Role of Proneurotensin in Cardiometabolic Diseases

The burden of cardiometabolic diseases is increasing worldwide. Early detection of high-risk individuals is essential for appropriate diagnosis, better treatment outcomes, quality of life and lower health related costs. Aims: The overall aim of this thesis is to investigate the possible associations between plasma proneurotensin (Pro-NT) and risk of cardiovascular disease (CVD), type 2 diabetes (T2D), impaired glucose regulation, as well as diet-induced obesity in different study populations. As Pro-NT appears to be a novel risk marker for cardiometabolic morbidity and mortality, we also wanted to study the effects of dietary fat intake on circulating plasma Pro-NT and triglyceride levels. This thesis is based on epidemiological data from three population-based cohorts, The Malmö Preventive Project (MPP), The Malmö Diet and Cancer study- Cardiovascular Cohort (MDC-CC) and The MEDIM cohort (impact of Migration and Ethnicity on Diabetes in Malmö). Paper I, in this cohort including an elderly population, we identified that Pro-NT predicts incident CVD in both genders, but incident T2D in women only, after 5.4 years of follow up. Paper II, in a population based cohort of Iraqi and Swedish born men and women, higher Pro-NT levels were observed both in the Iraqi- vs Swedish-born group. However, elevated plasma Pro-NT was associated with impaired glucose regulations assessed as insulin secretion and action and HbA1c in the Iraqi-population only. Paper III, we found prompt increases in plasma Pro-NT every hour for four hours, after an oral lipid load in healthy individuals. Post-lipid rise of circulating plasma Pro-NT correlated with the changes in plasma triglyceride levels, irrespective of cream and olive oil. Paper IV, in this longitudinal study, we identified that high Pro-NT levels predicted all-cause mortality (ACM) and cause- specific mortalities (CSM) due to CVD, gastrointestinaltract (GIT) diseases, mental and behavioral diseases, and diseases of unspecific causes, in both gender. Conclusion: This thesis shows that circulating Pro-NT is a biomarker that in an elderly population predicts CVD in both gender, but T2D in women only . Irrespective of gender, Pro-NT predicts ACM and CSM. Pro-NT is more strongly associated with impaired glucose regulation in a Middle Eastern immigrant population and may partly explain the increased T2D in this group. Furthermore, oral lipid intake increases Pro-NT levels, which facilitates triglyceride increase in blood in healthy individuals, supporting intestinal lipid absorption as being one key action of Pro-NT.