Periodic Reporting for period 3 - PRIME (Prevention and Remediation of Insulin Multimorbidity in Europe)
Reporting period: 2023-01-01 to 2024-06-30
PRIME addresses insulin signalling as a novel and key modulator of comorbid mental and nonmental 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 brain disorders, dementias and Alzheimer disease (AD) in particular. Our own work has suggested that the spectrum of brain-based ‘insulinopathies’ is broader, also extending to compulsivity-linked, neurodevelopmental disorders (obsessive compulsive disorder (OCD) and autism spectrum disorders (ASDs).
The somatic diseases linked to altered insulin signalling affect over 20% of the population; these
prevalence estimates for insulin-related multimorbidity may be strong underestimates. At the current time, 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 is to identify and specify the molecular mechanisms underlying insulin
multimorbidities, and to outline new directions for research and clinical care of those. Our specific objectives are:
1. Expand our knowledge of insulin multimorbidity patterns across the lifespan and in different subgroups of the population.
2. Delineate the molecular and cellular causal mechanisms underlying mental and non-mental insulin multimorbidity.
3. Study the role of KCNQ1, as a key molecule in insulin regulation, in insulinopathies 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 who are strong in research communication and able to translate research findings into products that benefit society.
The somatic diseases linked to altered insulin signalling affect over 20% of the population; these
prevalence estimates for insulin-related multimorbidity may be strong underestimates. At the current time, 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 is to identify and specify the molecular mechanisms underlying insulin
multimorbidities, and to outline new directions for research and clinical care of those. Our specific objectives are:
1. Expand our knowledge of insulin multimorbidity patterns across the lifespan and in different subgroups of the population.
2. Delineate the molecular and cellular causal mechanisms underlying mental and non-mental insulin multimorbidity.
3. Study the role of KCNQ1, as a key molecule in insulin regulation, in insulinopathies 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 who are strong in research communication and able to translate research findings into products that benefit society.
For objective 1, we have found that insulin resistance-related somatic diseases are linked to brain-based disorders and to cognitive performance. Based on population registry data as well as large-scale genetic data, we were able to show that the breath of this multimorbidity is even larger than anticipated at the start of the PRIME project, including also attention deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anorexia nervosa (AN) and schizophrenia (SCZ).
For objective 2, we have performed genetic analyses in the world-wide largest genome-wide
genetic datasets and showed amongst other that genetic variants related to insulin and immunity
are associated with mental and non-mental insulin multimorbidity. Furthermore, we have generated
KCNQ1 knockout induced pluripotent stem cell-based (iPSC) lines to investigate KCNQ1 function
in human neurons, and these have shown us that knockout of KCNQ1 leads to less neurite outgrowth, indicating another link between insulin signaling and brain function. Employing mouse models, we showed differences in cognition and behaviour in experimental models characterised by alterations in insulin signalling (TALLYHO/JngJ and KCNQ1 knock-out). Within the brains of these animals, we also found differences in proteins related to the immune system. Lastly, we showed that a mouse model centered around impaired immune activation indeed (also) exhibits both altered insulin signaling as well as impairments in cognition. .
For objective 3, we have investigated the role of KCNQ1 across human data, cell data and animal data. In the human data we confirm the association between KCNQ1 and DM2, but do not find associations with psychiatric disorders. Analyses with cognition are still ongoing. Within the animal work, we found links between KCNQ1 and metabolism as well as cognition. In the cell models, we showed that KCNQ1 is essential for normal brain cell growth. Within the project, we have also identified KCNQ1-modulation compounds that could be promising treatments.
For objective 4, we used the molecular landscape approach that flagged biological processes for further investigation. To validate our findings ,transcriptomic analyses of brain tissue from the animal models and cellshave started.
For objective 5, we are designing a multimorbidity subtyping algorithm and have tested the algorithm on different data sets.
For objective 6, the mHealth APP for use in PRIME has been finalized (PRIME-DM2 APP) in order
to study cognitive performance in real time. First results indicate that physical activity is a promising target for preventive strategies.
For objective 7, first results show that repurposing of insulin signaling-targeted drugs for the treatment of mental phenotypes is effective in human and animal data.
For objective 8, we have started with a review of existing guidelines. Recommendations will depend
on findings/results to come available in the experimental work packages.
For objective 9, PRIME early career researchers (ECRs) have been trained in different aspects of
interdisciplinary knowledge through webinars, masterclasses, a mentoring program and site visits through secondments.
For objective 2, we have performed genetic analyses in the world-wide largest genome-wide
genetic datasets and showed amongst other that genetic variants related to insulin and immunity
are associated with mental and non-mental insulin multimorbidity. Furthermore, we have generated
KCNQ1 knockout induced pluripotent stem cell-based (iPSC) lines to investigate KCNQ1 function
in human neurons, and these have shown us that knockout of KCNQ1 leads to less neurite outgrowth, indicating another link between insulin signaling and brain function. Employing mouse models, we showed differences in cognition and behaviour in experimental models characterised by alterations in insulin signalling (TALLYHO/JngJ and KCNQ1 knock-out). Within the brains of these animals, we also found differences in proteins related to the immune system. Lastly, we showed that a mouse model centered around impaired immune activation indeed (also) exhibits both altered insulin signaling as well as impairments in cognition. .
For objective 3, we have investigated the role of KCNQ1 across human data, cell data and animal data. In the human data we confirm the association between KCNQ1 and DM2, but do not find associations with psychiatric disorders. Analyses with cognition are still ongoing. Within the animal work, we found links between KCNQ1 and metabolism as well as cognition. In the cell models, we showed that KCNQ1 is essential for normal brain cell growth. Within the project, we have also identified KCNQ1-modulation compounds that could be promising treatments.
For objective 4, we used the molecular landscape approach that flagged biological processes for further investigation. To validate our findings ,transcriptomic analyses of brain tissue from the animal models and cellshave started.
For objective 5, we are designing a multimorbidity subtyping algorithm and have tested the algorithm on different data sets.
For objective 6, the mHealth APP for use in PRIME has been finalized (PRIME-DM2 APP) in order
to study cognitive performance in real time. First results indicate that physical activity is a promising target for preventive strategies.
For objective 7, first results show that repurposing of insulin signaling-targeted drugs for the treatment of mental phenotypes is effective in human and animal data.
For objective 8, we have started with a review of existing guidelines. Recommendations will depend
on findings/results to come available in the experimental work packages.
For objective 9, PRIME early career researchers (ECRs) have been trained in different aspects of
interdisciplinary knowledge through webinars, masterclasses, a mentoring program and site visits through secondments.
The PRIME project is pioneering, in terms of its expected impacts on the care and prevention of insulin-resistance related multimorbidity. The involvement of insulin regulation in early-onset neurodevelopmental disorders is 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. Further, our results have considerably added to our understanding of the molecular mechanisms – including insulin- and immune-related signaling – underlying this overlap. Moreover, our results highlight the potential for (KCNQ1-modulating) drug repurposing, and we are identifying additional biomarkers and drug targets. In addition, we are reviewing clinical guidelines for the treatment of brain disorders and somatic insulin-related diseases, with the aim of including information on insulin dysregulation in these guidelines. Lastly, we are actively disseminating our results to the scientific community, patients, and the wider public, e.g. through webinars, symposia at congresses, and participation in activities of patient organisations.