Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes

Abstract

Objective: Steatosis associates with insulin resistance and may even predict type 2 diabetes and cardiovascular complications. Because muscular insulin resistance relates to myocellular fat deposition and disturbed energy metabolism, we hypothesized that reduced hepatic ATP turnover (fATP) underlies insulin resistance and elevated hepatocellular lipid (HCL) contents.

Research design and methods: We measured hepatic fATP using (31)P magnetic resonance spectroscopy in patients with type 2 diabetes and age- and body mass-matched controls. Peripheral (M and M/I) and hepatic (suppression of endogenous glucose production) insulin sensitivity were assessed with euglycemic-hyperinsulinemic clamps.

Results: Diabetic individuals had 29% and 28% lower peripheral and hepatic insulin sensitivity as well as 42% reduced fATP than controls. After adjusting for HCL, fATP correlated positively with peripheral and hepatic insulin sensitivity but negatively with waist circumference, BMI, and fasting plasma glucose. Multiple regression analysis identified waist circumference as an independent predictor of fATP and inorganic phosphate (P(I)) concentrations, explaining 65% (P = 0.001) and 56% (P = 0.003) of the variations. Hepatocellular P(I) primarily determined the alterations in fATP.

Conclusions: In patients with type 2 diabetes, insulin resistance relates to perturbed hepatic energy metabolism, which is at least partly accounted for by fat depots.

Figure 1

Liver MR data of one patient with type 2 diabetes. A: Axial slice through the liver (gradient echo, prone position). The grid corresponds to the chemical shift imaging matrix. The voxels surrounded by the bold white line were selected for quantification. The MR spectrum corresponding to the “×” in the image is shown on the right panel. B: MR spectra from the saturation transfer experiment (solid line). The ATP resonance is completely suppressed, and the P_I signal is lower than in the baseline control experiment (dashed line).

Figure 2

Correlations with hepatocellular ATP production (fATP) with (A) hepatic insulin resistance (EGP suppression; all: r = 0.77, P = 0.002; type 2 diabetic subjects: r = 0.79, P = 0.01; controls: r = 0.54, P = 0.17), (B) waist circumference (all: r = −0.78, P = 0.001; type 2 diabetic subjects: r = 0.57, P = 0.11; controls: r = 0.68, P = 0.064), (C) HCL contents (all: r = −0.51, P = 0.038; type 2 diabetic subjects r = −0.20, P = 0.61; controls: r = 0.62, P = 0.10), (D) hepatic concentrations of P_I (all: r = 0.77, P = 0.0003; type 2 diabetic subjects: r = 0.57, P = 0.11; controls: r = 0.68, P = 0.064) across all participants (type 2 diabetic subjects: ●, controls: △).