Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

Nature Communications

Volumn 5, Issue , 2014, Pages

  Gerdes, Jantje M ^a,b   Christou Savina, Sonia ^c   Xiong, Yan ^a   Moede, Tilo ^a   Moruzzi, Noah ^a,b   Karlsson Edlund, Patrick ^a   Leibiger, Barbara ^a   Leibiger, Ingo B ^a   Östenson, Claes Göran ^d   Beales, Philip L ^c   Berggren, Per Olof ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

^b Helmholtz Center Munich   (Germany)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOSE; INSULIN; INSULIN RECEPTOR; BBS4 PROTEIN, MOUSE; MICROTUBULE ASSOCIATED PROTEIN;

DIABETES; ENZYME ACTIVITY; RODENT; SECRETION;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL STIMULATION; CILIARY DYSKINESIA; CILIARY MOTILITY; CONTROLLED STUDY; DIABETOGENESIS; EUKARYOTIC FLAGELLUM; EX VIVO STUDY; EXPERIMENTAL OBESITY; FEMALE; GENE EXPRESSION; HUMAN; HUMAN CELL; HUMAN TISSUE; IMPAIRED GLUCOSE TOLERANCE; IN VIVO STUDY; INSULIN BLOOD LEVEL; INSULIN RELEASE; KINETOSOME; MALE; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET BETA CELL; PANCREAS ISLET CELL FUNCTION; PRIMARY CELL; RAT; RODENT MODEL; SIGNAL TRANSDUCTION; ANIMAL; C57BL MOUSE; COMPLICATION; DEFICIENCY; DIABETES MELLITUS, TYPE 2; DISEASE MODEL; DISEASE PREDISPOSITION; GENETICS; HOMEOSTASIS; KNOCKOUT MOUSE; METABOLISM; OBESITY; PANCREAS ISLET; PATHOPHYSIOLOGY; PHENOTYPE; PHYSIOLOGY; SECRETION (PROCESS);

MURINAE; MUS; RATTUS; RODENTIA;

ANIMALS; CILIA; DIABETES MELLITUS, TYPE 2; DISEASE MODELS, ANIMAL; DISEASE SUSCEPTIBILITY; FEMALE; GLUCOSE; HOMEOSTASIS; INSULIN; INSULIN-SECRETING CELLS; ISLETS OF LANGERHANS; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MICROTUBULE-ASSOCIATED PROTEINS; OBESITY; PHENOTYPE; SIGNAL TRANSDUCTION;

EID: 84923277743     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms6308     Document Type: Article

References (57)

