Creatine kinase is associated with glycated haemoglobin in a nondiabetic population. The Tromsø study

PLOS ONE RESEARCH ARTICLE Creatine kinase is associated with glycated haemoglobin in a nondiabetic population. The Tromsø study Svein Ivar Bekkelund ID1,2* 1 Department of Clinical Medicine, UiT – The Arctic University of Norway, Tromsø, Norway, 2 Department of Neurology, University Hospital of North Norway, Tromsø, Norway a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 * Abstract Background OPEN ACCESS Citation: Bekkelund SI (2023) Creatine kinase is associated with glycated haemoglobin in a nondiabetic population. The Tromsø study. PLoS ONE 18(2): e0281239. https://doi.org/10.1371/ journal.pone.0281239 Editor: Shengxu Li, Children’s Hospitals and Clinics of Minnesota, UNITED STATES Received: October 9, 2021 Creatine kinase (CK) has been associated with insulin resistance and identified as a risk marker of cardiovascular disease largely by its relationship with hypertension and increased body mass index. This study determined whether CK is a predictor of glycated haemoglobin (HbA1C) in a nondiabetic general population. Methods Associations between CK and the outcome variable HbA1C (%) were performed by variance and multivariate analyses in 11662 nondiabetic subjects defined as HbA1C (%) <6.5 who participated in the population based Tromsø study (Tromsø 6) in Norway. Accepted: January 6, 2023 Published: February 2, 2023 Results Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0281239 Abnormal elevated CK was detected in 543/11662 participants (4.66%). Mean HbA1C (%) in the “high CK” group was 5.62 (SD = 0.33) compared to 5.52 (SD = 0.36) in the “normal CK” group, P <0.001. CK increased significantly and linearly with higher levels of HbA1C (%) quartiles in women (P <0.001) and non-linearly in men (P <0.001). In a multivariate analysis, CK was independently associated with HbA1C (%) after adjusting for age, sex, body mass index, blood pressure, glucose, lipids, C-reactive protein, creatinine, alanine transaminase and aspartate aminotransferase. A 1-unit increase in log CK was associated with a 0.17-unit increase in HbA1C (%). Copyright: © 2023 Svein Ivar Bekkelund. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Due to ethical and legal restrictions, data is only available upon request to the Tromsø Study. Any enquiries should be sent to the Institutional Data Access committee of The Tromsø study, Department of Community Conclusion These data demonstrate a positive and independent association between CK and glycated haemoglobin in a nondiabetic general population. PLOS ONE | https://doi.org/10.1371/journal.pone.0281239 February 2, 2023 1/9 PLOS ONE Medicine, Faculty of Health Sciences, UiT- The Arctic University of Tromsø (). Funding: The author received no specific funding for this work. Competing interests: The author has declared that no competing interests exist. Creatine kinase and glycated haemoglobin Introduction The enzymatic activity of creatine kinase (CK) is an important biological reaction in the formation of adenosine triphosphate (ATP), which is necessary for energy-demanding processes in human and animal cells, especially muscle contractions [1]. Both animal and human studies have shown relationships between CK and insulin resistance. Myocytes and adipocytes are important sites of insulin action, glucose uptake, and insulin resistance [2, 3], and ATP is involved in the muscular glucose uptake process [4]. Moreover, cytosolic CK reacts with glycolytic enzymes involved in ATP-generation, like pyruvate kinase [5]. Muscular activity, especially long-term and intense exercise and eccentric muscular training, may increase CK markedly [6, 7], while leisure physical exercise increases CK modestly; i.e., approximately 5% [8]. In addition to physiological elevation of CK, population studies have identified slightly increased CK as a possible cardiovascular disease (CVD) risk factor which include hypertension, obesity, and metabolic syndrome [9–12], although the mechanisms are largely unexplained. Thus, exercise increases insulin sensitivity and thereby reduces cardiovascular risk [13]. Differences in metabolic activity between muscle fibre types may explain some of the shared biological effects between glucose metabolism and CK. Higher CK activity and reduced insulin sensitivity are reported features of type 2B muscle fibres in contrast to type 1 fibres which to a greater extent promote oxidative metabolic reactions [14]. Animal studies have shown a shift from muscle fibre 2 to type 1 predominance upon CK inhibition and thereby stimulating oxidative phosphorylation, weight loss, and insulin sensitivity [15–17]. Consequently, subjects with relatively more 2B muscle fibres hypothetically run a higher CVD risk than those with muscle fibre type 1 predominance [18]. To further elaborate the connection between CK and glucose metabolism, this study hypothesized that CK is independently associated with glycated haemoglobin (HbA1c) in a population of nondiabetic subjects recruited from a general Causation population. Materials and methods The present cross-sectional designed study is based on data from the 6th Tromsø Study, which is a prospective population-based study recruiting inhabitants from the community of Tromsø, Norway. At the beginning in 1974, it mainly focused on cardiovascular diseases. Inhabitants of the municipality of Tromsø and samples from certain age groups of subjects previously participated in the survey (4th Tromsø study) plus a 10% random sample from age groups 30–39, all participants aged 40–49 and between 60–87 years (mean 58 years) were selected for inclusion. The data were collected from October 2007 to 19 September 2008. In total, 11662 mainly Causations (87.3% ethnic Norwegians, 1.6% Sami ethnicity, 1.3% Finnish origin, 2.2% of other ethnicities, and 7.6% without information about ethnicity) participated [19]. Those with diabetes (n = 1286) defined as HbA1c �6.5% were excluded. This definition was used since fasting blood sugar and use of antidiabetic medication were not measured in the Tromsø study. Written consent was obtained, and the Norwegian Committee for Medical and Health Research Ethics (REC) approved the study (reference number 121/2006). All samples carried out in accordance with relevant guidelines and regulations are described elsewhere [20]. Serum-CK was obtained in an automated chemistry analyzer (Modular P, Roche) by photometry using an enzymatic method (CK-NAC, Roche Diagnostics, Mannheim, Germany) with an analytica (...truncated)