Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes
| Autor: | Emilia Galli, Jonna Saarimäki-Vire, Diego Balboa, Timo Otonkoski, Mantas Survila, Hanna Huopio, Jarkko Ustinov, Solja Eurola, Päivi Lindholm, Kirmo Wartiovaara, Juha Partanen, Heli Grym, Daniel Borshagovski |
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| Přispěvatelé: | Centre of Excellence in Stem Cell Metabolism, Research Programme for Molecular Neurology, Timo Pyry Juhani Otonkoski / Principal Investigator, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki Institute of Life Science HiLIFE, Joint Activities, Developmental neurogenetics, Biosciences, Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, Molecular and Integrative Biosciences Research Programme, University Management, Children's Hospital, Clinicum, HUS Children and Adolescents |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cell type Insulin gene mutations induced pluripotent stem cells QH301-705.5 Science medicine.medical_treatment mTORC1 Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences ENDOPLASMIC-RETICULUM STRESS beta-cell development Diabetes mellitus Internal medicine REVEALS medicine Biology (General) Induced pluripotent stem cell GENE-EXPRESSION General Immunology and Microbiology UNFOLDED PROTEIN RESPONSE General Neuroscience Insulin General Medicine IN-VITRO ER STRESS medicine.disease DYSFUNCTION 3. Good health 030104 developmental biology medicine.anatomical_structure Endocrinology 3121 General medicine internal medicine and other clinical medicine endoplasmic reticulum stress Medicine 3111 Biomedicine CRISPR-Cas9 Stem cell Beta cell PANCREATIC PROGENITORS Pancreas MUTANT PROINSULIN GENERATION |
| Zdroj: | eLife eLife, Vol 7 (2018) |
| Popis: | Insulin is a hormone that is crucial for maintaining normal blood sugar levels and is produced by so called beta cells in the pancreas. If the beta cells in the body stop making insulin, blood sugar levels start to rise, which can lead to diabetes. A form of diabetes known as neonatal diabetes, where the body stops making insulin, usually appears during the first six months of life. Infants affected by this early onset of diabetes often have mutations in one copy of the gene that encodes insulin. This means that they can still produce half of the amount of insulin, but it is not enough to keep blood sugar stable. Instead, insulin production stops completely after a few months. Scientists believe that this is because the mutant insulin has a toxic effect on beta cells. Mutations in the insulin gene can affect the structure of insulin. As a result, insulin accumulates inside the beta cells, which stresses them and eventually makes them fail. The mechanisms behind this process are still unclear. Now, Balboa et al. used stem cells (which can turn into other cell types) taken from patients with this rare type of insulin mutation to find out more. They corrected the mutant insulin gene in these stem cells with a technique called CRISPR and then induced the mutant and corrected stem cells to turn into beta cells. The results showed that the mutant beta cells slowed down their rate of cell division but did not die more frequently. When the cells were implanted into mice their growth and development changed. The mutant cells were more stressed and smaller than the cells with the repaired genes. They also had fewer signalling molecules that help cells grow. As a consequence, the cells were struggling to grow and mature. Although this type of diabetes is rare, beta cells come under stress in other forms of the disease. In a separate study, Riahi et al. found that boosting molecular signals for cell growth could protect beta cells in mice with mutant insulin. If this could also work in humans, it may lead to new ways to prevent diabetes. |
| Databáze: | OpenAIRE |
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