Periodic Reporting for period 4 - PRIME (Prevention and Remediation of Insulin Multimorbidity in Europe)
Período documentado: 2024-07-01 hasta 2024-12-31
PRIME addresses insulin signalling as a novel and key modulator of comorbid mental and non-mental diseases. Dysregulation of insulin signalling has been implicated in multimorbidity across the lifespan, in particular in type 2 diabetes (DM2), metabolic syndrome (MetS), and obesity. Altered insulin signalling has also been implicated in neurodegenerative disorders. In PRIME, we investigated whether the spectrum of brain-based ‘insulinopathies’ is broader, and extended it to neurodevelopmental and other mental disorders.
We hypothesized that the prevalence estimates for insulin-related multimorbidity are strong underestimates. Currently, the recognition and clinical management of insulin comorbidity remains poorly established; brain-based comorbidity is generally neglected, and medical efforts are only devoted towards the management of the primary somatic diagnoses.
The overall aim of PRIME was to identify and specify the molecular mechanisms underlying insulin multimorbidities, and to outline new directions for research and clinical care. Our objectives were:
1. Expand our knowledge of insulin multimorbidity patterns across the lifespan and in different subgroups of the population.
2. Delineate the molecular and cellular mechanisms underlying mental and non-mental insulin multimorbidity.
3. Study the role of KCNQ1, as a key molecule in insulin regulation, across different levels of organismal organisation.
4. Identify and validate novel biomarkers for diagnosis and/or disease monitoring.
5. Develop data-driven prediction models to enable an early diagnosis and prediction of the prognosis of insulin multimorbidities using machine learning methods.
6. Identify non-pharmacological preventive and treatment strategies
7. Develop and test repurposed and novel pharmacological therapeutic strategies.
8. Outline new directions for research and clinical care of insulin multimorbidities.
9. Train practicing clinicians and a new generation of interdisciplinary researchers in research communication and in translating research findings into society.
We hypothesized that the prevalence estimates for insulin-related multimorbidity are strong underestimates. Currently, the recognition and clinical management of insulin comorbidity remains poorly established; brain-based comorbidity is generally neglected, and medical efforts are only devoted towards the management of the primary somatic diagnoses.
The overall aim of PRIME was to identify and specify the molecular mechanisms underlying insulin multimorbidities, and to outline new directions for research and clinical care. Our objectives were:
1. Expand our knowledge of insulin multimorbidity patterns across the lifespan and in different subgroups of the population.
2. Delineate the molecular and cellular mechanisms underlying mental and non-mental insulin multimorbidity.
3. Study the role of KCNQ1, as a key molecule in insulin regulation, across different levels of organismal organisation.
4. Identify and validate novel biomarkers for diagnosis and/or disease monitoring.
5. Develop data-driven prediction models to enable an early diagnosis and prediction of the prognosis of insulin multimorbidities using machine learning methods.
6. Identify non-pharmacological preventive and treatment strategies
7. Develop and test repurposed and novel pharmacological therapeutic strategies.
8. Outline new directions for research and clinical care of insulin multimorbidities.
9. Train practicing clinicians and a new generation of interdisciplinary researchers in research communication and in translating research findings into society.
For objective 1, we found that insulin resistance-related somatic diseases and traits are linked to brain-based disorders and to cognitive performance. Based on population registry data and large-scale genetic data, we showed that the breadth of this multimorbidity is even larger than anticipated at the start of the PRIME project, additionally including attention deficit/hyperactivity disorder, major depressive disorder, anorexia nervosa, and schizophrenia. Longitudinal data revealed that T2D, insulin-related and inflammation-related markers all associate with cognitive decline.
For objective 2, we performed (epi)genetic analyses and showed that genetic variants related to insulin and immunity are associated with insulin multimorbidity. Furthermore, we generated KCNQ1 knockout induced pluripotent stem cell (iPSC)-based lines to investigate KCNQ1 function in human neurons, showing that knockout of KCNQ1 leads to less neurite outgrowth and differences in immune-related mechanisms, insulin signalling, and mitochondrial function. Employing mouse models, we showed differences in cognition and behaviour in experimental models characterised by alterations in insulin signalling. In the brains of these animals, we found differences in proteins related to the immune system. Lastly, we showed that a mouse model centered around impaired immune activation (also) exhibits both altered insulin signaling and impairments in cognition.
For objective 3, we investigated the role of KCNQ1 across human, cell, and animal data. In the human data, we confirmed the association with T2D, but found no associations with psychiatric disorders or cognition. With the animal work, we found links between KCNQ1 and metabolism and cognition. In the cell models, we showed that KCNQ1 is essential for brain cell growth. We also identified KCNQ1-modulating compounds that could be promising treatments.
