Vesicular monoamine transporter 2 (VMAT2) uptakes cytoplasmic monoamines into vesicles for storage. VMAT2 plays a role in modulating insulin release by regulating dopamine levels in the pancreas, although the exact mechanism remains elusive. We found that VMAT2 expression in β-cells specifically increases under high blood glucose conditions. The islets isolated from β-cell–specific Vmat2 knockout (βVmat2KO) mice show elevated insulin secretion levels in response to glucose stimulation. Under prolonged high-fat diet feedings, the βVmat2KO mice exhibit impaired glucose and insulin tolerance and progressive β-cell dysfunction. Here we demonstrate VMAT2 uptake of dopamine to protect dopamine from degradation by monoamine oxidase, thereby safeguarding β-cells from excess reactive oxygen species (ROS) exposure. In the context of high demand for insulin secretion, the absence of VMAT2 leads to elevated ROS in β-cells, which accelerates β-cell dedifferentiation and β-cell loss. Therefore, VMAT2 controls the amount of dopamine in β-cells, thereby protecting pancreatic β-cells from excessive oxidative stress.
There is increasing evidence that dopamine (DA) functions as a negative regulator of glucose-stimulated insulin secretion (GSIS); however, the underlying molecular mechanism remains unknown. Using total internal reflection fluorescence microscopy, we monitored insulin granule exocytosis in primary islet cells to dissect the effect of DA. We found that D1 receptor antagonists rescued the DA-mediated inhibition of glucose-stimulated calcium (Ca2+) flux, thereby suggesting a role of D1 in the DA-mediated inhibition of insulin secretion. Overexpression of D2 but not D1 alone exerted an inhibitory and toxic effect that abolished the glucose-stimulated Ca2+ influx and insulin secretion in beta-cells. Proximity ligation and western blot assays revealed that D1 and D2 form heteromers in beta-cells. Treatment with a D1-D2 heteromer agonist, SKF83959, transiently inhibited glucose-induced Ca2+ influx and insulin granule exocytosis. Co-expression of D1 and D2 enabled beta-cells to bypass the toxic effect of D2 overexpression. DA transiently inhibited glucose-stimulated Ca2+ flux and insulin exocytosis by activating the D1-D2 heteromer. We conclude that D1 protects beta-cells from the harmful effects of DA by modulating D2 signaling. The finding will contribute to our understanding of the DA signaling in regulating insulin secretion and improve methods for preventing and treating diabetes.
<p> </p> <p>There is increasing evidence that dopamine (DA) functions as a negative regulator of glucose-stimulated insulin secretion (GSIS); however, the underlying molecular mechanism remains unknown. Using total internal reflection fluorescence microscopy, we monitored insulin granule exocytosis in primary islet cells to dissect the effect of DA. We found that D1 receptor antagonists rescued the DA-mediated inhibition of glucose-stimulated calcium (Ca2+) flux, thereby suggesting a role of D1 in the DA-mediated inhibition of insulin secretion. Overexpression of D2 but not D1 alone exerted an inhibitory and toxic effect that abolished the glucose-stimulated Ca2+ influx and insulin secretion in beta-cells. Proximity ligation and western blot assays revealed that D1 and D2 form heteromers in beta-cells. Treatment with a D1-D2 heteromer agonist, SKF83959, transiently inhibited glucose-induced Ca2+ influx and insulin granule exocytosis. Co-expression of D1 and D2 enabled beta-cells to bypass the toxic effect of D2 overexpression. DA transiently inhibited glucose-stimulated Ca2+ flux and insulin exocytosis by activating the D1-D2 heteromer. We conclude that D1 protects beta-cells from the harmful effects of DA by modulating D2 signaling. The finding will contribute to our understanding of the DA signaling in regulating insulin secretion and improve methods for preventing and treating diabetes.</p>
Vesicular monoamine transporter 2 (VMAT2) uptakes cytoplasmic monoamines into vesicles for storage. VMAT2 plays a role in modulating insulin release by regulating dopamine levels in the pancreas, although the exact mechanism remains elusive. We found that VMAT2 expression in beta-cells specifically increases under high blood glucose conditions. The islets isolated from beta-cell specific <i>Vmat2</i> knock-out (βVmat2KO) mice show elevated insulin secretion levels in response to glucose stimulation. Under prolonged high-fat diet feedings, the βVmat2KO mice exhibit impaired glucose and insulin tolerance and progressive beta-cell dysfunction. We demonstrate here that VMAT2 uptakes dopamine to protect it from degradation by monoamine oxidase, thereby safeguarding beta-cells from excess reactive oxygen species (ROS) exposure. When under high demand for insulin secretion, the absence of VMAT2 leads to elevated ROS in beta-cells, which accelerates beta-cell dedifferentiation and beta-cell loss. Therefore, VMAT2 controls the amount of dopamine in beta-cells thereby protecting pancreatic beta-cells from excessive oxidative stress.
<p> </p> <p>There is increasing evidence that dopamine (DA) functions as a negative regulator of glucose-stimulated insulin secretion (GSIS); however, the underlying molecular mechanism remains unknown. Using total internal reflection fluorescence microscopy, we monitored insulin granule exocytosis in primary islet cells to dissect the effect of DA. We found that D1 receptor antagonists rescued the DA-mediated inhibition of glucose-stimulated calcium (Ca2+) flux, thereby suggesting a role of D1 in the DA-mediated inhibition of insulin secretion. Overexpression of D2 but not D1 alone exerted an inhibitory and toxic effect that abolished the glucose-stimulated Ca2+ influx and insulin secretion in beta-cells. Proximity ligation and western blot assays revealed that D1 and D2 form heteromers in beta-cells. Treatment with a D1-D2 heteromer agonist, SKF83959, transiently inhibited glucose-induced Ca2+ influx and insulin granule exocytosis. Co-expression of D1 and D2 enabled beta-cells to bypass the toxic effect of D2 overexpression. DA transiently inhibited glucose-stimulated Ca2+ flux and insulin exocytosis by activating the D1-D2 heteromer. We conclude that D1 protects beta-cells from the harmful effects of DA by modulating D2 signaling. The finding will contribute to our understanding of the DA signaling in regulating insulin secretion and improve methods for preventing and treating diabetes.</p>
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