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Serum cathepsin S is associated with decreased insulin sensitivity and the development of diabetes type 2 in a community-based cohort of elderly men
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.ORCID iD: 0000-0003-2256-6972
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.ORCID iD: 0000-0003-2247-8454
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2013 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 1, 163-165 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

RESEARCH DESIGN AND METHODS:

Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

RESULTS:

After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01).

CONCLUSIONS:

Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.

Place, publisher, year, edition, pages
2013. Vol. 36, no 1, 163-165 p.
Keyword [en]
Cathepsin S inflammation adipose tissue insulin resistance diabetes
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-233997DOI: 10.2337/dc12-0494ISI: 000314465700048PubMedID: 22923671OAI: oai:DiVA.org:uu-233997DiVA: diva2:755055
Available from: 2014-10-13 Created: 2014-10-13 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Cathepsin S as a Biomarker of Low-grade Inflammation, Insulin Resistance, and Cardiometabolic Disease Risk
Open this publication in new window or tab >>Cathepsin S as a Biomarker of Low-grade Inflammation, Insulin Resistance, and Cardiometabolic Disease Risk
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer.

The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations.

This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial.

In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol.

Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1046
Keyword
epidemiology, cathepsin S, inflammation, insulin resistance, diabetes, mortality, cardiovascular mortality, cancer mortality, healthy Nordic diet.
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-234027 (URN)978-91-554-9083-6 (ISBN)
Public defence
2014-12-04, sal IV, Universitetshuset, Biskopsgatan 3, 751 05 Uppsala, 13:00 (Swedish)
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Available from: 2014-11-12 Created: 2014-10-13 Last updated: 2015-02-03

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