title: Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes.
abstract: The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased Ca(2+) sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences Malmo, Lund University, Malmo, Sweden. anders.rosengren@med.lu.se
authors.forename: Anders H
authors.initials: AH
authors.lastname: Rosengren
authors.forename: Matthias
authors.initials: M
authors.lastname: Braun
authors.forename: Taman
authors.initials: T
authors.lastname: Mahdi
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Andersson
authors.forename: Mary E
authors.initials: ME
authors.lastname: Travers
authors.forename: Makoto
authors.initials: M
authors.lastname: Shigeto
authors.forename: Enming
authors.initials: E
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: Annika S
authors.initials: AS
authors.lastname: Axelsson
authors.forename: Anna
authors.initials: A
authors.lastname: Edlund
authors.forename: Morten Gram
authors.initials: MG
authors.lastname: Pedersen
authors.forename: Anna
authors.initials: A
authors.lastname: Jonsson
authors.forename: Reshma
authors.initials: R
authors.lastname: Ramracheya
authors.forename: Yunzhao
authors.initials: Y
authors.lastname: Tang
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Walker
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Paul R V
authors.initials: PR
authors.lastname: Johnson
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
mesh_terms: D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D005089:Exocytosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D000099161:Kcnj11 Channel
chemical_list: D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D051657:KCNQ1 Potassium Channel; D024661:Potassium Channels, Inwardly Rectifying; D018341:Receptors, Adrenergic, alpha-2; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D000099161:Kcnj11 Channel; C547768:ADRA2A protein, human; C078492:HHEX protein, human; C496909:KCNQ1 protein, human; C495680:SLC2A2 protein, human; C544894:TCF7L2 protein, human