TY - JOUR
T1 - Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans
AU - Ding, Lingling
AU - Goossens, Gijs H.
AU - Oligschlaeger, Yvonne
AU - Houben, Tom
AU - Blaak, Ellen E.
AU - Shiri-Sverdlov, Ronit
N1 - Funding Information:
This work was funded by TI Food and Nutrition (grant to EEB and GHG), Alpro Foundation (grant to EEB and GHG), a public-private partnership on pre-competitive research on food and nutrition (grant to EEB and GHG), the Dutch Organization for Scientific Research (NWO) (Vidi grant no. 016.126.327 to RS-S), ASPASIA (grant no. 015.008.043 to RS-S), TKI-LSH (grant no. 40-41200-98-9306 to RS-S) and VCK (grant no. Swu16.0057-VT to RS-S). LD is supported by the Chinese Scholarship Council with file number 201709110146. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/2
Y1 - 2020/2
N2 - 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-H-2(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 high-insulin infusion [40 mU/(m(2) x 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-alpha (IL-8: standardised beta = 0.495, p <0.001; TNF-alpha: standardised beta = 0.264, p = 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised beta = -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-alpha were not significantly correlated with hepatic insulin sensitivity. Conclusions/interpretation We 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.
AB - 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-H-2(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 high-insulin infusion [40 mU/(m(2) x 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-alpha (IL-8: standardised beta = 0.495, p <0.001; TNF-alpha: standardised beta = 0.264, p = 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised beta = -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-alpha were not significantly correlated with hepatic insulin sensitivity. Conclusions/interpretation We 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.
KW - Hepatic insulin sensitivity
KW - Inflammatory cytokines
KW - Lysosomal enzyme
KW - Type 2 diabetes
KW - NECROSIS-FACTOR-ALPHA
KW - ADIPOSE-TISSUE
KW - RESISTANCE
KW - GLUCOSE
KW - FAT
KW - METFORMIN
KW - MUSCLE
KW - INTERLEUKIN-6
KW - METABOLISM
KW - BIOMARKERS
U2 - 10.1007/s00125-019-05025-2
DO - 10.1007/s00125-019-05025-2
M3 - Article
C2 - 31690989
SN - 0012-186X
VL - 63
SP - 374
EP - 384
JO - Diabetologia
JF - Diabetologia
IS - 2
ER -