Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans

• Published in: Nature medicine Vol. 25; no. 11; pp. 1739 - 1747
• Main Authors: Gómez-Banoy, Nicolás, Guseh, J. Sawalla, Li, Ge, Rubio-Navarro, Alfonso, Chen, Tong, Poirier, BreAnne, Putzel, Gregory, Rosselot, Carolina, Pabón, Maria A., Camporez, João Paulo, Bhambhani, Vijeta, Hwang, Shih-Jen, Yao, Chen, Perry, Rachel J., Mukherjee, Sushmita, Larson, Martin G., Levy, Daniel, Dow, Lukas E., Shulman, Gerald I., Dephoure, Noah, Garcia-Ocana, Adolfo, Hao, Mingming, Spiegelman, Bruce M., Ho, Jennifer E., Lo, James C.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2019; Nature Publishing Group
• Subjects: 692/163; 692/163/2743; 692/163/2743/137; 692/163/2743/137/773; Animals; Apoptosis; Beta cells; Biomedical and Life Sciences; Biomedicine; Body Mass Index; Body size; Cancer Research; Care and treatment; Cell death; Cell Dedifferentiation - drug effects; Complement; Complement C3a - genetics; Complement component C3a; Complement factor D; Complement Factor D - genetics; Complement Factor D - pharmacology; Complications and side effects; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Dual-Specificity Phosphatases - genetics; Gene expression; Glucose; Glucose - metabolism; Humans; Hyperglycemia; Hyperglycemia - drug therapy; Hyperglycemia - genetics; Hyperglycemia - pathology; Infectious Diseases; Insulin; Insulin - genetics; Insulin resistance; Insulin Resistance - genetics; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - pathology; Islet cells; Letter; Metabolic Diseases; Mice; Mice, Inbred NOD; Mitogen-Activated Protein Kinase Phosphatases - genetics; Molecular Medicine; Mortality; Neurosciences; Pancreas; Pancreatic beta cells; Replenishment; Risk factors; Type 2 diabetes
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-019-0610-4

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function 1 , 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 diabetes 3 , 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 secretion 5 . 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. Targeting the adipokine adipsin and its downstream pathway may provide an approach for preservation of beta cell loss in type 2 diabetes.