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

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MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes. / Ganic, Elvira; Singh, Tania; Luan, Cheng; Fadista, Joao; Johansson, Jenny; Cyphert, Holly Ann; Bennet, Hedvig; Storm, Petter; Prost, Gaelle; Ahlenius, Henrik; Renström, Erik; Stein, Roland; Groop, Leif; Fex, Malin; Artner, Isabella.

In: Cell Reports, Vol. 14, No. 8, 2016, p. 1991-2002.

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T1 - MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes.

AU - Ganic, Elvira

AU - Singh, Tania

AU - Luan, Cheng

AU - Fadista, Joao

AU - Johansson, Jenny

AU - Cyphert, Holly Ann

AU - Bennet, Hedvig

AU - Storm, Petter

AU - Prost, Gaelle

AU - Ahlenius, Henrik

AU - Renström, Erik

AU - Stein, Roland

AU - Groop, Leif

AU - Fex, Malin

AU - Artner, Isabella

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2016.02.002

DO - 10.1016/j.celrep.2016.02.002

M3 - Article

C2 - 26904947

VL - 14

SP - 1991

EP - 2002

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 8

ER -