TY - JOUR
T1 - Liver-Derived Systemic Factors Drive β Cell Hyperplasia in Insulin-Resistant States
AU - El Ouaamari, Abdelfattah
AU - Kawamori, Dan
AU - Dirice, Ercument
AU - Liew, Chong Wee
AU - Shadrach, Jennifer L.
AU - Hu, Jiang
AU - Katsuta, Hitoshi
AU - Hollister-Lock, Jennifer
AU - Qian, Wei Jun
AU - Wagers, Amy J.
AU - Kulkarni, Rohit N.
N1 - Funding Information:
We are grateful to C. Ronald Kahn for sharing the LIRKO model. We thank the laboratory of Gordon Weir for assistance in transplantation experiments, T. Roderick Bronson for assistance with histology, and Amarnath Kurpad, Marta Robledo, Samantha Haring, Rachael Martinez, and Ben Hambro for technical assistance. This work is supported by NIH RO1 DK 067536 (to R.N.K.); Société Francophone du Diabète, Association Française des Diabétiques, and American Diabetes Association (to A.E.O.); R01 DK 074795 (to W.-J.Q.); and the Burroughs Wellcome Fund, NIH 5 P30 DK36836-20, and NIH 1 DP2 OD004345 (to A.J.W.). A.J.W. is an Early Career Scientist of the Howard Hughes Medical Institute. Part of the study was supported by a Harvard Stem Cell Institute Seed Grant (to R.N.K.) and by a grant from the Juvenile Diabetes Research Foundation/Sanofi Aventis Strategic Alliance (17-2011-644) (to R.N.K.).
PY - 2013
Y1 - 2013
N2 - Integrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β cell growth factor(s) in insulin-resistant states.
AB - Integrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β cell growth factor(s) in insulin-resistant states.
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U2 - 10.1016/j.celrep.2013.01.007
DO - 10.1016/j.celrep.2013.01.007
M3 - Article
C2 - 23375376
AN - SCOPUS:84874241199
SN - 2211-1247
VL - 3
SP - 401
EP - 410
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -
