In:
The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 46.08-46.08
Abstract:
We discovered that the cytokine interleukin-22 (IL-22) is an efficient natural inhibitor of cellular stress and exogenous IL-22 improved insulin quality in pancreatic β-cells in preclinical models of Type 2 diabetes. Importantly, IL-22 completely restored glucose tolerance, suppressed fasting hyperinsulinemia/hyperproinsulinemia, and restored insulin sensitivity in obese animals. Moreover, metabolic improvements were accompanied by significant improvements in circulating triglycerides, liver function (AST:ALT ratio) and a reduction in hepatic lipid accumulation. Whilst the IL-22 receptor, IL-22RA1 is highly expressed in the pancreas and liver, its endogenous role in these tissues remains elusive. To explore this, we generated tissue specific IL-22ra1 knockout mice lacking the receptor in pancreatic β-cells (Il-22ra1fl/fl x Ins2Cre: IL-22ra1β-cell−/−) and hepatocytes (Il-22ra1fl/fl x AlbCre: IL-22ra1Hep−/−). We assessed their metabolic phenotype including glycemic control, hepatic lipid accumulation, and hepatic markers of cellular stress, lipid, and glucose metabolism with age or with obesity. We discovered that IL-22ra1β-cell−/− animals developed hyperglycemia with age and had defective insulin secretion, which was exacerbated when on a high fat diet. Interestingly, they also had a significant increase in markers of hepatic inflammation and cellular stress. In conclusion we demonstrate, for the first time, that local endogenous IL-22 secretion in pancreatic β-cells maintains insulin biosynthesis. Moreover, our work highlights the importance of the pancreatic-β-cell-liver axis as the absence of pancreatic IL-22ra1 signaling leads to a marked increase in liver inflammation and cellular stress.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.208.Supp.46.08
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2022
detail.hit.zdb_id:
1475085-5
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