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PCSK9 Levels and Metabolic Profiles in Elderly Subjects with Different Journal of Clinical Medicine Article PCSK9 Levels and Metabolic Profiles in Elderly Subjects with Different Glucose Tolerance under Statin Therapy Kari A. Mäkelä 1,*, Jari Jokelainen 2 , Ville Stenbäck 1,3, Juha Auvinen 2, Marjo-Riitta Järvelin 2,4,5, Mikko Tulppo 1, Juhani Leppäluoto 1, Sirkka Keinänen-Kiukaanniemi 2 and Karl-Heinz Herzig 1,6,* 1 Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland; ville.stenback@oulu.fi (V.S.); mikko.tulppo@oulu.fi (M.T.); juhani.leppaluoto@oulu.fi (J.L.) 2 Center for Life Course Health Research and Medical Research Center, Faculty of Medicine, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland; jari.jokelainen@oulu.fi (J.J.); juha.auvinen@oulu.fi (J.A.); [email protected] (M.-R.J.); sirkka.keinanen-kiukaanniemi@oulu.fi (S.K.-K.) 3 Biocenter Oulu, University of Oulu, 90014 Oulu, Finland 4 MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, St Mary’s Campus, Norfolk Place, London W2 1PG, UK 5 Unit of Primary Care, Oulu University Hospital, 90029 Oulu, Finland 6 Institute of Pediatrics, Poznan University of Medical Sciences, 60-512 Poznan, Poland * Correspondence: kari.makela@oulu.fi (K.A.M.); karl-heinz.herzig@oulu.fi (K.-H.H.); Tel.: +358-294-48-5274 (K.A.M.) Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein Citation: Mäkelä, K.A.; Jokelainen, J.; cholesterol (LDL-C) receptors, and thus regulates the LDL-C levels in the circulation. Type 2 diabetics Stenbäck, V.; Auvinen, J.; Järvelin, M.-R.; often have elevated LDL-C levels. However, the functions of PCSK9 in patients with alterations of Tulppo, M.; Leppäluoto, J.; glu-cose metabolism and statin therapy are still unclear. Method: we investigated a large cohort of Keinänen-Kiukaanniemi, S.; Herzig, 608 subjects, born in 1945 in Oulu, Finland (Oulu Cohort 1945). We studied the effects of PSCK9 K.-H. PCSK9 Levels and Metabolic lev-els with different glucose tolerances (normal glucose tolerance (NGT), prediabetes (PreDM) Profiles in Elderly Subjects with or type 2 diabetes (T2D)) with and without statin medication, and analyzed clinical data, NMR Different Glucose Tolerance under Statin Therapy. J. Clin. Med. 2021, 10, metabolomics and PCSK9 plasma levels. Results: PCSK9 plasma levels did not significantly differ 994. https://doi.org/10.3390/ between the three groups. Statin therapy significantly increased the PCSK9 levels in NGT, PreDM jcm10050994 and T2D groups compared with subjects with no statins. In the NGT group, negative associations between PCSK9 and LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density Academic Editor: Francesca Zimetti lipoprotein cholesterol (VLDL-C), total cholesterol and LDL and IDL triglycerides were observed under statin medication. In contrast, in the PreDM and T2D groups, these associa-tions were lost. Received: 21 January 2021 Conclusions: our data suggest that in subjects with abnormal glucose metabolism and statin therapy, Accepted: 22 February 2021 the significant PCSK9-mediated effects on the lipid metabolites are lost com-pared to NGT subjects, Published: 2 March 2021 but statins reduced the LDL-C and VLDL-C levels. Publisher’s Note: MDPI stays neutral Keywords: PCSK9; prediabetes; type 2 diabetes; LDL cholesterol; statin therapy; elderly; cohort study with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by binding and degrading LDL-C receptors, and thus Copyright: © 2021 by the authors. increasing the levels of circulating LDL-C [1]. Gain-of-function mutations in the PCSK9 Licensee MDPI, Basel, Switzerland. gene cause autosomal familial hypercholesterolemia [2,3]. In contrast, loss-of-function This article is an open access article distributed under the terms and mutations are located in the LDL receptor (LDLR) and apolipoprotein B (APOB) genes, and conditions of the Creative Commons are associated with decreased LDL-C levels [4]. Elevated LDL-C levels increase the risk of Attribution (CC BY) license (https:// cardiovascular diseases [5]. Individuals with type 2 diabetes (T2D) develop dyslipidemia creativecommons.org/licenses/by/ with elevated LDL-C levels, which are commonly treated with antihyperlipidemic drugs [6]. 