreekumaran
AU - Lanza, Ian R.
N1 - Funding Information:
We are grateful for the expert technical assistance from Roberta Soderberg, Katherine Klaus, Daniel Jakaitis, Dawn Morse, Jill Schimke, Peg Helwig, Dennis Hanson, Xin Ge, and Ronald Karwoski. This work was supported by Clinical and Translational Science Awards Grant KL2 TR-000136 from the National Center for Advancing Translational Science, and National Institutes of Health Grants DK041973 (to K.S.N.), AG009531 (to K.S.N.), and T32DK007352 (to A.R.K., M.M.R.), and T32 DK007198 (to M.L.J.). Additional funding was provided by The Strickland Career Development Award (to I.R.L.), The Minnesota Obesity Center Grant DK50456, and Grant U24DK100469 from the National Institute of Diabetes and Digestive and Kidney Diseases and originates from the National Institutes of Health Director''s Common Fund.
PY - 2016/2
Y1 - 2016/2
N2 - 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)wereindependent negative predictors of peripheral insulin sensitivity, whereasVO2peak(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) andAFVISC (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 agerelated changes in the content and distribution of adipose tissue and is independent of muscle mitochondrial function or chronological age.
AB - 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)wereindependent negative predictors of peripheral insulin sensitivity, whereasVO2peak(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) andAFVISC (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 agerelated changes in the content and distribution of adipose tissue and is independent of muscle mitochondrial function or chronological age.
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U2 - 10.1210/jc.2015-2892
DO - 10.1210/jc.2015-2892
M3 - Article
C2 - 26709968
AN - SCOPUS:84959421108
SN - 0021-972X
VL - 101
SP - 626
EP - 634
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 2
ER -