TY - JOUR
T1 - Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans
AU - Gómez-Banoy, Nicolás
AU - Guseh, J. Sawalla
AU - Li, Ge
AU - Rubio-Navarro, Alfonso
AU - Chen, Tong
AU - Poirier, Bre Anne
AU - Putzel, Gregory
AU - Rosselot, Carolina
AU - Pabón, Maria A.
AU - Camporez, João Paulo
AU - Bhambhani, Vijeta
AU - Hwang, Shih Jen
AU - Yao, Chen
AU - Perry, Rachel J.
AU - Mukherjee, Sushmita
AU - Larson, Martin G.
AU - Levy, Daniel
AU - Dow, Lukas E.
AU - Shulman, Gerald I.
AU - Dephoure, Noah
AU - Garcia-Ocana, Adolfo
AU - Hao, Mingming
AU - Spiegelman, Bruce M.
AU - Ho, Jennifer E.
AU - Lo, James C.
N1 - Funding Information:
1Weill Center for Metabolic Health and Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. 2Corrigan Minehan Heart Center, Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 3Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA. 4Jill Roberts Institute for Research in Inflammatory Bowel Disease, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. 5Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 6Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. 7Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. 8Framingham Heart Study, Framingham, MA, USA. 9Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 10Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. 11Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. *e-mail: jho1@mgh.harvard.edu; jlo@med.cornell.edu
Funding Information:
N.G.B. is supported by an American Diabetes Association postdoctoral fellowship (118PMF032). J.S.G. was supported by an MGH NIH T32 Training Grant (HL007208), the John S. LaDue Memorial Fellowship and the MGH Physician Scientist Development Program. This work was supported by a Weill Cornell Department of Medicine Seed Grant for Innovative Research to J.C.L., the JPB Foundation (to B.M.S.), Jill Roberts IBD Institute (to G.P.) and NIH grants DK097303 (to J.C.L.), R03 DK111762 (to J.C.L.), R01 DK121844 (to J.C.L.), R01 HL140224 (to J.E.H.) and R01 HL134893 (to J.E.H.). This work was partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (contracts N01HC25195 and HHSN268201500001I) and by the Division of Intramural Research (to P.C., G.S., C.L., S.J.H. and D.L.) of the National Heart, Lung and Blood Institute. We acknowledge support from the Yale Mouse Metabolic Phenotyping Center via NIH grants nos. U24 DK059635, R01 DK116774, R01 DK114793 and P30 DK045735 (all to G.I.S.). We acknowledge the Microscopy and Image Analysis Core Facility at Weill Cornell Medicine for analysis of the images presented in this study, J. Cao for his help with confocal microscopy and the Human Islet and Adenovirus Core of the Einstein–Sinai Diabetes Research Center (NIH grant no. P30 DK02054138) for the human islet studies. The views expressed in this Letter are those of the authors and do not necessarily represent the views of the National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung and Blood Institute, the National Institutes of Health or the US Department of Health and Human Services.
Publisher Copyright:
© 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.
AB - Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=85074862412&partnerID=8YFLogxK
U2 - 10.1038/s41591-019-0610-4
DO - 10.1038/s41591-019-0610-4
M3 - Article
C2 - 31700183
AN - SCOPUS:85074862412
SN - 1078-8956
VL - 25
SP - 1739
EP - 1747
JO - Nature Medicine
JF - Nature Medicine
IS - 11
ER -