Periodic Reporting for period 2 - PRIME (Prevention and Remediation of Insulin Multimorbidity in Europe)
Reporting period: 2021-07-01 to 2022-12-31
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), obesity, and Romano Ward Syndrome (RWS). 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), see Figure.
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 bidirectional phenotypic links of somatic insulin-related conditions and brain disorders in population registers. Such links were also observed for insulin-related and cognitive traits. In addition, we have used genetics to show evidence for novel brain-based insulinopathies. Based on the breadth of correlations between somatic insulinopathies and psychiatric disorders observed in those hypothesis-generating analyses, attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were added to the PRIME disorders of interest.
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 started to differentiate these lines into neuronal precursor cells (NPCs) and into cortical neurons. In addition, we developed iPSC lines from individuals with DM2 and age-matched healthy controls and started functional analyses. Employing mouse models, we showed differences in cognition and behaviour of an experimental model characterised by alterations in insulin signalling (TALLYHO/JngJ) across adolescence, young adulthood, and full maturity in male and female animals compared to control mice. Analogous studies are currently ongoing in an independent experimental model, the APP/PS1 mouse, a validated experimental model resembling features of Alzheimer’s disease.
For objective 3, we have started collecting f a new cohort of patients with Romano Ward Syndrome. Moreover, we have started studying KCNQ1 in the animal models and in the iPSC-derived neurons, and in silico studies have been conducted for known agonists and antagonists for KCNQ1 to investigate the potential for repurposing these drugs. For objective 4, we are in the process of building molecular landscapes, starting with the genetic overlap of AD with MetS, DM2, and obesity. First biological processes involved in the genetic overlap between these disorders have been flagged for further investigation. Data collection for transcriptomics analyses of brain tissue from the animal models has been 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. Data collection has started and is ongoing, also including detailed real-time records of nutritional intake and physical activity.
For objective 7, analyses are still in the preparative or preliminary phase across most work packages. one of the medications for repurposing starting to be tested in animal models is the DM2 medication metformin.
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 on a range of topics. Two masterclasses were held, one where ECRs presented their research plans and received feedback from each other and members of the Scientific Advisory Board, and one where they prepared an elevator pitch. ECRs have been included in a mentoring program, have delineated their learning objectives in a training and supervision plan, and have made plans for secondments within the PRIME consortium.
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 started to differentiate these lines into neuronal precursor cells (NPCs) and into cortical neurons. In addition, we developed iPSC lines from individuals with DM2 and age-matched healthy controls and started functional analyses. Employing mouse models, we showed differences in cognition and behaviour of an experimental model characterised by alterations in insulin signalling (TALLYHO/JngJ) across adolescence, young adulthood, and full maturity in male and female animals compared to control mice. Analogous studies are currently ongoing in an independent experimental model, the APP/PS1 mouse, a validated experimental model resembling features of Alzheimer’s disease.
For objective 3, we have started collecting f a new cohort of patients with Romano Ward Syndrome. Moreover, we have started studying KCNQ1 in the animal models and in the iPSC-derived neurons, and in silico studies have been conducted for known agonists and antagonists for KCNQ1 to investigate the potential for repurposing these drugs. For objective 4, we are in the process of building molecular landscapes, starting with the genetic overlap of AD with MetS, DM2, and obesity. First biological processes involved in the genetic overlap between these disorders have been flagged for further investigation. Data collection for transcriptomics analyses of brain tissue from the animal models has been 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. Data collection has started and is ongoing, also including detailed real-time records of nutritional intake and physical activity.
For objective 7, analyses are still in the preparative or preliminary phase across most work packages. one of the medications for repurposing starting to be tested in animal models is the DM2 medication metformin.
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 on a range of topics. Two masterclasses were held, one where ECRs presented their research plans and received feedback from each other and members of the Scientific Advisory Board, and one where they prepared an elevator pitch. ECRs have been included in a mentoring program, have delineated their learning objectives in a training and supervision plan, and have made plans for secondments within the PRIME consortium.
PRIME is charting new territory with ramifications for care and prevention. Especially knowledge about the involvement of insulin regulation in early-onset neurodevelopmental disorders is novel. Understanding the extent of such problems and getting insight into the underlying mechanisms goes far beyond current state of the art. A first important result of PRIME is that the overlap between insulin-related somatic diseases and brain disorders is considerably broader – both phenotypic and genetic – than expected.
While most experiments are still ongoing, PRIME is already active in preparing to create societal impact: We are studying the potential for (KCNQ1-modulating) drug repurposing, we are identifying additional drug targets through bioinformatic approaches, and we are reviewing clinical guidelines for the treatment of brain disorders and somatic insulin-related diseases, with an eye to including information on insulin dysregulation. Additionally, we are introducing the subject to the scientific community, patients, and the wider public, e.g. through webinars, symposia at congresses, and participation in activities of patient organisations.
While most experiments are still ongoing, PRIME is already active in preparing to create societal impact: We are studying the potential for (KCNQ1-modulating) drug repurposing, we are identifying additional drug targets through bioinformatic approaches, and we are reviewing clinical guidelines for the treatment of brain disorders and somatic insulin-related diseases, with an eye to including information on insulin dysregulation. Additionally, we are introducing the subject to the scientific community, patients, and the wider public, e.g. through webinars, symposia at congresses, and participation in activities of patient organisations.