title: Stress-impaired transcription factor expression and insulin secretion in transplanted human islets.
abstract: Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive β cell dysfunction. Excess glucose and lipid impair β cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human β cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human β cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and β cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.forename: Nora S
authors.initials: NS
authors.lastname: Kayton
authors.forename: Alena
authors.initials: A
authors.lastname: Shostak
authors.forename: Greg
authors.initials: G
authors.lastname: Poffenberger
authors.forename: Holly A
authors.initials: HA
authors.lastname: Cyphert
authors.forename: Radhika
authors.initials: R
authors.lastname: Aramandla
authors.forename: Courtney
authors.initials: C
authors.lastname: Thompson
authors.forename: Ioannis G
authors.initials: IG
authors.lastname: Papagiannis
authors.forename: Christopher
authors.initials: C
authors.lastname: Emfinger
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shiota
authors.forename: John M
authors.initials: JM
authors.lastname: Stafford
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D064593:Heterografts; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D016381:Islets of Langerhans Transplantation; D051258:MafB Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout
chemical_list: D018398:Homeodomain Proteins; C490407:MAFB protein, human; D051258:MafB Transcription Factor; C105201:NKX6-1 protein, human