Insulin Release
We are studying the release of insulin from pancreatic β-cells by exocytosis of insulin granules. Exocytosis is accomplished by SNARE-mediated membrane fusion and controlled by calcium. We found that β-cells contain two types of insulin granules with different properties, lipid and protein contents, and different sensitivities of membrane fusion to calcium. Interestingly, high affinity calcium granules are released from cells under type 1 diabetes (T1D) conditions and low affinity calcium granules are released from cells under type 2 diabetes (T2D) conditions, whereas healthy cells secrete insulin from both types of granules. The calcium sensor synaptotagmin activates SNAREs for fusion by a lipid-mediated mechanism that is hypothesized to include plasma membrane PIP2 in the vicinity of docked insulin granules.
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Recent Key Publications:
Amos C, Kiessling V, Kreutzberger AJB, Schenk NA, Mohan R, Nyenhuis S, Doyle CA, Wang H-J, Levental K, Levental I, Anantharam A, Tamm LK (2024). Membrane lipids couple synaptotagmin to SNARE-mediated granule fusion in insulin-secreting cells. Mol Biol Cell 35:1-12. doi: https://doi.org/10.1091/mbc.E23-06-0225 (https://pubmed.ncbi.nlm.nih.gov/38117594/)
Kreutzberger AJB, Kiessling V, Doyle CA, Schenk N, Upchurch CM, Elmer-Dixon M, Ward AE, Preobraschenski J, Hussain SS, Tomaka W, Seelheim P, Kattan I, Harris M, Liang B, Kenworthy AK, Desai BN, Leitinger N, Anantharam A, Castle JD, Tamm LK (2020) Distinct insulin granules reveal molecular machinery underlying secretory pathology of diabetes. Elife, Epub:( https://elifesciences.org/articles/62506)
Kreutzberger AJB, Kiessling V, Stroupe C, Liang B, Preobraschenski J, Ganzella M, Kreutzberger MAB, Nakamoto R, Jahn R, Castle JD, Tamm LK. In vitro fusion of single synaptic and dense core vesicles reproduces key physiological properties. Nat Commun. 2019 Aug 29;10(1):3904. doi: 10.1038/s41467-019-11873-8. (https://www.ncbi.nlm.nih.gov/pubmed/31467284)