The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome

Abstract

We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin-resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an approximately 20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-alpha, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-alpha, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.

Conflict of interest statement

Conflict of interest statement: B.B.K. has a research grant from Takeda Pharmaceuticals and is an inventor on a patent for RBP-4.

Figures

Fig. 1.

Plasma concentrations of glucose (A), insulin (B), triglyceride (C), and fatty acids (D) in insulin-sensitive (○) and insulin-resistant (■) participants before and after the mixed meals.

Fig. 2.

13C MRS measurements of changes in muscle (A) and liver (B) glycogen concentrations and 1H MRS measurements of changes in intramyocellular triglyceride (C) and hepatic triglyceride (D) content in insulin-sensitive and insulin-resistant subjects after the mixed meals.

Fig. 3.

MRI imaging of intraabdominal fat of several slices through the abdomen in a subject (A), three-dimensional reconstruction of intraabdominal fat in the same subject (B), and intraabdominal fat volume in the insulin-sensitive and insulin-resistant subjects (C).

Fig. 4.

Fractional de novo lipogenesis in insulin-sensitive and insulin-resistant subjects after the two high-carbohydrate mixed meals.

Fig. 5.

Schematic of whole-body energy distribution after high-carbohydrate mixed meals in insulin-sensitive and insulin-resistant individuals.