Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents.
Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the β-cell primary cilium in type 2 diabetes susceptibility. We find impaired glucose handling in young Bbs4(-/-) mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. Insulin receptor is recruited to the cilium of stimulated β-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated β-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the β-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility.
1] The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden [2] Institute for Diabetes and Regeneration Research, Helmholtz Center Munich, Business Campus Garching, Parkring 11, D-85748 Garching, Germany.
Jantje M
JM
Gerdes
Molecular Medicine Unit, UCL Institute of Child Health, London WCN1N 1EH, UK.
Sonia
S
Christou-Savina
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Yan
Y
Xiong
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Tilo
T
Moede
1] The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden [2] Institute for Diabetes and Regeneration Research, Helmholtz Center Munich, Business Campus Garching, Parkring 11, D-85748 Garching, Germany.
Noah
N
Moruzzi
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Patrick
P
Karlsson-Edlund
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Barbara
B
Leibiger
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Ingo B
IB
Leibiger
Department of Molecular Medicine and Surgery, Endocrine and Diabetes Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Claes-Göran
CG
Östenson
Molecular Medicine Unit, UCL Institute of Child Health, London WCN1N 1EH, UK.
Philip L
PL
Beales
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Per-Olof
PO
Berggren
D000818:Animals; D002923:Cilia / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000209:etiology* / Q000503:physiopathology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009765:Obesity / Q000150:complications / Q000503:physiopathology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology
C506281:BBS4 protein, mouse; D007328:Insulin; D008869:Microtubule-Associated Proteins; D005947:Glucose