A glucose time in range of 70% attenuates the senescence-inducing and pro-inflammatory effects of hyperglycemia

The Time In Range (TIR) represents the amount of time spent by a given individual in the range close to normoglycemia, i.e. 70-180 mg/dl. On the basis of studies demonstrating an association of TIR with the incidence of diabetes complications, guidelines recommend a target of at least 70% of TIR for most people with diabetes. However, no study has explored the effect of variable degrees of TIR on molecular mechanisms relevant for the development of diabetes complications.

We exposed endothelial cells and monocytes to increasing percentages of TIR, i.e. 50%, 70%, 85% by changing cell media twice a day as appropriate, as well as to constant normoglycemia (i.e. fixed 100 mg/dl of glucose for endothelial cells) and hyperglycemia (i.e. 500 mg/dl glucose), evaluating the development of senescence, of the associated pro-inflammatory response, and monocytes adhesion to endothelial cells as a functional assay. We then assessed the expression of a plethora of markers of senescence and inflammation at the mRNA level in peripheral blood mononuclear cells (PBMC)s derived from individuals with early (i.e. 1-year post-diagnosis) type 1 diabetes (T1D, n = 37), categorized according to the TIR (< or > 70%) observed in the previous 14 days, comparing the two groups through ANCOVA adjusted for HbA1c. As a confirmatory analysis, we also compared the expression of the same markers in people with Time Above Range (TAR), considered as the whole time above 180 mg/dl, ≥ vs < 30%. Correlations between TIR values and the expression of the same markers were tested through linear regression.

Constant hyperglycemia promoted the development of senescence in endothelial cells and induced inflammatory responses in both endothelial cells and monocytes, promoting also monocytes adhesion to endothelial cells. A TIR of 70%, but not of 50%, suppressed these effects while a TIR of 85% did not provide additional benefit. Data from people with T1D mirrored such results, as demonstrated by the higher expression of p16, a marker of senescence, and of IL-6, MCP-1, and CXCL1, three inflammatory mediators, in PBMCs from individuals with TIR < 70% and compared with those with TIR > 70%, independently of HbA1c. Similar results were obtained when comparing people with TAR ≥ vs < 30%. When considered as a continuous variable, TIR values were correlated with p16, IL-6, and CXCL1.

A TIR above 70% is associated with attenuated pro-senescence and pro-inflammatory effects of hyperglycemia. These molecular results support the TIR target currently recommended by guidelines, especially for people with T1D.