Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice.
Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with β-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a ∼211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving β-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to β-cell dysfunction in T2D.
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia sof@unimelb.edu.au.
Sofianos
S
Andrikopoulos
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Barbara C
BC
Fam
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Anita
A
Holdsworth
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Sherley
S
Visinoni
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Zheng
Z
Ruan
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Maria
M
Stathopoulos
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Anne W
AW
Thorburn
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Christos N
CN
Joannides
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Michael
M
Cancilla
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Lois
L
Balmer
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Joseph
J
Proietto
Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.
Grant
G
Morahan
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D064233:Sulfonylurea Receptors / Q000235:genetics*; D000099161:Kcnj11 Channel
D001786:Blood Glucose; D005947:Glucose; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577508:Abcc8 protein, mouse
Islet cells; gene expression; glucose metabolism; insulin secretion