Abstract
A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or Th1 cytokine production, respectively. These data suggest that Treg control of Teff metabolism regulates inflammation differentially in prediabetes compared with type 2 diabetes. Queries of genes that impact mitochondrial function or pathways leading to transcription of lipid metabolism genes identified the fatty acid importer CD36 as highly expressed in Treg but not Teff from subjects with prediabetes. Pharmacological blockade of CD36 in Treg from subjects with prediabetes decreased Teff production of the Th17 cytokines that differentiate overall prediabetes inflammation. We conclude that Treg control CD4+ T cell cytokine profiles through mechanisms determined, at least in part, by host metabolic status. Furthermore, Treg CD36 uniquely promotes Th17 cytokine production by Teff in prediabetes.
| Original language | English |
|---|---|
| Pages (from-to) | 264-274 |
| Number of pages | 11 |
| Journal | Diabetes |
| Volume | 71 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2022 |
Bibliographical note
Publisher Copyright:© 2022 by the American Diabetes Association.
Funding
University of Southern California, Los Angeles, CA, for important suggestions that contributed to rigor of results. Funding. This work was funded by National Institute of Diabetes and Digestive and Kidney Diseases (grant R01DK108056 to D.A.L., P.A.K., and B.S.N.), the University of Kentucky Pharmaceutical Sciences PhD Program (R.L.), the Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA 177558), Barnstable Brown Diabetes and Obesity Center (B.S.N.), National Institutes of Health National Center for Advancing Translational Sciences UL1TR001998 (P.A.K.), and the Army Institute for Collaborative Biotechnologies Cooperative Agreement W911NF-19-2-0026 from the Army Research Office (D.A.L.). All statistics and bioinformatics analysis was funded by collaborative grants or support from the authors’ institutions. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. R.L. researched data and wrote the manuscript. G.H.P., E.T., and K.T. researched data. K.T. and D.A.L. researched data and wrote the manuscript. P.A.K. provided clinical expertise and human samples and wrote the manuscript. B.S.N. researched data and wrote the manuscript. All authors edited the manuscript and contributed to discussion. All statistics and bioinformatics analysis was done collaboratively by R.L., E.T., K.T., and D.A.L. B.S.N. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This work was funded by National Institute of Diabetes and Digestive and Kidney Diseases (grant R01DK108056 to D.A.L., P.A.K., and B.S.N.), the University of Kentucky Pharmaceutical Sciences PhD Program (R.L.), the Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA 177558), Barnstable Brown Diabetes and Obesity Center (B.S.N.), National Institutes of Health National Center for Advancing Translational SciencesUL1TR001998 (P.A.K.), and the Army Institute for Collaborative Biotechnologies Cooperative AgreementW911NF-19-2-0026 from the Army Research Office (D.A.L.). All statistics and bioinformatics analysis was funded by collaborative grants or support from the authors? institutions.
| Funders | Funder number |
|---|---|
| Army Institute for Collaborative Biotechnologies Cooperative | |
| National Institutes of Health National Center for Advancing Translational Sciences | UL1TR001998 |
| National Institutes of Health National Center for Advancing Translational SciencesUL1TR001998 | |
| University of Kentucky Department of Pharmaceutical Sciences | |
| National Institute of Diabetes and Digestive and Kidney Diseases | R01DK108056 |
| Army Research Office | |
| National Center for Advancing Translational Sciences (NCATS) | TL1TR001997 |
| Army Research Office Institute for Collaborative Biotechnologies | W911NF-19-2-0026 |
| University of Kentucky Markey Cancer Center | P30 CA 177558 |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