1. International Diabetes Federation. IDF Diabetes Atlas, 6 edn (International Diabetes Federation, Brussels, Belgium, 2013).
2. Roglic, G. et al. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 28, 2130-2135 (2005).
3. Gerdes, J. M., Davis, E. E. & Katsanis, N. The vertebrate primary cilium in development, homeostasis, and disease. Cell 137, 32-45 (2009).
4. Badano, J. L., Mitsuma, N., Beales, P. L. & Katsanis, N. The ciliopathies: an emerging class of human genetic disorders. Annu. Rev. Genomics Hum. Genet. 7, 125-148 (2006).
5. Slavotinek, A. M. et al. Mutations in MKKS cause Bardet-Biedl syndrome. Nature Genet. 26, 15-16 (2000).
6. Bettini, V. et al. The progression from obesity to type 2 diabetes in Alstrom syndrome. Pediatr. Diabetes 13, 59-67 (2012).
7. Goetz, S. & Anderson, K. The primary cilium:a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331-344 (2010).
8. Bialas, N. J. et al. Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J. Cell Sci. 122, 611-624 (2009).
9. Schafer, J. C. et al. IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation in Caenorhabditis elegans. J. Cell Sci. 119, 4088-4100 (2006).
10. Cano, D., Murcia, N., Pazour, G. & Hebrok, M. orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Development 131, 3457-3467 (2004).
11. Green, W. R. Abnormal cilia in human pancreas. Hum. Pathol. 11, 686687 (1980).
12. Therét, C. & Tamboise, E. Formation ciliaires observées au microscope electronique dans des cellules sécrétoires néoformées de l'adenohypophysis et du pancreas endocrine. Comp. Rend. Acad. Sci. 256, 2025-2027 (1963).
13. Pietrzak-Nowacka, M. et al. Glucose metabolism parameters during an oral glucose tolerance test in patients with autosomal dominant polycystic kidney disease. Scand. J. Clin. Lab. Invest. 70, 561-567 (2010).
14. Rowe, I. et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nature Med. 19, 488-493 (2013).
15. Eichers, E. et al. Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity. Hum. Genet. 120, 211-226 (2006).
16. Mykytyn, K. et al. Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc. Natl Acad. Sci. USA 101, 8664-8669 (2004).
17. Lee, B., Liu, J., Wong, D., Srinivasan, S. & Ashrafi, K. Hyperactive Neuroendocrine Secretion Causes Size, Feeding, and Metabolic Defects of C. elegans Bardet-Biedl Syndrome Mutants. PLoS Biol. 9, e1001219 (2011).
18. Rahmouni, K. et al. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J. Clin. Invest. 118, 1458-1467 (2008).
19. Ferrante, M. I. et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nature Genet. 38, 112-117 (2006).
20. Mokrzan, E. M., Lewis, J. S. & Mykytyn, K. Differences in renal tubule primary cilia length in a mouse model of Bardet-Biedl Syndrome. Nephron Exp. Nephrol. 106, e88-e96 (2007).
21. Yang, S. N. & Berggren, P. O. The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology. Endocr. Rev. 27, 621-676 (2006).
22. Ahren, B. & Pacini, G. Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies. Eur. J. Endocrinol. 150, 97-104 (2004).
23. Trent, D. F., Fletcher, D. J., May, J. M., Bonner-Weir, S. & Weir, G. C. Abnormal islet and adipocyte function in young B-cell-deficient rats with near-normoglycemia. Diabetes 33, 170-175 (1984).
24. Kim, J. C. et al. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nature Genet. 36, 462-470 (2004).
25. Lacy, P., Howell, S., Young, D. & Fink, C. New hypothesis of insulin secretion. Nature 219, 1177-1179 (1968).
26. Lacy, P., Walker, M. & Fink, C. Perifusion of isolated rat islets in vitro-participation of the microtubular system in the biphasic release of insulin. Diabetes 21, 987-998 (1972).
27. Boyd, 3rd A. E., Bolton, W. E. & Brinkley, B. R. Microtubules and beta cell function: effect of colchicine on microtubules and insulin secretion in vitro by mouse beta cells. J. Cell Biol. 92, 425-434 (1982).
28. Somers, G. et al. Dynamics of insulin release and micotubular-microfilamentous system. Eur. J. Clin. Invest. 4, 299-305 (1974).
29. Howell, S. & Tyhurst, M. Microtubules, microfilaments and insulin-secretion. Diabetologia 22, 301-308 (1982).
30. Rosenbaum, J. L. & Carlson, K. Cilia regeneration in Tetrahymena and its inhibition by colchicine. J. Cell Biol. 40, 415-425 (1969).
31. Gerdes, J. M. et al. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nature Genet. 39, 1350-1360 (2007).
32. Yoder, B. K. et al. Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium. Am. J. Physiol. Renal Physiol. 282, F541-F552 (2002).
33. Sharma, N., Kosan, Z. A., Stallworth, J. E., Berbari, N. F. & Yoder, B. K. Soluble levels of cytosolic tubulin regulate ciliary length control. Mol. Biol. Cell 22, 806-816 (2011).
34. Kulkarni, R. et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96, 329-339 (1999).
35. Otani, K. et al. Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in BIRKO mice. Am. J. Physiol. Endocrinol. Metab. 286, E41-E49 (2004).
36. Zhu, D., Shi, S., Wang, H. & Liao, K. Growth arrest induces primary-cilium formation and sensitizes IGF-1-receptor signaling during differentiation induction of 3T3-L1 preadipocytes. J. Cell Sci. 122, 2760-2768 (2009).
37. Longo, N., Shuster, R., Griffin, L., Langley, S. & Elsas, L. Activation of insulin receptor signaling by a single amino acid substitution in the transmembrane domain. J. Biol. Chem. 267, 12416-12419 (1992).
38. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature reviews. Mol. Cell Biol. 7, 85-96 (2006).
39. Rush, J. et al. Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature Biotechnol. 23, 94-101 (2005).
40. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101 (2005).
41. Jacinto, E. et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125-137 (2006).
42. Kaneko, K. et al. Class IA phosphatidylinositol 3-kinase in pancreatic beta-cells controls insulin secretion by multiple mechanisms. Cell Metab. 12, 619-632 (2010).
43. Yang, S. et al. Syntaxin 1 interacts with the L(D)-subtype of voltage-gates Ca(2 + ) channels in pancreatic beta-cells. Proc. Natl Acad. Sci. USA 96, 10164-10169 (1999).
44. Takahashi, N. et al. SNARE conformational changes that prepare vesicles for exocytosis. Cell Metab. 12, 19-29 (2010).
45. Blacque, O. E. et al. Functional genomics of the cilium, a sensory organelle. Curr. Biol. 15, 935-941 (2005).
46. Efimenko, E. et al. Analysis of xbx genes in C. elegans. Development 132, 1923-1934 (2005).
47. Leibiger, B. et al. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol. Cell 7, 559-570 (2001).
48. Uhles, S., Moede, T., Leibiger, B., Berggren, P. O. & Leibiger, I. B. Selective gene activation by spatial segregation of insulin receptor B signaling. FASEB J. 21, 1609-1621 (2007).
49. Leibiger, B. et al. Insulin-feedback via PI3K-C2alpha activated PKBalpha/Akt1 is required for glucose-stimulated insulin secretion. FASEB J. 24, 1824-1837 (2010).
50. Ostenson, C. G. & Efendic, S. Islet gene expression and function in type 2 diabetes; studies in the Goto-Kakizaki rat and humans. Diabetes Obes. Metab. 9(Suppl 2), 180-186 (2007).
51. Portha, B. et al. The GK rat beta-cell: a prototype for the diseased human beta-cell in type 2 diabetes? Mol. Cell Endocrinol. 297, 73-85 (2009).
52. Ghanaat-Pour, H., Huang, Z., Lehtihet, M. & Sjoholm, A. Global expression profiling of glucose-regulated genes in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats. J. Mol. Endocrinol. 39, 135-150 (2007).
53. Folli, F. et al. Altered insulin receptor signalling and beta-cell cycle dynamics in type 2 diabetes mellitus. PLoS ONE 6, e28050 (2011).
54. Keller, M. et al. A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res. 18, 706-716 (2008).
55. Otsu, N. Threshold selection method from gray-level histograms. IEEE Trans. Syst. Man. Cybern. 9, 62-66 (1979).
56. Berggren, P. O. et al. Removal of Ca2 + channel beta3 subunit enhances Ca2 + oscillation frequency and insulin exocytosis. Cell 119, 273-284 (2004).
57. Sterneberg, P., Rubins, N., Bartoov-Shifman, R., Walker, M. & Edlund, H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab. 1, 245-258 (2005).