For objective 4, we integrated genetic data in a molecular landscaping approach, and linked genetic data to potential immune-related and antidiabetic drug targets. Using animal and cell models we showed that metformin, a drug frequently used in T2D, normalises the biological pathways dysregulated in T2D and improves cognition.
For objective 5, we worked on designing a multimorbidity subtyping algorithm and tested it on different data sets. While we found some predictors, their influence was not as strong and stable as we initially hoped for.
For objective 6, we used the mHealth APP in order to study cognitive performance in real time. Our results indicate that diet and physical activity both can have positive influences on cognition and are promising for preventive strategies.
For objective 7, our results showed that repurposing of insulin signalling-targeted drugs for the treatment of mental phenotypes is effective in human and animal data.
For objective 8, we have conducted a systematic review of existing guidelines and then systematically compiled all clinically relevant findings from PRIME. The insights gained from this were synthesized into a white paper. This document has been made available to guideline committees and policymakers, providing a valuable foundation for future clinical recommendations.
For objective 9, PRIME early career researchers have been trained in different aspects of interdisciplinary knowledge through webinars, masterclasses, a mentoring program, and site visits. In addition, we prepared an e-learning course for clinicians about the co-occurrence of cardiometabolic and mental diseases, which is available online and free of charge.
For objective 2, we performed (epi)genetic analyses and showed that genetic variants related to insulin and immunity are associated with insulin multimorbidity. Furthermore, we generated KCNQ1 knockout induced pluripotent stem cell (iPSC)-based lines to investigate KCNQ1 function in human neurons, showing that knockout of KCNQ1 leads to less neurite outgrowth and differences in immune-related mechanisms, insulin signalling, and mitochondrial function. Employing mouse models, we showed differences in cognition and behaviour in experimental models characterised by alterations in insulin signalling. In the brains of these animals, we found differences in proteins related to the immune system. Lastly, we showed that a mouse model centered around impaired immune activation (also) exhibits both altered insulin signaling and impairments in cognition.
For objective 3, we investigated the role of KCNQ1 across human, cell, and animal data. In the human data, we confirmed the association with T2D, but found no associations with psychiatric disorders or cognition. With the animal work, we found links between KCNQ1 and metabolism and cognition. In the cell models, we showed that KCNQ1 is essential for brain cell growth. We also identified KCNQ1-modulating compounds that could be promising treatments.
For objective 4, we integrated genetic data in a molecular landscaping approach, and linked genetic data to potential immune-related and antidiabetic drug targets. Using animal and cell models we showed that metformin, a drug frequently used in T2D, normalises the biological pathways dysregulated in T2D and improves cognition.
For objective 5, we worked on designing a multimorbidity subtyping algorithm and tested it on different data sets. While we found some predictors, their influence was not as strong and stable as we initially hoped for.
For objective 6, we used the mHealth APP in order to study cognitive performance in real time. Our results indicate that diet and physical activity both can have positive influences on cognition and are promising for preventive strategies.
For objective 7, our results showed that repurposing of insulin signalling-targeted drugs for the treatment of mental phenotypes is effective in human and animal data.
For objective 8, we have conducted a systematic review of existing guidelines and then systematically compiled all clinically relevant findings from PRIME. The insights gained from this were synthesized into a white paper. This document has been made available to guideline committees and policymakers, providing a valuable foundation for future clinical recommendations.
For objective 9, PRIME early career researchers have been trained in different aspects of interdisciplinary knowledge through webinars, masterclasses, a mentoring program, and site visits. In addition, we prepared an e-learning course for clinicians about the co-occurrence of cardiometabolic and mental diseases, which is available online and free of charge.
The PRIME project is pioneering in terms of its expected impacts on the care and prevention of insulin resistance-related multimorbidity. Our findings on the involvement of insulin regulation in early-onset neurodevelopmental disorders are particularly novel. Understanding the extent of the insulin-brain disorder multimorbidity and getting insights into the underlying mechanisms goes beyond the current state of the art. Firstly, PRIME clarified that the overlap between insulin-related somatic diseases and brain disorders is considerably broader – both phenotypic and genetic – than expected. We also advanced understanding of the underlying molecular mechanisms, which includes insulin- and immune-related signaling. Our results also highlight the potential for (KCNQ1-modulating) drug repurposing, and identified additional biomarkers and drug targets. In addition, we provided a white paper with a foundation for future clinical recommendations for the treatment of brain disorders and somatic insulin-related diseases, based on the PRIME results. Lastly, we are actively disseminating our results to the scientific community, patients, and the wider public, e.g. through webinars, conferences, and participation in activities of patient organisations, and we created an e-learning module for clinicians to strengthen clinical impact of our findings.