In:
Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
Abstract:
Aims: ACC1 couples glucose metabolism with de novo lipogenesis in lipogenic tissues, by converting acetyl-CoA to malonyl-CoA. In β-cells, ACC1 plays a critical role in β-cell growth and insulin secretion. However, very little is known about ACC1 regulation in β-cell. The aims of this study were to 1) assess the role of ACC1S79 in β-cell function and whole body glucose homeostasis; and 2) screen for novel phosphosites that may regulate ACC1 activity in β-cell. Methods: 1) ACC1 single knock-in mouse model, with ACC1S79 mutated to alanine ACC1S79A, was obtained by crossing ACC1 double knock-in mice with wild type mice to isolate the ACC1S79A point mutation. 2) ACC1 protein was purified from INS1 β-cell following culture with different glucose concentrations. Quantitative phosphoproteomics was performed to characterise ACC1 phosphosites using a Q-Executive MS. Data analysed using MaxQuant and Perseus. Results: 1) Female ACC1S79A mice exhibited no alternations in glucose homeostasis. In male mice we found no differences in serum insulin, GTT or ITT, although a small but significant reduction in fasting blood glucose was recorded in ACC1S79A mice compared to littermate controls. There was no significant change in GSIS from isolated ACC1S79A islets at 2mM glucose or in response to 7.5 and 20mM glucose, suggesting that ACC1S79 phosphorylation does not play a role in insulin secretion under physiological conditions.2) Using phosphoproteomics, we identified twenty phosphosites on ACC1 protein in β-cells. ACC1S1215 was highly phosphorylated at 2mM glucose, and showed a significant reduction in phosphorylation in response to 15mM glucose. In contrast, phosphorylation of ACC1S25 was lower at basal glucose and increased upon glucose stimulation. Conclusions: Our data show that ACC1S79 phosphorylation does not play a major role as a glucose-regulated phosphosite in β-cells. However, other phosphosites show greater dynamic regulation by glucose and may play a role in regulating β-cell ACC1 activity. Disclosure R. Bany bakar: None. S. Liberatori: Employee; Self; LONZA. A. Veprik: None. N. N. Tebeka: None. B. E. Kemp: None. S. Mohammed: None. J. Cantley: Other Relationship; Self; Oxstem Beta.
Type of Medium:
Online Resource
ISSN:
0012-1797
,
1939-327X
Language:
English
Publisher:
American Diabetes Association
Publication Date:
2021
detail.hit.zdb_id:
1501252-9
