Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly

Clare Flannery, Sylvie Dufour, Rasmus Rabøl, Gerald I Shulman, Kitt Falk Petersen, Clare Flannery, Sylvie Dufour, Rasmus Rabøl, Gerald I Shulman, Kitt Falk Petersen

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.

Figures

FIG. 1.
FIG. 1.
Plasma concentrations in response to two carbohydrate-rich mixed meals ingested at 10 a.m. and 1 p.m. during a resting study. MRS occurred between 4 p.m. and 8 p.m., during which time no plasma samples were drawn. ○, young subjects (n = 12); ●, elderly subjects (n = 12). A: Plasma concentrations of glucose. B: Plasma concentrations of insulin. C: Plasma concentrations of C-peptide. D: Plasma concentrations of TG. E: Plasma concentrations of chylomicron-free TG. n = 9 for the elderly subjects. F: Plasma concentrations of FAs. *P < 0.05.
FIG. 1.
FIG. 1.
Plasma concentrations in response to two carbohydrate-rich mixed meals ingested at 10 a.m. and 1 p.m. during a resting study. MRS occurred between 4 p.m. and 8 p.m., during which time no plasma samples were drawn. ○, young subjects (n = 12); ●, elderly subjects (n = 12). A: Plasma concentrations of glucose. B: Plasma concentrations of insulin. C: Plasma concentrations of C-peptide. D: Plasma concentrations of TG. E: Plasma concentrations of chylomicron-free TG. n = 9 for the elderly subjects. F: Plasma concentrations of FAs. *P < 0.05.
FIG. 2.
FIG. 2.
13C and 1H MRS measurements of changes in muscle glycogen concentrations (A) and IMCL contents (B) after two carbohydrate-rich mixed meals. Open bars, young subjects (N = 12); closed bars, elderly subjects (N = 12).
FIG. 3.
FIG. 3.
13C and 1H MRS measurements of changes in hepatic glycogen concentrations (A) and hepatic TG (B) contents after two carbohydrate-rich mixed meals. Open bars, young subjects (N = 12); closed bars, elderly subjects (N = 12).
FIG. 4.
FIG. 4.
Hepatic DNL after the ingestion of two carbohydrate-rich mixed meals. Open bars, young subjects; closed bars, elderly subjects.

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