Journal
DIABETES
Volume 69, Issue 6, Pages 1178-1192Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db19-0951
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-104998, R01-DK-090490]
- National Institute of Neurological Disorders and Stroke training grant [T32NS45549]
- Fraternal Order of Eagles Diabetes Research Center
- American Diabetes Association [1-17-IBS-132]
- National Institute of Diabetes and Digestive and Kidney Diseases, Integrated Islet Distribution Program at City of Hope [2UC4-DK-098085]
- National Institutes of Health [1 S10 RR025439-01, 1 S10 RR018998-01]
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Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse beta-cells, LDs are prominent in human beta-cells. However, the regulation of LD mobilization (lipolysis) in human beta-cells remains unclear. We found that glucose increases lipolysis in nondiabetic human islets but not in islets in patients with type 2 diabetes (T2D), indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets with shRNA targeting ATGL (shATGL) increased triglycerides (TGs) and the number and size of LDs, indicating that ATGL is the principal lipase in human beta-cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS), and insulin secretion to 3-isobutyl-1-methylxanthine and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose-responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL-deficient INS1 cells and human pseudoislets showed reduced SNARE protein syntaxin 1a (STX1A), a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL-deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human beta-cells and supports insulin secretion by stabilizing STX1A. The dysregulated lipolysis may contribute to LD accumulation and beta-cell dysfunction in T2D islets.
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