MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes
Open accessAbstract
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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There is a positive correlation between CHRNB2 expression and GIIS.
“There is a positive correlation between the expression of CHRNB2 expression and GIIS (199).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [199]
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Cites
Active Smoking and the Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis
Willi, C., Bodenmann, P., Ghali, W. A., Faris, P. D., & Cornuz, J. (2007) · JAMA · doi:10.1001/jama.298.22.2654 · Cited by 1,268 · see citing works
Innervation Patterns of Autonomic Axons in the Human Endocrine Pancreas
Rodriguez-Diaz, R., Abdulreda, M. H., Formoso, A. L., Gans, I., Ricordi, C., Berggren, P.-O., & Caicedo, A. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.05.008 · Cited by 356 · cited 3× · see citing works
“However, nicotinic acetylcholine receptor activity was previously thought to not be significantly involved in this process (Gautam et al., 2006; Rodriguez-Diaz et al., 2011b).”
BackgroundGautam, D., Han, S.-J., Hamdan, F. F., Jeon, J., Li, B., Li, J. H., Cui, Y., Mears, D., Lu, H., Deng, C., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.04.009 · Cited by 299 · see citing works
Ahrén, B., & Holst, J. J. (2001) · Diabetes · doi:10.2337/diabetes.50.5.1030 · Cited by 292 · see citing works
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Research works printed but not linked: 34
- Ahré n B 2000 Autonomic regulation of islet hormone secretion-implications for health and disease Diabetologia 43 393 410 10819232
- Alkondon M Pereira EF Almeida LE Randall WR Albuquerque EX 2000 Nicotine at concentrations found in cigarette smokers activates and desensitizes nicotinic acetylcholine receptors in CA1 interneurons of rat hippocampus Neuropharmacology 39 2726 2739 11044743
- Artner I Hang Y Mazur M Yamamoto T Guo M Lindner J Magnuson MA Stein R 2010 MafA and MafB regulate genes critical to beta-cells in a unique temporal manner Diabetes 59 2530 2539 20627934 PMC3279542
- Brouwers B de Faudeur G Osipovich AB Goyvaerts L Lemaire K Boesmans L Cauwelier EJ Granvik M Pruniau VP Van Lommel L 2014 Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression Cell Metab 20 979 990 25470546 PMC5674787
- Dai C Brissova M Hang Y Thompson C Poffenberger G Shostak A Chen Z Stein R Powers AC 2012 Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets Diabetologia 55 707 718 22167125 PMC3268985
- Duttaroy A Zimliki CL Gautam D Cui Y Mears D Wess J 2004 Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in m3 muscarinic acetylcholine receptor-deficient mice Diabetes 53 1714 1720 15220195
- Fadista J Vikman P Laakso EO Mollet IG Esguerra JL Taneera J Storm P Osmark P Ladenvall C Prasad RB 2014 Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism Proc. Natl. Acad. Sci. USA 111 13924 13929 25201977 PMC4183326
- Ganic E Johansson JK Bennet H Fex M Artner I 2015 Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes Biochem. Biophys. Res. Commun 468 629 635 26546820
- Gilsbach R Faron-Górecka A Rogóz Z Brüss M Caron MG Dziedzicka-Wasylewska M Bönisch H 2006 Norepinephrine transporter knockout-induced up-regulation of brain alpha2A/C-adrenergic receptors J. Neurochem 96 1111 1120 16417582
- Goto M Eich TM Felldin M Foss A Källen R Salmela K Tibell A Tufveson G Fujimori K Engkvist M Korsgren O 2004 Refinement of the automated method for human islet isolation and presentation of a closed system for in vitro islet culture Transplantation 78 1367 1375 15548977
- Guo Y Traurig M Ma L Kobes S Harper I Infante AM Bogardus C Baier LJ Prochazka M 2006 CHRM3 gene variation is associated with decreased acute insulin secretion and increased risk for early-onset type 2 diabetes in Pima Indians Diabetes 55 3625 3629 17130513
- Guo S Dai C Guo M Taylor B Harmon JS Sander M Robertson RP Powers AC Stein R 2013 Inactivation of specific β cell transcription factors in type 2 diabetes J. Clin. Invest 123 3305 3316 23863625 PMC3726150
- Halban PA Polonsky KS Bowden DW Hawkins MA Ling C Mather KJ Powers AC Rhodes CJ Sussel L Weir GC 2014 β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment J. Clin. Endocrinol. Metab 99 1983 1992 24712577 PMC5393482
- Hang Y Yamamoto T Benninger RK Brissova M Guo M Bush W Piston DW Powers AC Magnuson M Thurmond DC Stein R 2014 The MafA transcription factor becomes essential to islet β-cells soon after birth Diabetes 63 1994 2005 24520122 PMC4030115
- Herrera PL 2000 Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages Development 127 2317 2322 10804174
- Johansson JK Voss U Kesavan G Kostetskii I Wierup N Radice GL Semb H 2010 N-cadherin is dispensable for pancreas development but required for beta-cell granule turnover Genesis 48 374 381 20533404 PMC2921608
