Skeletal Muscle Insulin Resistance Promotes Increased Hepatic De Novo Lipogenesis, Hyperlipidemia, and Hepatic Steatosis in the Elderly

Abstract

Aging is closely associated with muscle insulin resistance, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. We examined the hypothesis that muscle insulin resistance in healthy aging promotes increased hepatic de novo lipogenesis (DNL) and hyperlipidemia by altering the distribution pattern of postprandial energy storage. Healthy, normal weight, sedentary elderly subjects pair-matched to young subjects were given two high-carbohydrate meals followed by 13C/1H magnetic resonance spectroscopy measurements of postprandial changes in muscle and liver glycogen and lipid content, and assessment of DNL using 2H2O. Net muscle glycogen synthesis was reduced by 45% (P < 0.007) in the elderly subjects compared with the young, reflecting severe muscle insulin resistance. Net liver glycogen synthesis was similar between groups (elderly, 143 ± 23 mmol/L vs. young, 138 ± 13 mmol/L; P = NS). Hepatic DNL was more than twofold higher in the elderly than in the young subjects (elderly, 14.5 ± 1.4% vs. young, 6.9 ± 0.7%; P = 0.00015) and was associated with approximately threefold higher postprandial hepatic triglyceride (TG) content (P < 0.005) and increased fasting plasma TGs (elderly, 1.19 ± 0.18 mmol/L vs. young, 0.74 ± 0.11 mmol/L; P = 0.02). These results strongly support the hypothesis that muscle insulin resistance in aging promotes hyperlipidemia and NAFLD by altering the pattern of postprandial carbohydrate storage away from muscle glycogen and into hepatic DNL.

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

“…In addition to the re-esterification of fatty acids, w25% of the lipid content within the liver of patients with NAFLD is derived from de novo lipogenesis (16). Although insulin promotes lipogenesis, it is clear that systemic IR is also associated with increased hepatic lipogenesis (124). This idea of 'selective' IR whereby insulin fails to suppress hepatic gluconeogenesis while promoting hepatic lipogenesis has been discussed previously but the mechanisms underpinning this are not yet fully elucidated (125).…”

Association of Insulin Resistance with Lower Glomerular Filtration Rate and All-Cause Mortality in the Korean Elderly Population: A Community-Based Prospective Cohort Study

“…In our cohort, participants in the first quintile of HOMA-IR values were older and had lower BMI values and total cholesterol levels. Obese subjects have greater IR than non-obese subjects (Goodpaster et al 1997) and aging-related hyperlipidemia is associated with IR (Flannery et al 2012). It is possible that lower BMI values and lower lipid levels could have affected HOMA-IR index values in our first HOMA-IR quintile group.…”

Lower Fasting Muscle Mitochondrial Activity Relates to Hepatic Steatosis in Humans

“…This would increase VLDL export and in turn raise circulating triglycerides (TGs) and LDL cholesterol (3). Some exercise studies support this concept in that reversal of muscle insulin resistance decreases HCL and dyslipidemia in humans at risk for type 2 diabetes (4,5).…”

“…On the other hand, steatosis may result from inadequate hepatic oxidation rates (6), subsequently leading to increased lipid flux to skeletal muscle. Indeed, insulin resistance frequently associates with accumulation of IMCL or lipid metabolites (3). As greater lipid availability does not necessarily increase IMCL (7,8), muscle lipid oxidation could be the link between liver and muscle metabolism (9,10).…”

“…novo lipogenesis (3). This would increase VLDL export and in turn raise circulating triglycerides (TGs) and LDL cholesterol (3).…”