Factors Associated with Higher Pro-Inflammatory Tumor Necrosis Factor-α Levels in Young Women with Type 1 Diabetes

Abstract

Aims While cytokines play a role in the etiology of type 1 diabetes, cytokines later in the disease are less understood. We therefore investigated associations of pro-inflammatory tumor necrosis factor-α levels measured at prolonged disease duration with C-peptide at diagnosis, long-term glycemic control, diabetes duration, clinical factors, and health behaviors. Methods Data and blood were collected during an ancillary study to the longitudinal Wisconsin Diabetes Registry, a population-based cohort followed since diagnosis of type 1 diabetes. The ancillary study was conducted at 13-18 years diabetes duration, and enrolled premenopausal women age 18-45 years (n=87). Results Higher tumor necrosis factor-α levels at 13-18 years diabetes duration were independently associated with longer duration (p=0.0004) and worse current renal function (p=0.02). Additionally, diabetes duration modified both of the positive associations of tumor necrosis factor-α levels (both interactions p≤0.01) with mean glycemic control during the previous 10 years (significant only in women with longer durations) and current daily caffeine intake (significant only in women with shorter durations). In women with C-peptide measured at diagnosis (n=50), higher tumor necrosis factor-α levels at 13-18 years duration were associated with lower C-peptide (p=0.01), independent of glycemic control during the previous 10 years. Conclusions Lower residual C-peptide at diagnosis and poor long-term glycemic control independently predicted higher pro-inflammatory tumor necrosis factor-α levels years later. The novel relationship with C-peptide needs confirmation in a larger cohort. Given the association between tumor necrosis factor-α and diabetes complications, further longitudinal studies may help clarify the potentially complex associations between glycemic control, inflammatory cytokines, and complications.

Dominant TNFα and impaired IL‐2 cytokine profiles of CD4+ T cells from children with type‐1 diabetes

“…In the LEW.1AR1‐ iddm rat animal model of T1D, treatment with anti‐TNFα only in combination with anti‐ T‐cell receptor antibodies restored normoglycemia, normalized C‐peptide and increased beta‐cell proliferation 36 . Furthermore, T1D patients studies identified increased TNFα plasma concentration associated with higher HbA1c 37 and lower C‐peptide levels 38 . In accordance, we found TNFα‐dominant T MEM responses especially at long‐term T1D stage.…”

Dermal fibroblasts cultured from donors with type 2 diabetes mellitus retain an epigenetic memory associated with poor wound healing responses

“…A pro-inflammatory environment can increase MMP expression which has been implicated in impaired wound healing in both T2DM and animal models of diabetic skin 24,38,39 . Furthermore, in a pro-inflammatory environment, increased activity of MMPs has been shown to impair dermal fibroblast migration 15,20,40 . Therefore, we sought to establish whether there was a difference in expression and activity of MMPs and TIMPS between ND-DF and T2DM-DF, or their responses to TNF-α.…”

“…Therefore, excessive and extensive exposure may contribute to chronic non-healing wounds prevalent in T2DM. Circulating plasma levels of TNF-α are typically around 10 pg/ml 18 but in diabetic patients can be almost tenfold higher 19 and circulating TNF-α concentrations positively correlate with diabetes duration 20 . In healthy skin tissue, concentrations of TNF-α are highly variable but typically in the order of 1.5 ng/ml 21 .…”