Insulin secretory deficiency and glucose intolerance in Rab3A null mice.
Insulin secretory dysfunction of the pancreatic beta-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 beta-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 approximately 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 [Ca(2+)](i) flux between Rab3A(-/-) and Rab3A(+/+) islet beta-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 beta-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.
Yaekura
Kazuro
K
Pacific Northwest Research Institute and Departments of Pharmacology and Medicine, University of Washington, Seattle, Washington 98122, USA.
Julyan
Richard
R
Wicksteed
Barton L
BL
Hays
Lori B
LB
Alarcon
Cristina
C
Sommers
Scott
S
Poitout
Vincent
V
Baskin
Denis G
DG
Wang
Yong
Y
Philipson
Louis H
LH
Rhodes
Christopher J
CJ
D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018149:Glucose Intolerance; D006943:Hyperglycemia; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011384:Proinsulin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D020826:rab3A GTP-Binding Protein / Q000737:chemistry* / Q000235:genetics*
D007328:Insulin; D012333:RNA, Messenger; D011384:Proinsulin; D001120:Arginine; D020826:rab3A GTP-Binding Protein; D005947:Glucose; D010100:Oxygen