title: IG20/MADD plays a critical role in glucose-induced insulin secretion.
abstract: Pancreatic β-cell dysfunction is a common feature of type 2 diabetes. Earlier, we had cloned IG20 cDNA from a human insulinoma and had shown that IG20/MADD can encode six different splice isoforms that are differentially expressed and have unique functions, but its role in β-cell function was unexplored. To investigate the role of IG20/MADD in β-cell function, we generated conditional knockout (KMA1ko) mice. Deletion of IG20/MADD in β-cells resulted in hyperglycemia and glucose intolerance associated with reduced and delayed glucose-induced insulin production. KMA1ko β-cells were able to process insulin normally but had increased insulin accumulation and showed a severe defect in glucose-induced insulin release. These findings indicated that IG20/MADD plays a critical role in glucose-induced insulin release from β-cells and that its functional disruption can cause type 2 diabetes. The clinical relevance of these findings is highlighted by recent reports of very strong association of the rs7944584 single nucleotide polymorphism (SNP) of IG20/MADD with fasting hyperglycemia/diabetes. Thus, IG20/MADD could be a therapeutic target for type 2 diabetes, particularly in those with the rs7944584 SNP.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL.
authors.forename: Liang-cheng
authors.initials: LC
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Ryan
authors.initials: R
authors.lastname: Carr
authors.forename: Christine Samir
authors.initials: CS
authors.lastname: Haddad
authors.forename: Ze
authors.initials: Z
authors.lastname: Li
authors.forename: Lixia
authors.initials: L
authors.lastname: Qian
authors.forename: Jose
authors.initials: J
authors.lastname: Oberholzer
authors.forename: Ajay V
authors.initials: AV
authors.lastname: Maker
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C491371:Madd protein, mouse; D005947:Glucose