Periodic Reporting for period 2 - PREVENT-2024 (MOVING FROM BIOMARKERS TO MECHANISM ORIENTED PREVENTION OF CARDIOMETABOLIC DISEASE)
Periodo di rendicontazione: 2022-07-01 al 2023-12-31
The number of individuals affected by obesity and type 2 diabetes is increasing rapidly in the EU and globally and therefore poses a great threat to cardiovascular health. It is known since decades that switching to a healthier diet and more physical activity will counteract cardiometabolic disease but the increase in obesity and diabetes suggests other complementary strategies than population wide-advice on diet and physical activity are needed for effective prevention.
Just like the responses to treatment of overt disease varies greatly between individuals and needs to be personalized, the effect of primary prevention of cardiometabolic disease (i.e. effect of actions taken years before disease onset) is highly diverse. Partly, this can be explained by varying degree of compliance to preventive therapies (such as physical activity and diet), but also inter-individual biological diversity play a major role. We have identified three novel hormonal cardiometabolic risk factors, which are present in large parts of the population. The current project tests if manipulation and therapeutic alteration of levels of these hormones – specifically in individuals indicated to be at risk by as indicated by value of any of the three hormones- can ameliorate cardiometabolic risk.
Specifically, the objectives are to test if cardiometabolic risk can be reduced by: (1) blockade of the hormone neurotensin, a hormone which promotes fat-absorption and central fat accumulation, (2) suppression of the water regulating and diabetes predictive hormone vasopressin by increasing water intake and (3) altered intravascular compartmentalization or production of the bio-active form of adrenomedullin.
If our goals are achieved, the project will give completely novel tools for personalized (hormone-level guided) prevention of cardiometabolic disease in large subsets of the population. This is of great importance for society in EU and globally as obesity and diabetes increase in occurrence and cardiovascular disease is the most common cause of death.
Just like the responses to treatment of overt disease varies greatly between individuals and needs to be personalized, the effect of primary prevention of cardiometabolic disease (i.e. effect of actions taken years before disease onset) is highly diverse. Partly, this can be explained by varying degree of compliance to preventive therapies (such as physical activity and diet), but also inter-individual biological diversity play a major role. We have identified three novel hormonal cardiometabolic risk factors, which are present in large parts of the population. The current project tests if manipulation and therapeutic alteration of levels of these hormones – specifically in individuals indicated to be at risk by as indicated by value of any of the three hormones- can ameliorate cardiometabolic risk.
Specifically, the objectives are to test if cardiometabolic risk can be reduced by: (1) blockade of the hormone neurotensin, a hormone which promotes fat-absorption and central fat accumulation, (2) suppression of the water regulating and diabetes predictive hormone vasopressin by increasing water intake and (3) altered intravascular compartmentalization or production of the bio-active form of adrenomedullin.
If our goals are achieved, the project will give completely novel tools for personalized (hormone-level guided) prevention of cardiometabolic disease in large subsets of the population. This is of great importance for society in EU and globally as obesity and diabetes increase in occurrence and cardiovascular disease is the most common cause of death.
Previous studies have shown that absence of proneurotensin in mice (knock-out model) protects from high-fat diet induced obesity and liver steatosis, partially through reduced intestinal absorption of fat. Moreover, human studies showed that high plasma concentration of proneurotensin independently predicts obesity, diabetes, liver steatosis, cardiovascular disease and mortality. We therefore tested the therapeutic potential of proneurotensin blockade by administration of a monoclonal antibody (vs control) against proneurotensin in mice, who had been made obese though high fat diet. We found that mice treated with antibodies blocking proneurotensin had greater weight loss, smaller fat depots, increased faecal cholesterol excretion, reduced liver fat and larger muscle fibre size. The results indicate that antibody-based blockade of proneurotensin reduces the adverse cardiometabolic risk associated with high levels of the hormone. To date, antibody-based blockade of proneurotensin is not available in humans. We therefore assess if inhibition of intestinal production and secretion of proneurotensin, using the drug orlistat, may reduce liver steatosis and cardiometabolic risk factors in obese humans with non-alcoholic fatty liver disease and high plasma concentration of proneurotensin (>150 pmol/L). This is the first ever randomized controlled study in humans targeting proneurotensin for cardiometabolic disease prevention. Recruitment is ongoing and results will be available during the last year of this ERC-ADG project.
We and others have shown that high plasma concentration of vasopressin, as measured by copeptin, is consistently independently predictive of future risk of diabetes in healthy individuals. In turn, the most common cause of high vasopressin in the healthy state is a low water intake and in low-water drinkers vasopressin level can be effectively lowered by increasing water intake. In the current project, we therefore undertake a large-scale randomized clinical trial testing if diabetes can be prevented by increasing water intake with 1.5 L daily (vs control therapy) during 12 months in subjects with habitually low water intake and high plasma concentration of vasopressin. Recruitment is finished and results expected Q1 2025.
Studies on the effects of the effects of intravascular compartmentalization and genetic effects on production of bioactive adrenomedullin are ongoing.
We and others have shown that high plasma concentration of vasopressin, as measured by copeptin, is consistently independently predictive of future risk of diabetes in healthy individuals. In turn, the most common cause of high vasopressin in the healthy state is a low water intake and in low-water drinkers vasopressin level can be effectively lowered by increasing water intake. In the current project, we therefore undertake a large-scale randomized clinical trial testing if diabetes can be prevented by increasing water intake with 1.5 L daily (vs control therapy) during 12 months in subjects with habitually low water intake and high plasma concentration of vasopressin. Recruitment is finished and results expected Q1 2025.
Studies on the effects of the effects of intravascular compartmentalization and genetic effects on production of bioactive adrenomedullin are ongoing.
Identification of disease risk using biomarkers is a very common research aim, but alone (i.e. identification of risk per se) it does not help improving population health. This project stands out as it moves from biomarker-identification of risk to testing of personalized interventions against biomarker-identified risk. This requires human randomized controlled trials that are expensive and time consuming. In the current project, subjects at high risk of cardiometabolic disease due to high levels of the hormones proneurotensin and vasopressin are randomized to therapies that specifically reduce these two hormones in order to test if such personalized preventive therapies can lower risk of cardiometabolic disease. If results are positive, new ways of personalized prevention that will benefit large segments of the population will be provided by the project.