Proprotein Convertase Subtilisin / Kexin type 9 a ff ects insulin but not lipid metabolism in cystic fi brosis

Purpose: Cystic Fibrosis (CF) is the most common genetic disorder and, with improved survival, glucose abnormalities have emerged as a major comorbidity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of plasma LDL-cholesterol homeostasis, is associated with lipid and glucose metabolism in healthy individuals. Here we report on the link between PCSK9 and markers of metabolism in CF. Methods: Cross-sectional analysis was performed on CF patients (≥ 18 years, N=94) from the Montreal Cohort, without known diabetes, and on healthy individuals (N=19). The levels of PCSK9 and lipid markers were quantified and all subjects underwent a 2 h oral glucose tolerance test. Results: No significant differences in PCSK9 levels were found between healthy individuals and patients with CF, or between the groups with different degrees of glucose tolerance. No association was found between PCSK9 and markers of lipid metabolism; however, a positive correlation was found between PCSK9 and total insulin secretion and a negative one with insulin sensitivity in CF patients who had normal glucose tolerance. Conclusion: Circulating levels of PCSK9 in the CF population are comparable to those in the healthy population. There are no associations between PCSK9 levels and either glucose or lipid homeostasis parameters. Nevertheless, a statistically significant link was observed between PCSK9 and markers of insulin homeostasis, solely in CF patients who presented normal glucose tolerance. Further exploration of the relationship between PCSK9 and insulin homeostasis in CF patients with normal glucose tolerance is warranted. ORIGINAL RESEARCH © 2017 CIM Clin Invest Med • Vol 40, no 2, April 2017 E59 Correspondence to: Dr. Yves Berthiaume Institut de recherches cliniques de Montréal (IRCM) 110 avenue des Pins Ouest Montréal, Québec, Canada, H2W 1R7 E-mail: yves.berthiaume@ircm.qc. ca Manuscript submitted 20th September, 2016 Manuscript accepted 24th January, 2017 Clin Invest Med 2017; 40 (2): E59-E65. Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in Caucasians. CF is a multisystemic disease that affects the gastrointestinal, pulmonary and reproductive systems. CF chronic lung disease is associated with respiratory infection and inflammation, which, in turn, lead to severe lung damage and eventually to respiratory failure [1]. In the past 20 years, the life expectancy of CF patients has improved to such an extent that they now display new challenging complications. CF-related diabetes (CFRD), caused by a significant decrease in insulin levels, is one of the most common complications [2,3] and is associated with accelerated clinical deterioration (loss of weight and lung function) [4]. Numerous CF clinics now report an important prevalence of overweight and obesity in their populations (23% in the United-States and 18% in Canada) [5-7]. Long-term studies are important to determine if this excess weight eventually leads to harmful health complications in these patients. Predominantly synthesized in the liver, the proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial player in the regulation of plasma cholesterol homeostasis [8,9]. In addition, numerous studies have associated increased circulating PCSK9 levels with higher concentrations of metabolic factors related to glucose and insulin homeostasis in healthy individuals [10]. Furthermore, the presence of metabolic syndrome or obesity in non-CF patients has been found to be associated with an increase in circulating PCSK9 levels [11]. No studies have yet explored PCSK9 levels in an adult population of CF patients, especially in the diabetic sub-population [12,13]. We hypothesized that patients with CF may display higher PCSK9 levels than the normal population, possibly due to increased inflammation [9]. An association exists between the levels of circulating PCSK9 and the markers of lipid, glucose and insulin homeostasis [14,10]; hence, we assessed plasma levels of PCSK9 at baseline in patients with CF and then compared these values with those of healthy subjects as well as between glucose tolerance categories. Finally, we studied the association between PCSK9 and biomarkers of lipid or glucose metabolism, such as total insulin secretion and sensitivity.