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Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors.

ABSTRACT: Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic ?- and ?-cells express the catecholamine biosynthetic and signaling machinery, and that ?-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both ?- and ?-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at ?_2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D₂-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet ?- and ?-cell targets to produce metabolic disturbances.

SUBMITTER: Aslanoglou D

PROVIDER: S-EPMC7884786 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors.

Aslanoglou Despoina D Bertera Suzanne S Sánchez-Soto Marta M Benjamin Free R R Lee Jeongkyung J Zong Wei W Xue Xiangning X Shrestha Shristi S Brissova Marcela M Logan Ryan W RW Wollheim Claes B CB Trucco Massimo M Yechoor Vijay K VK Sibley David R DR Bottino Rita R Freyberg Zachary Z

Translational psychiatry 20210216 1

Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mous ...[more]

PMID: 33589583

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Project description:Appropriate glucagon secretion from pancreatic alpha cells in response to hypoglycemia is an important component of maintaining glucose homeostasis. Dysregulated glucagon secretion leads to the delayed recovery from a hypoglycemic attack in type 1 diabetes patients which can be lethal. Although elucidating the precise mechanism of glucagon secretion in hypoglycemia is warranted, the underlying mechanism remains poorly understood.The present study provides evidence of the role of autophagy in glucagon secretion in hypoglycemia by demonstrating that autophagy regulates adrenergic stimulation of glucagon secretion downstream of beta2 adrenergic receptor. First, from the analyses of T1D human islets and the published database of scRNA-seq of T1D human alpha cells, we described autophagy pathways altered in T1D alpha cells. Second, we generated alpha cell-specific Atg7KO mice (alphaAtg7KO) and clarified that the lack of autophagy in alpha cells impairs the reactive glucagon secretion in acute hypoglycemia. Third, to interrogate the molecular mechanism of autophagy-mediated glucagon regulation, we analyzed top genes downregulated inT1D and T2D alpha cells and found the expression of beta2 adrenergic receptor showed significant down-regulation in T1D alpha cells. We confirmed the decreased expression of beta2 adrenergic receptor in alpha cells of the T1D pancreas section, the islets of alphaAtg7KO mice, and a murine alpha cell line with stable knockdown of Atg7. Furthermore, in vivo and ex vivo studies of alphaAtg7KO mice exhibited that lack of autophagy led to the loss of stimulatory effect of beta2-adrenergic signaling on glucagon secretion. Finally, we established the Atg7 knockdown model in sorted human alpha cells and confirmed the effect of autophagy on the expression of the beta2 adrenergic receptor. Together, our study provides novel insights into the regulatory role of autophagy in glucagon secretion in response to hypoglycemia and provides therapeutic options to achieve stable glycemic control in T1D patients.

Dataset Information

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors.

Publications

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors.

Similar Datasets

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