Mika Hilvo1, Tuire Salonurmi2,3,4, Aki S Havulinna5, Dimple Kauhanen1, Eva Ringdal Pedersen6, Grethe S Tell7, Klaus Meyer8, Anna-Maria Teeriniemi2,4,9, Tiina Laatikainen5,10,11, Pekka Jousilahti5, Markku J Savolainen2,3,4, Ottar Nygård6,12, Veikko Salomaa5, Reijo Laaksonen13,14,15. 1. Zora Biosciences Oy, Biologinkuja 1, 02150, Espoo, Finland. 2. Department of Internal Medicine, Oulu University Hospital, Oulu, Finland. 3. Research Center for Internal Medicine and Biocenter Oulu, Oulu, Finland. 4. Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. 5. Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. 6. Department of Clinical Science, University of Bergen, Bergen, Norway. 7. Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. 8. Bevital AS, Bergen, Norway. 9. Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland. 10. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. 11. Joint Municipal Authority for North Karelia Social and Health services, Joensuu, Finland. 12. Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. 13. Zora Biosciences Oy, Biologinkuja 1, 02150, Espoo, Finland. reijo.laaksonen@zora.fi. 14. Finnish Cardiovascular Research Center, University of Tampere, Tampere, Finland. reijo.laaksonen@zora.fi. 15. Finnish Clinical Biobank Tampere, Tampere University Hospital, Tampere, Finland. reijo.laaksonen@zora.fi.
Abstract
AIMS/HYPOTHESIS: Ceramide lipids have a role in the development of insulin resistance, diabetes and risk of cardiovascular disease. Here we investigated four ceramides and their ratios to find the best predictors of incident diabetes. METHODS: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. RESULTS: Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals who had 5% or more weight loss. CONCLUSIONS/ INTERPRETATION: The Cer(d18:1/18:0)/Cer(d18:1/16:0) ratio is an independent predictive biomarker for incident diabetes, and may be modulated by lifestyle intervention.
AIMS/HYPOTHESIS: Ceramidelipids have a role in the development of insulin resistance, diabetes and risk of cardiovascular disease. Here we investigated four ceramides and their ratios to find the best predictors of incident diabetes. METHODS: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. RESULTS: Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals who had 5% or more weight loss. CONCLUSIONS/ INTERPRETATION: The Cer(d18:1/18:0)/Cer(d18:1/16:0) ratio is an independent predictive biomarker for incident diabetes, and may be modulated by lifestyle intervention.
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