Abstract
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.
Highlights
Insulin is the major anabolic hormone controlling metabolic homeostasis, and without an effective supply of insulin diabetes mellitus ensues
The insulin secretory dysfunction in type-2 diabetes is derived from -cell secretory abnormalities, proposed to be either at the level irregular glucose metabolism required for generating secondary signals necessary to trigger insulin exocytosis and/or deficiencies in the exocytotic mechanism itself [1, 3]
By immunoblot analysis it was first confirmed that Rab3A protein was absent in isolated Rab3AϪ/Ϫ mice versus Rab3Aϩ/ϩ control mice compared with other -granule proteins involved in insulin exocytosis, such as VAMP-2 (Fig. 1)
Summary
Insulin is the major anabolic hormone controlling metabolic homeostasis, and without an effective supply of insulin diabetes mellitus ensues. There was a similar rate of glucose oxidation and glucose-induced rise in cytosolic [Ca2؉]i flux between Rab3A؊/؊ and Rab3A؉/؉ islet -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.
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