4.0/). PCSK9 inhibitors have been demonstrated to be very effective tools for treating high J. Clin. Med. 2021, 10, 994. https://doi.org/10.3390/jcm10050994 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 994 2 of 10 circulating LDL-C levels [5]. Furthermore, PCSK9 is also expressed in tissues other than the liver, with additional effects on the immune system, glucose metabolism, pancreas and kidney [3]. Earlier studies found elevated blood PCSK9 levels in diabetics compared with non-diabetic subjects [7–9]. On the contrary, other investigators did not find differences in PCSK9 levels between diabetic and non-diabetic subjects [10,11]. Type 2 diabetes is characterized by a chronic hyperglycemia, due to resistance to the insulin action in the cells of the body [12]. T2D is preceded by prediabetes, in which the blood glucose levels are higher than normal, but still below the criterion for diagnosis of T2D [13]. In a recent article, circulating PCSK9 levels were positively associated with glucose homeostasis parameters, such as insulin and hemoglobin A1c (HbA1c) [6,14]. In addition, a possible role of PCSK9 inhibitors in the risk for development of T2D has also been discussed [15,16]. Colhoun et al. [15] found that the use of the PCSK9 inhibitor did not lead to the development of new-onset diabetes, while de Carvalho and colleagues [16] showed increased plasma glucose and HbA1c after the treatment with the PCSK9 inhibitor, but they did not find an increased incidence risk for diabetes. Currently, the connection between PCSK9 and impaired blood glucose homeostasis is not clear. PCSK9 was detected by Western blotting in human aortic smooth muscle cells and carotid atherosclerotic plaques [17]. However, PCSK9 mRNA could not be detected in monocytes or macrophages. The protein is secreted by smooth muscle cells and decreases LDLR expression in macrophages, affecting foam cell formation. Short-term treatment with PCSK9 inhibitors reduced arterial stiffness in patients with familiar hypercholesterolemia, or procedures of percutaneous transluminal coronary angioplasty [18]. Circulating PCSK9 correlated positively with high sensitive C-reactive protein (CRP) in patients with stable coronary artery disease or acute coronary syndromes [19,20]. Statin treatment increased PCSK9 (neural apoptosis-regulated convertase-1; NARC-1) mRNA expression in human liver cancer cell line (HepG2) cells and primary hepato- cytes [21]. In patients with high LDL levels, statin therapy significantly increased plasma fasting PCSK9 levels in subjects using atorvastatin 40 mg/day, while lower amounts (10 mg/day) did not affect serum PCSK9 levels in a limited number of study subjects [22]. In another study, however, even a 10 mg/day dose of atorvastatin was enough to signifi- cantly raise plasma PCSK9 levels [23]. In the latter study, the PCSK9 plasma values were 100-fold higher than in the previous study using an immunoblot system. In prediabetic subjects (PreDM) receiving statins, PCSK9 plasma levels were higher compared with non- medicated subjects [24], while statin-treated patients with symptoms of coronary artery disease showed no difference in their PCSK9 plasma levels, compared with non-treated patients with similar symptoms [25]. Thus, the effects of statins on blood PCSK9 levels need further investigation. The aim of the present study was to determine plasma PCSK9 levels and metabolic pro- files of elderly subjects with different glucose tolerance profiles (normal glucose tolerance (NGT), prediabetes (PreDM) and type 2 diabetes (T2D)) under statin therapy. 2. Materials and Methods We investigated individuals that were born in 1945 and who live in the city of Oulu (Oulu Cohort 1945), which is located in North Ostrobothnia, Finland (65◦ North). The original data collection was done between the years 2001–2002, and it included 1332 partic- ipants (Figure1)[ 26]. In this study, we used data from the follow-up health examinations, which were carried out from 2013–2015. Blood samples were taken from 696 subjects, and oral glucose tolerance tests were done for 670 participants (281 men and 389 women) [27]. PCSK9 and metabolomics analyses were performed from 608 subjects (Figures2 and3). The subjects continued their prescribed medication, and the use of statin medication was asked about by questionnaire. Statin medication mainly consisted of atorvastatin and simvastatin. Blood pressure (BP) was determined with an automated blood pressure monitor (Omron M3, Omron Healthcare Europe B.V., Hoofddorp, The Netherlands). Waist circumference, height and weight were measured with a standardized protocol. The habitual physical J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 12 blood pressure monitor (Omron M3, Omron Healthcare Europe B.V., Hoofddorp, the J. Clin. Med. 2021, 10, 994 Netherlands). Waist circumference, height and weight were measured with3 of 10 a standard- ized protocol. The habitual physical activity of the participants was measured objectively with a wrist-worn acceleration meter for two weeks (Polar Active,
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