期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 1, 页码 261-271出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64941
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资金
- NIH [T32ES016645, R01DK075046]
- American Heart Association
- American Diabetes Association
- MRC [MC_U105178805] Funding Source: UKRI
- Medical Research Council [MC_U105178805] Funding Source: researchfish
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL079392] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK075046] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [T32ES016645] Funding Source: NIH RePORTER
Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13(-/-)) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor alpha 1 (Il-13r alpha 1), which suggests that the IL-13R alpha 1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.
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