- Karlsson S Bood M Ahrén B 1987 The mechanism of 2-deoxy-glucose-induced insulin secretion in the mouse J. Auton. Pharmacol 7 135 144 3308892
- Matsuoka TA Zhao L Artner I Jarrett HW Friedman D Means A Stein R 2003 Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells Mol. Cell. Biol 23 6049 6062 12917329 PMC180917
- Mazur MA Winkler M Ganic E Colberg JK Johansson JK Bennet H Fex M Nuber UA Artner I 2013 Microphthalmia transcription factor regulates pancreatic β-cell function Diabetes 62 2834 2842 23610061 PMC3717881
- Molina J Rodriguez-Diaz R Fachado A Jacques-Silva MC Berggren PO Caicedo A 2014 Control of insulin secretion by cholinergic signaling in the human pancreatic islet Diabetes 63 2714 2726 24658304 PMC4113066
- Ohtani M Oka T Badyuk M Xiao Y Kellar KJ Daly JW 2006 Mouse beta-TC6 insulinoma cells: high expression of functional alpha3beta4 nicotinic receptors mediating membrane potential, intracellular calcium, and insulin release Mol. Pharmacol 69 899 907 16332988
- Pasquali L Gaulton KJ Rodríguez-Seguí SA Mularoni L Miguel-Esca-lada I Akerman I Tena JJ Morán I Gómez-Marín C van de Bunt M 2014 Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants Nat. Genet 46 136 143 24413736 PMC3935450
- Porte D Jr Williams RH 1966 Inhibition of insulin release by norepinephrine in man Science 152 1248 1250 5327883
- Raum JC Hunter CS Artner I Henderson E Guo M Elghazi L Sosa-Pineda B Ogihara T Mirmira RG Sussel L Stein R 2010 Islet beta-cell-specific MafA transcription requires the 5’-flanking conserved region 3 control domain Mol. Cell. Biol 30 4234 4244 20584984 PMC2937551
- Ravassard P Hazhouz Y Pechberty S Bricout-Neveu E Armanet M Czernichow P Scharfmann R 2011 A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion J. Clin. Invest 121 3589 3597 21865645 PMC3163974
- Rodriguez-Diaz R Dando R Jacques-Silva MC Fachado A Molina J Abdulreda MH Ricordi C Roper SD Berggren PO Caicedo A 2011b Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans Nat. Med 17 888 892 21685896 PMC3132226
- Rosengren AH Jokubka R Tojjar D Granhall C Hansson O Li DQ Nagaraj V Reinbothe TM Tuncel J Eliasson L 2010 Overexpression of alpha2A–adrenergic receptors contributes to type 2 diabetes Science 327 217 220 19965390
- Shabalin AA 2012 Matrix eQTL: ultra fast eQTL analysis via large matrix operations Bioinformatics 28 1353 1358 22492648 PMC3348564
- Taneera J Lang S Sharma A Fadista J Zhou Y Ahlqvist E Jonsson A Lyssenko V Vikman P Hansson O 2012 A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets Cell Metab 16 122 134 22768844
- Thorens B 2011 Brain glucose sensing and neural regulation of insulin and glucagon secretion Diabetes Obes. Metab 13 Suppl 1 82 88 21824260
- Winzell MS Ahrén B 2007 Role of VIP and PACAP in islet function Peptides 28 1805 1813 17559974
- Xie XT Liu Q Wu J Wakui M 2009 Impact of cigarette smoking in type 2 diabetes development Acta Pharmacol. Sin 30 784 787 19434055 PMC4002374
- Yoshikawa H Hellström-Lindahl E Grill V 2005 Evidence for functional nicotinic receptors on pancreatic beta cells Metabolism 54 247 254 15690320
- Zhang C Moriguchi T Kajihara M Esaki R Harada A Shimohata H Oishi H Hamada M Morito N Hasegawa K 2005 MafA is a key regulator of glucose-stimulated insulin secretion Mol. Cell. Biol 25 4969 4976 15923615 PMC1140590
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
- Authors
- Ganic, E., Singh, T., Luan, C., Fadista, J., Johansson, J. K., Cyphert, H. A., Bennet, H., Storm, P., Prost, G., Ahlenius, H., Renström, E., Stein, R., Groop, L., Fex, M., & Artner, I.
- Affiliations
- Lund University (SE)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Artner, Isabella
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 14
- Issue
- 8
- Pages
- 1991-2002
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5918632
- OpenAlex
- W2274238354
- Cited by
- 41
- References
- 4
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 1
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090570)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- MafA, nicotinic acetylcholine receptors, insulin secretion, pancreatic beta cells, type 2 diabetes, autonomic nervous system, acetylcholine signaling, monoamines, CHRNB4, ADRA2A, genetic polymorphism, transcriptional regulation, impaired glucose tolerance
- MeSH terms
- Animals, Autonomic Nervous System, Binding Sites, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Glucose Tolerance Test, Humans, Insulin, Nerve Tissue Proteins, Polymorphism, Genetic, Protein Binding, Receptors, Nicotinic, Transcription, Genetic, Signal Transduction, Receptors, Adrenergic, alpha-2, Mice, Knockout, Insulin-Secreting Cells, Mice, Maf Transcription Factors, Large
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