title: MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes.
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.
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden; Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Elvira
authors.initials: E
authors.lastname: Ganic
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden; Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Tania
authors.initials: T
authors.lastname: Singh
authors.affiliation: Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luan
authors.affiliation: Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden; Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Jenny K
authors.initials: JK
authors.lastname: Johansson
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Holly Ann
authors.initials: HA
authors.lastname: Cyphert
authors.affiliation: Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.affiliation: Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Prost
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ahlenius
authors.affiliation: Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.affiliation: Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.affiliation: Stem Cell Center, Lund University, Klinikgatan 26, Lund 22184, Sweden; Lund University Diabetes Center, Lund University, Klinikgatan 26, Lund 22184, Sweden. Electronic address: isabella.artner@med.lu.se.
authors.forename: Isabella
authors.initials: I
authors.lastname: Artner
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000378:metabolism; D001665:Binding Sites; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051473:Maf Transcription Factors, Large / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D007328:Insulin; D051473:Maf Transcription Factors, Large; D009419:Nerve Tissue Proteins; D018341:Receptors, Adrenergic, alpha-2; D011978:Receptors, Nicotinic; C547769:Adra2a protein, mouse; C486720:Chrnb4 protein, mouse; C485160:Mafa protein, mouse