MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes

Cell Reports
Elvira GanicIsabella Artner

Abstract

Monoamine and acetylcholine neurotransmitters from the autonomic nervous system (ANS) regulate insulin secretion in pancreatic islets. The molecular mechanisms controlling neurotransmitter signaling in islet β cells and their impact on diabetes development are only partially understood. Using a glucose-intolerant, MafA-deficient mouse model, we demonstrate that MAFA controls ANS-mediated insulin secretion by activating the transcription of nicotinic (ChrnB2 and ChrnB4) and adrenergic (Adra2A) receptor genes, which are integral parts of acetylcholine- and monoamine-signaling pathways. We show that acetylcholine-mediated insulin secretion requires nicotinic signaling and that nicotinic receptor expression is positively correlated with insulin secretion and glycemic control in human donor islets. Moreover, polymorphisms spanning MAFA-binding regions within the human CHRNB4 gene are associated with type 2 diabetes. Our data show that MAFA transcriptional activity is required for establishing β cell sensitivity to neurotransmitter signaling and identify nicotinic signaling as a modulator of insulin secretion impaired in type 2 diabetes.

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Citations

Sep 13, 2016·Diabetes, Obesity & Metabolism·R ScharfmannO Albagli
Nov 7, 2018·The Journal of Biological Chemistry·Dhananjay GuptaThomas L Jetton
May 24, 2018·Acta Physiologica·L R Cataldo BascuñanM Fex
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Sep 10, 2021·Molecular Metabolism·Lena OppenländerHeiko Lickert
Jan 4, 2022·Acta Physiologica·Luis Rodrigo CataldoIsabella Artner

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Methods Mentioned

BETA
RIP
immunoprecipitation
RNA-seq
transfection
genotyping
ELISA
PCR
Assay
transfections
ChIP

Software Mentioned

R Matrix eQTL
Graphpad Prism
Zen
AxioVision Rel

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