Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis

Abstract

Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.

Figure 1. Schematic representation of selective postreceptor (partial) hepatic insulin resistance.

In insulin-resistant states in mice, the ability of insulin to suppress hepatic gluconeogenesis is impaired (dashed red arrows), whereas insulin-stimulated de novo lipogenesis is increased (solid green arrows) (5). Only selected signaling intermediaries are shown. INSR, insulin receptor. Asterisks indicate signaling components in which human genetic defects have been reported to date.

Figure 2. Lipid profiles of patients with severe insulin resistance.

(A) Fasting serum TG and (B) cholesterol concentrations in patients with insulin receptoropathy, lipodystrophy, or idiopathic severe insulin resistance (IR). (C) Comparison of lipid profiles between diabetic and nondiabetic subjects with either genetic INSR defects presenting at or after puberty or severe insulin resistance of unknown, but likely genetic, etiology. No significant differences were detected by ANOVA. DS, Donohue syndrome; RMS, Rabson-Mendenhall syndrome; TA, post-pubertal severe insulin resistance due to genetic insulin receptor defects; TB, type B insulin resistance; PLD, familial partial lipodystrophy due to LMNA mutations; GLD, generalized lipodystrophy; SIR, severe insulin resistance. Dashed lines represent World Health Organization thresholds for the diagnosis of the metabolic syndrome for TG (>1.7 mmol/l) and HDL cholesterol (<1.0 mmol/l for females). Error bars represent SEM.

Figure 3. Metabolic phenotyping of patients with insulin receptor mutations.

(A–C) Plasma glucose (A), insulin (B), and non-esterified FFAs (C) before and after a 75-g oral glucose challenge in patients (n = 4) with type A insulin resistance due to insulin receptor mutations (filled triangles) and in healthy controls (n = 6; gray squares). (D) De novo lipogenesis (DNL) in healthy controls (n = 6; white bar) and in patients with severe insulin resistance due to mutations in the insulin receptor (INSR; n = 4; light gray bar), AKT2 (n = 2; dark gray bar) or partial lipodystrophy (LD; n = 3; black bar). All data represent mean ± SEM. *P < 0.05 versus control.

Figure 4. Abdominal and liver fat measurements in patients with severe insulin resistance.

Representative abdominal fat distribution (at the L4 vertebral level) (top row), together with T₂-weighted HASTE transaxial images of the liver (middle row), and the corresponding liver fat spectra (bottom row) from 4 women. The control volunteer was a 38-year-old female (BMI, 24.2 kg/m²), INSR A1135E was a 17-year-old female (BMI, 21.5 kg/m²; patient 3 in Table 2), AKT2 R274H was a 40-year-old female (BMI, 26.7 kg/m²; patient 5 in Table 2), and LMNA was a 45-year-old woman (BMI, 25.0 kg/m² with FPLD2; she was a compound heterozygote for LMNA S583L and T528M; ref. 40). VAT is shown in yellow. IHL, intrahepatic lipid as determined by magnetic resonance spectroscopy; SCAT, subcutaneous adipose tissue (red).