Hepatic mitochondrial respiratory capacity in patients with type 2 diabetes and Non-Alcoholic Steatohepatitis (NASH)

Background:

Obese humans without steatohepatitis (NASH) exhibit upregulated hepatic mitochondrial capacity, which is lost with liver disease progression. However, the role of type 2 diabetes for hepatic mitochondrial function in NASH remains unclear.

Methods:

We studied patients with histologically proven NASH and with (T2D; n = 8, age 48 ± 6 years, body mass index 54.0 ± 6.8 kg/m²) or without type 2 diabetes (NDM; n = 12, 42 ± 10 years, 53.1 ± 9.1 kg/m²) as well as in healthy humans (CON; n = 12, 41 ± 3 years, 25.5 ± 0.7 kg/m²). Insulin sensitivity was measured by euglycemic-hyperinsulinemic clamps with [6,6-²H₂]glucose. High-resolution respirometry served to quantify mitochondrial respiration in liver tissue and isolated mitochondria, Amplex Red to assess hepatic H₂O₂ emission.

Results:

T2D exhibited good glycemic control but had higher HbA1c than the other groups (T2D 7.1 ± 1.1%, NDM 5.3 ± 0.2%, CON 5.1 ± 0.3%). They had similar liver fat content, NAFLD score and serum hsCRP compared with NDM. T2D had lower hepatic insulin sensitivity than NDM and CON. Mitochondrial oxidative capacity of liver tissue was 28% higher in NDM than CON, while T2D presented with 32% lower maximum respiration than NDM. Of note, respiratory rates of isolated mitochondria, mitochondrial coupling efficiency as well as H₂O₂ production by the liver were comparable between T2D and NDM. Among NASH patients, maximum respiration rates correlated negatively with fasting glycemia and HbA1c (r =-0.62, P < 0.01 and r =-0.52, P = 0.03, respectively).

Conclusion:

Hyperglycemia drives the loss of adaptation of hepatic oxidative capacity in humans with NASH, possibly due to decreased mitochondrial content, which likely contributes to accelerated progression of liver diseases in type 2 diabetes patients.