Cardiorespiratory Fitness and Insulin Sensitivity in Overweight or Obese Subjects May Be Linked Through Intrahepatic Lipid Content

Abstract

OBJECTIVELow cardiorespiratory fitness (CRF) predisposes one to cardiovascular disease and type 2 diabetes in part independently of body weight. Given the close relationship between intrahepatic lipid content (IHL) and insulin sensitivity, we hypothesized that the direct relationship between fitness and insulin sensitivity may be explained by IHL.RESEARCH DESIGN AND METHODSWe included 138 overweight to obese, otherwise healthy subjects (aged 43.6 ± 8.9 years, BMI 33.8 ± 4 kg/m2). Body composition was estimated by bioimpedance analyses. Abdominal fat distribution, intramyocellular, and IHL were assessed by magnetic resonance spectroscopy and tomography. Incremental exercise testing was performed to estimate an individual's CRF. Insulin sensitivity was determined during an oral glucose tolerance test.RESULTSFor all subjects, CRF was related to insulin sensitivity (r = 0.32, P < 0.05), IHL (r = −0.27, P < 0.05), and visceral (r = −0.25, P < 0.05) and total fat mass (r = −0.32, P < 0.05), but not to intramyocellular lipids (r = −0.08, NS). Insulin sensitivity correlated significantly with all fat depots. In multivariate regression analyses, independent predictors of insulin sensitivity were IHL, visceral fat, and fitness (r2 = −0.43, P < 0.01, r2 = −0.34, and r2 = 0.29, P < 0.05, respectively). However, the positive correlation between fitness and insulin sensitivity was abolished after adjustment for IHL (r = 0.16, NS), whereas it remained significant when adjusted for visceral or total body fat. Further, when subjects were grouped into high versus low IHL, insulin sensitivity was higher in those subjects with low IHL, irrespective of fitness levels.CONCLUSIONSOur study suggests that the positive effect of increased CRF on insulin sensitivity in overweight to obese subjects may be mediated indirectly through IHL reduction.

Metabolic flexibility and oxidative capacity independently associate with insulin sensitivity in individuals with newly diagnosed type 2 diabetes

“…In overweight non-obese individuals the association of V : O 2max with insulin sensitivity has been explained mainly by intrahepatic lipid content [10]. The present study found a similar association in people with recently diagnosed type 2 diabetes but detected no link with hepatic steatosis.…”

Physical exercise improves low cardiorespiratory fitness associated with intramyocellular lipids in patients with metabolic syndrome

“…The etiology of insulin resistance is multifactorial and involves both genetic and environmental factors. 2 Several lines of evidence have been provided in support of the hypothesis that intramyocellular lipids (IMCLs) and intrahepatic lipids (IHLs), as assessed non-invasively by localized 1 H-magnetic resonance spectroscopy, are associated with reduced-insulin action in both obese and non-obese subjects. 2,3 In addition, high IMCL levels are associated with the impairment of early insulin signal transduction in specimens obtained from muscle biopsies, because IMCLs and related intracellular substances, such as diacylglycerol or protein kinase C, are important regulators of insulin resistance in skeletal muscle.…”

“…2 Several lines of evidence have been provided in support of the hypothesis that intramyocellular lipids (IMCLs) and intrahepatic lipids (IHLs), as assessed non-invasively by localized 1 H-magnetic resonance spectroscopy, are associated with reduced-insulin action in both obese and non-obese subjects. 2,3 In addition, high IMCL levels are associated with the impairment of early insulin signal transduction in specimens obtained from muscle biopsies, because IMCLs and related intracellular substances, such as diacylglycerol or protein kinase C, are important regulators of insulin resistance in skeletal muscle. 4 Insulin-resistant individuals have a reduced rate of fat oxidation, compared with normal, insulin-sensitive individuals, and thus, the decreased mitochondrial fat oxidative capacity could lead to an increase in the intracellular fat content.…”

“…4 DeFronzo 5 stated that the accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, b-cells and arterial tissues contributes to insulin resistance, b-cell dysfunction and accelerated atherosclerosis, respectively, in individuals with type 2 diabetes. Given the close relationship between IHLs and insulin sensitivity, Haufe et al 2 investigated the relationship between IHLs and both fitness and insulin sensitivity, and concluded that the positive effect of increased cardiorespiratory fitness (CRF) on insulin sensitivity in overweight and obese subjects seems to be indirectly mediated by IHL content rather than the amount of total, visceral and subcutaneous fat. Potential mechanisms linking CRF and IHLs may include factors that regulate hepatic lipid oxidation.…”

“…Mitochondria occupy nearly 18% of the hepatocyte volume, and their function, a strong determinant of fitness, could conceivably affect hepatic lipid oxidation. 2 Low CRF is a predictor of all-cause mortality in patients with type 2 diabetes and in healthy people. 6 Sawada et al 7 investigated the relationship between long-term trends in CRF and the incidence of type 2 diabetes in a cohort of 41 787 non-diabetic Japanese men who completed annual health checkups and fitness tests for the estimation of maximal oxygen uptake over 7 years.…”