Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2
| Autor: | Syed S Hussein, Anne K. Kenworthy, Megan T. Harris, Alex J. B. Kreutzberger, Margaret Elmer-Dixon, Arun Anantharam, Volker Kiessling, Bimal N. Desai, Julia Preobraschenski, Iman Kattan, Norbert Leitinger, Noah A. Schenk, Amanda E. Ward, Patrick Seelheim, Catherine A. Doyle, Clint M Upchurch, Binyong Liang, J. David Castle, Weronika Tomaka, Lukas K. Tamm |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
fusion medicine.medical_treatment Palmitates Type 2 diabetes PC12 Cells Synaptotagmins 0302 clinical medicine Insulin-Secreting Cells Biology (General) Secretory Pathway diabetes Chemistry General Neuroscience Granule (cell biology) General Medicine Sphingomyelins 3. Good health secretion Cholesterol Medicine Cytokines medicine.symptom SNARE Proteins Research Article Human insulin medicine.medical_specialty Cell type QH301-705.5 Science Blood sugar Inflammation Exocytosis General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Internal medicine Diabetes mellitus medicine Animals Humans Type 1 diabetes General Immunology and Microbiology Insulin Cell Biology medicine.disease Rats synaptotagmin Diabetes Mellitus Type 1 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Calcium 030217 neurology & neurosurgery |
| Zdroj: | eLife eLife, Vol 9 (2020) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.62506 |
| Popis: | Insulin secretion from β-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of β-cells elicit secretory defects associated with type-1 or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics. We show that this behavior is correlated with two subpopulations of insulin granules whose relative abundance is differentially shifted depending on diabetic model condition. The two types of granules have different release characteristics, distinct lipid and protein compositions, and package different secretory contents alongside insulin. This complexity of β-cell secretory physiology establishes a direct link between granule subpopulation and type of diabetes and leads to a revised model of secretory changes in the diabetogenic process. eLife digest Diabetes is a disease that occurs when sugar levels in the blood can no longer be controlled by a hormone called insulin. People with type 1 diabetes lose the ability to produce insulin after their immune system attacks the β-cells in their pancreas that make this hormone. People with type 2 diabetes develop the disease when β-cells become exhausted from increased insulin demand and stop producing insulin. β-cells store insulin in small compartments called granules. When blood sugar levels rise, these granules fuse with the cell membrane allowing β-cells to release large quantities of insulin at once. This fusion is disrupted early in type 1 diabetes, but later in type 2: the underlying causes of these disruptions are unclear. In the laboratory, signals that trigger inflammation and molecules called fatty acids can mimic type 1 or type 2 diabetes respectively when applied to insulin-producing cells. Kreutzberger, Kiessling et al. wanted to know whether pro-inflammatory molecules and fatty acids affect insulin granules differently at the molecular level. To do this, insulin-producing cells were grown in the lab and treated with either fatty acids or pro-inflammatory molecules. The insulin granules of these cells were then isolated. Next, the composition of the granules and how they fused to lab-made membranes that mimic the cell membrane was examined. The experiments revealed that healthy β-cells have two types of granules, each with a different version of a protein called synaptotagmin. Cells treated with molecules mimicking type 1 diabetes lost granules with synaptotagmin-7, while granules with synaptotagmin-9 were lost in cells treated with fatty acids to imitate type 2 diabetes. Each type of granule responded differently to calcium levels in the cell and secreted different molecules, indicating that each elicits a different diabetic response in the body. These findings suggest that understanding how insulin granules are formed and regulated may help find treatments for type 1 and 2 diabetes, possibly leading to therapies that reverse the loss of different types of granules. Additionally, the molecules of these granules may also be used as markers to determine the stage of diabetes. More broadly, these results show how understanding how molecule release changes with disease in different cell types may help diagnose or stage a disease. |
| Databáze: | OpenAIRE |
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