Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans

Abstract

Aims/hypothesis Insulin resistance in skeletal muscle and liver plays a major role in the pathophysiology of type 2 diabetes. The hyperinsulinaemic-euglycaemic clamp is considered the gold standard for assessing peripheral and hepatic insulin sensitivity, yet it is a costly and labour-intensive procedure. Therefore, easy-to-measure, cost-effective approaches to determine insulin sensitivity are needed to enable organ-specific interventions. Recently, evidence emerged that plasma cathepsin D (CTSD) is associated with insulin sensitivity and hepatic inflammation. Here, we aimed to investigate whether plasma CTSD is associated with hepatic and/or peripheral insulin sensitivity in humans. Methods As part of two large clinical trials (one designed to investigate the effects of antibiotics, and the other to investigate polyphenol supplementation, on insulin sensitivity), 94 overweight and obese adults (BMI 25-35 kg/m 2 ) previously underwent a two-step hyperinsulinaemic-euglycaemic clamp (using [6,6-2 H 2 ]glucose) to assess hepatic and peripheral insulin sensitivity (per cent suppression of endogenous glucose output during the low-insulin-infusion step, and the rate of glucose disappearance during highinsulin infusion [40 mU/(m 2 × min)], respectively). In this secondary analysis, plasma CTSD levels, CTSD activity and plasma inflammatory cytokines were measured. Results Plasma CTSD levels were positively associated with the proinflammatory cytokines IL-8 and TNF-α (IL-8: standardised β = 0.495, p < 0.001; TNF-α: standardised β = 0.264, p = 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised β = −0.206, p = 0.043), independent of age, sex, BMI and waist circumference, but it was not associated with peripheral insulin sensitivity. However, plasma IL-8 and TNF-α were not significantly correlated with hepatic insulin sensitivity. Conclusions/interpretationWe demonstrate that plasma CTSD activity, but not systemic inflammation, is inversely related to hepatic insulin sensitivity, suggesting that plasma CTSD activity may be used as a non-invasive marker for hepatic insulin sensitivity in humans.

Plasma Cathepsin D Activity Rather Than Levels Correlates With Metabolic Parameters of Type 2 Diabetes in Male Individuals

“…Our data therefore point toward plasma CTSD as a novel metabolic regulator in type 2 diabetes. These findings are in line with our previous studies that demonstrated a role for plasma CTSD activity in lipid metabolism and insulin resistance ( 18 , 23 , 24 ).…”

“…diabetes (24). More specifically, increasing reports link CTSD activity to disturbances in lipid metabolism (18,23), a finding which we could also confirm in here in our study.…”

“…Our data therefore point toward plasma CTSD as a novel metabolic regulator in type 2 diabetes. These findings are in line with our previous studies that demonstrated a role for plasma CTSD activity in lipid metabolism and insulin resistance (18,23,24). Under healthy conditions, CTSD has been demonstrated to play important roles in maintaining numerous physiological functions, including degradation of intracellular proteins, activation of hormones, growth factors and enzymatic precursors, hydrolysis of LDL cholesterol, and regulating programmed cell death (15).…”

Cathepsin gene expression in abdominal subcutaneous adipose tissue of obese/overweight humans

“…In contrast, in rodent models it has been reported that whole-body pharmacological and genetic inactivation of CTSB protected against the development of hepatic steatosis and whole-body insulin resistance [ 24 ]. We previously observed in a sub-study of this cohort that plasma Cathepsin D (CTSD) activity, but not systemic inflammation, is inversely related to hepatic insulin sensitivity, suggesting that plasma CTSD activity may be used as a non-invasive marker for hepatic insulin sensitivity in humans [ 25 ]. The observed fasting lysosomal dysfunction might compromise the ability of the cell to perform quality control on the mitochondrial matrix, since autophagy plays a pivotal role in the degradation of defective mitochondria.…”

The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management

“…Similarly, plasma cathepsin D levels associated with metabolic alterations in liver during NAFLD [ 187 ]. Recent studies suggested that plasma cathepsin D levels correlated with type 2 diabetic patients [ 188 ] and moreover plasma cathepsin D activity is suggested as biomarker for hepatic insulin sensitivity [ 189 ]. Cathepsins Z and K are proposed diagnostic markers for osteoporosis [ 190 , 191 ].…”