Journal article
Acute Inhibition of Adipose Triglyceride Lipase by NG497 Dysregulates Insulin and Glucagon Secretion from Human Islets
Endocrinology (Philadelphia), Vol.166(7), bqaf090
05/19/2025
DOI: 10.1210/endocr/bqaf090
PMCID: PMC12119457
PMID: 40354133
Appears in UI Libraries Support Open Access
Abstract
Adipose triglyceride lipase (ATGL), which catalyzes the breakdown of triglycerides in lipid droplets (LDs), plays a critical role in releasing fatty acids to support insulin secretion in pancreatic beta cells. Based on genetic downregulation of ATGL in beta cells, multiple mechanisms are proposed that acutely or chronically regulate insulin secretion. Currently, the contribution of acute versus chronic mechanisms in the regulation of insulin secretion is unclear. Also, little is known whether ATGL affects alpha cell function. Using the human-specific ATGL inhibitor, NG497, this study investigates the impact of acute inhibition of ATGL on hormone secretion from human islets. In addition, morphological differences in LDs were assessed in confocal images of beta and alpha cells. Beta cells exposed to NG497 overnight showed notable increases in LD size and number under glucose-sufficient culture. The effect of NG497 on LD accumulation in alpha cells was more prominent under fasting-simulated conditions than glucose-sufficient conditions, pointing toward a critical role for ATGL lipolysis under conditions that stimulate hormone secretion in beta and alpha cells. When exposed to NG497 acutely, human islets reduced glucose-stimulated insulin secretion mildly, particularly first-phase insulin secretion, to an extent somewhat less pronounced than the impacts of chronic ATGL downregulation. Thus, chronic mechanisms may play a predominant role in reducing insulin secretion when ATGL is downregulated. Acute exposure of human islets to NG497 significantly reduced amino acid stimulated glucagon secretion at low glucose concentration, highlighting an important potential role of ATGL lipolysis in promoting hormone secretion acutely from alpha cells.
Details
- Title: Subtitle
- Acute Inhibition of Adipose Triglyceride Lipase by NG497 Dysregulates Insulin and Glucagon Secretion from Human Islets
- Creators
- Lucy B Kim - University of IowaSiming Liu - Iowa City Veterans Affairs Medical Center, Iowa City, IA, USASyreine Richtsmeier - University of IowaMichał Górniak - Warsaw University of Life SciencesAnamika Vikram - University of IowaYumi Imai - Iowa City Veterans Affairs Medical Center, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Endocrinology (Philadelphia), Vol.166(7), bqaf090
- DOI
- 10.1210/endocr/bqaf090
- PMID
- 40354133
- PMCID
- PMC12119457
- NLM abbreviation
- Endocrinology
- ISSN
- 1945-7170
- eISSN
- 1945-7170
- Publisher
- Oxford University Press
- Grant note
- National Institutes of Health: R01-DK090490 Department of Veteran Affairs: I01 BX005107 Fraternal Orders of Eagles Diabetes Research Center at the University of Iowa - Roy J. Carver Charitable TrustErasmus + mobility exchange program: KA 131 NIDDK-funded Integrated Islet Distribution Program: RRID:SCR _014387, U24DK098085
Y.I. is supported by the National Institutes of Health (R01-DK090490), Department of Veteran Affairs (I01 BX005107), and Fraternal Orders of Eagles Diabetes Research Center at the University of Iowa. A Zeiss 980 confocal microscope located in the University of Iowa Central Microscopy Research Facility (CMRF) was funded by the Roy J. Carver Charitable Trust. M.G. was supported by the Erasmus + mobility exchange program (KA 131). A part of human pancreatic islets was provided by the NIDDK-funded Integrated Islet Distribution Program (RRID:SCR _014387) at City of Hope, NIH Grant # U24DK098085. Human islets were also provided by the Alberta Diabetes Institute Islet Core at the University of Alberta in Edmonton with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN), and other Canadian organ procurement organizations.
- Language
- English
- Electronic publication date
- 05/12/2025
- Date published
- 05/19/2025
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984822962002771
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