Fasting and Glucose Metabolism Differentially Impact Peripheral Inflammation in Human Type 2 Diabetes.

Publisher: MDPI Publishing Country of Publication: Switzerland NLM ID: 101521595 Publication Model: Electronic Cited Medium: Internet ISSN: 2072-6643 (Electronic) Linking ISSN: 20726643 NLM ISO Abbreviation: Nutrients Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI Publishing

Diabetes Mellitus, Type 2*/metabolism ; Inflammation*/metabolism ; Fasting* ; Cytokines*/metabolism ; Leukocytes, Mononuclear*/metabolism ; CD4-Positive T-Lymphocytes*/metabolism; Humans ; Male ; Female ; Middle Aged ; Blood Glucose/metabolism ; Glucose/metabolism ; Adult ; Aged

Cytokines produced by peripheral T-helper 1/17 cells disproportionately contribute to the inflammation (i.e., metaflammation) that fuels type 2 diabetes (T2D) pathogenesis. Shifts in the nutrient milieu could influence inflammation through changes in T-cell metabolism. We aimed to determine whether changes in glucose utilization alter cytokine profiles in T2D. Peripheral blood mononuclear cells (PBMCs), CD4 ⁺ T-cells, and CD4 ⁺ CD25 ^- T-effector (T eff ) cells were isolated from age-matched humans classified by glycemic control and BMI. Cytokines secreted by CD3/CD28-stimulated PBMCs and T eff were measured in supernatants with multiplex cytokine assays and a FLEXMAP-3D. Metabolic activity of stimulated CD4 ⁺ T-cells was measured by a Seahorse XFe96 analyzer. In this study, we demonstrated that T-cell stimulated PBMCs from non-fasted people with T2D produced higher amounts of cytokines compared to fasting. Although dysglycemia characterizes T2D, cytokine production by PBMCs or CD4 ⁺ T-cells in T2D was unaltered by hyperglycemic media. Moreover, pharmacological suppression of mitochondrial glucose oxidation did not change T-cell metabolism in T2D, yet enhanced cytokine competency. In conclusion, fasting and glucose metabolism differentially impact peripheral inflammation in human T2D, suggesting that glucose, along with fatty acid metabolites per our previous work, partner to regulate metaflammation. These data expose a major disconnect in the use of glycemic control drugs to target T2D-associated metaflammation.

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T32DK007778 United States NH NIH HHS; TL1UL1TR001998 United States NH NIH HHS; R01DK108056 United States NH NIH HHS; UL1TR001998 United States NH NIH HHS; P30CA177558 United States CA NCI NIH HHS; College of Medicine University of Kentucky

Keywords: Hba1C; cytokines; extracellular flux; glycemic control; obesity; partial least squares discriminant analysis; systemic inflammation

0 (Cytokines)
0 (Blood Glucose)
IY9XDZ35W2 (Glucose)

Date Created: 20240525 Date Completed: 20240525 Latest Revision: 20240527

20240527

PMC11124302

10.3390/nu16101404

38794641