Abstract
1458-P: Lipophagy Is Constitutively Active in Pancreatic Beta Cells and Maintains Insulin Secretion
Diabetes (New York, N.Y.), Vol.71(Supplement_1)
06/01/2022
DOI: 10.2337/db22-1458-P
Abstract
Lipid droplets (LDs) , organelles important for intracellular lipid metabolism, are actively formed in rat and human adult beta cells and affect islet function and health. Acute mobilization of LDs by adipose triglyceride lipase in beta cells is known to support insulin secretion. As LD degradation by lysosomal acid lipase (LIPA) through lipophagy is an alternative pathway for LD catabolism, we addressed whether LIPA regulates beta cell function. LDs in human beta cells are associated with autophagy (LC3) and lysosomal (LAMP1) markers. LIPA suppression via siRNA and LIPA inhibitor (lalistat2) in INS1 cells increased LD size (DMSO 0.5 vs. Lali2 1.5 µm2/cell, p<0.05, p value by Student's t test unless specified otherwise) and number (Scr 2/cell vs. siLIPA 14/cell, p<0.05; DMSO 4.5/cell vs. Lali2 16/cell, p<0.05) . Rat and human beta cells treated with Lali2 also showed increased in LD area and/or number of LDs per cell (p<0.05) . In all three models, LIPA suppression increased TG contents confirming constitutively active lipophagy. While acute inhibition of LIPA by Lali2 had little effect on glucose-stimulated insulin secretion (GSIS) , chronic (over 48 h) LIPA suppression by Lali2 or siRNA reduced GSIS from INS1 cells, rat islets, and human islets. Lentiviral shRNA transduction in human pseudoislets decreased insulin secretion in response to glucose (41 ± 10.5% of Scr, p<0.05) and to KCl (61.3 ±16.1% of Scr, p<0.05) in vitro. When Scr and shLIPA human pseudoislets were transplanted under kidney capsules of NSG mice on Western diet, human insulin secretion in response to intraperitoneal glucose load was blunted in mice carrying shLIPA islets compared with shScr control (2-Way ANOVA, p<0.05) . In summary, lipophagy is constitutively active in human and rat beta cells and serves as a pathway for LD catabolism that is acutely insensitive to glucose. However, LIPA mediated LD catabolism is needed for beta cell function in a long-term.
Details
- Title: Subtitle
- 1458-P: Lipophagy Is Constitutively Active in Pancreatic Beta Cells and Maintains Insulin Secretion
- Creators
- Siming Liu - Iowa City, IABrianna Brennecke - Iowa City, IAUseong Yang - Iowa City, IAJames Ankrum - Iowa City, IAYumi Imai - Iowa City, IA
- Resource Type
- Abstract
- Publication Details
- Diabetes (New York, N.Y.), Vol.71(Supplement_1)
- Publisher
- American Diabetes Association
- DOI
- 10.2337/db22-1458-P
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 06/01/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984363159502771
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