The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic β-cell dysfunction

Erik J. Zmuda, Ling Qi, Michael X. Zhu, Raghu Mirmira, Marc R. Montminy, Tsonwin Hai

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Abstract

Most people with type 2 diabetes (T2D) have reduced β-cell mass, and apoptosis is a key factor for this reduction. Previously, we showed that ATF3, an adaptive-response gene, is induced by various stress signals relevant to T2D, such as high glucose and high fatty acid. Because ATF3 is proapoptotic in β-cells, we tested the hypothesis that ATF3 plays a detrimental role and contributes to the development of T2D. We compared wild-type (WT) and ATF3 knockout (KO) mice in an animal model for T2D, high-fat diet-induced diabetes. We also used INS-1 β-cells and primary islets to analyze the roles of ATF3 in β-cell function, including insulin gene expression and glucose-induced insulin secretion. Surprisingly, WT mice performed better in glucose tolerance test than KO mice, suggesting a protective, rather than detrimental, role of ATF3. At 12 wk on high-fat diet, no β-cell apoptosis was observed, and the WT and KO mice had comparable β-cell areas. However, ATF3 deficiency significantly reduced serum insulin levels in the KO mice without affecting insulin sensitivity, suggesting reduced β-cell function in the KO mice. Analyses using INS-1 cells and primary islets support the notion that this defect is due, at least partly, to reduced insulin gene transcription in the KO islets without detectable reduction in glucose-induced calcium influx, a critical step for insulin secretion. In conclusion, our results support a model in which, before apoptosis becomes obvious, expression of ATF3 can be beneficial by helping β-cells to cope with higher metabolic demand.

Original languageEnglish
Pages (from-to)1423-1433
Number of pages11
JournalMolecular Endocrinology
Volume24
Issue number7
DOIs
StatePublished - 2010

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High Fat Diet
Knockout Mice
Type 2 Diabetes Mellitus
Insulin
Genes
Apoptosis
Islets of Langerhans
Glucose
Glucose Tolerance Test
Insulin Resistance
Fatty Acids
Animal Models
Calcium
Gene Expression
Serum

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology
  • Medicine(all)

Cite this

The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic β-cell dysfunction. / Zmuda, Erik J.; Qi, Ling; Zhu, Michael X.; Mirmira, Raghu; Montminy, Marc R.; Hai, Tsonwin.

In: Molecular Endocrinology, Vol. 24, No. 7, 2010, p. 1423-1433.

Research output: Contribution to journalArticle

Zmuda, Erik J. ; Qi, Ling ; Zhu, Michael X. ; Mirmira, Raghu ; Montminy, Marc R. ; Hai, Tsonwin. / The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic β-cell dysfunction. In: Molecular Endocrinology. 2010 ; Vol. 24, No. 7. pp. 1423-1433.
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