Insulin secretory deficiency and glucose intolerance in Rab3A Null mice

Kazuro Yaekura, Richard Julyan, Barton L. Wicksteed, Lori B. Hays, Cristina Alarcon, Scott Sommers, Vincent Poitout, Denis G. Baskin, Yong Wang, Louis H. Philipson, Christopher J. Rhodes*

*Corresponding author for this work

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Insulin secretory dysfunction of the pancreatic β-cell in type-2 diabetes is thought to be due to defective nutrient sensing and/or deficiencies in the mechanism of insulin exocytosis. Previous studies have indicated that the GTP-binding protein, Rab3A, plays a mechanistic role in insulin exocytosis. Here, we report that Rab3A-/- mice develop fasting hyperglycemia and upon a glucose challenge show significant glucose intolerance coupled to ablated first-phase insulin release and consequential insufficient insulin secretion in vivo, without insulin resistance. The in vivo insulin secretory response to arginine was similar in Rab3A-/- mice as Rab3A+/+ control animals, indicating a phenotype reminiscent of insulin secretory dysfunction found in type-2 diabetes. However, when a second arginine dose was given 10 min after, there was a negligible insulin secretory response in Rab3A-/- mice, compared with that in Rab3A+/+ animals, that was markedly increased above that to the first arginine stimulus. There was no difference in β-cell mass or insulin production between Rab3A-/- and Rab3A+/+ mice. However, in isolated islets, secretagogue-induced insulin release (by glucose, GLP-1, glyburide, or fatty acid) was ∼60-70% lower in Rab3A-/- islets compared with Rab3A+/+ controls. Nonetheless, there was a similar rate of glucose oxidation and glucose-induced rise in cytosolic [Ca2+]i flux between Rab3A-/- and Rab3A+/+ islet β-cells, indicating the mechanistic role of Rab3A lies downstream of generating secondary signals that trigger insulin release, at the level of secretory granule transport and/or exocytosis. Thus, Rab3A plays an important in vivo role facilitating the efficiency of insulin exocytosis, most likely at the level of replenishing the ready releasable pool of β-granules. Also, this study indicates, for the first time, that the in vivo insulin secretory dysfunction found in type-2 diabetes can lie solely at the level of defective insulin exocytosis.

Original languageEnglish (US)
Pages (from-to)9715-9721
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number11
DOIs
StatePublished - Mar 14 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Insulin secretory deficiency and glucose intolerance in Rab3A Null mice'. Together they form a unique fingerprint.

  • Cite this

    Yaekura, K., Julyan, R., Wicksteed, B. L., Hays, L. B., Alarcon, C., Sommers, S., Poitout, V., Baskin, D. G., Wang, Y., Philipson, L. H., & Rhodes, C. J. (2003). Insulin secretory deficiency and glucose intolerance in Rab3A Null mice. Journal of Biological Chemistry, 278(11), 9715-9721. https://doi.org/10.1074/jbc.M211352200