The dilute plasma cytokine milieu associated with Type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-β-mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age.
To evaluate the contemporary prevalence of diabetic peripheral neuropathy (DPN) in participants with type 1 diabetes in the T1D Exchange Clinic Registry throughout the U.S. RESEARCH DESIGN AND METHODSDPN was assessed with the Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ) in adults with ‡5 years of type 1 diabetes duration. A score of ‡4 defined DPN. Associations of demographic, clinical, and laboratory factors with DPN were assessed. RESULTSAmong 5,936 T1D Exchange participants (mean 6 SD age 39 6 18 years, median type 1 diabetes duration 18 years [interquartile range 11, 31], 55% female, 88% non-Hispanic white, mean glycated hemoglobin [HbA 1c ] 8.1 6 1.6% [65.3 6 17.5 mmol/mol]), DPN prevalence was 11%. Compared with those without DPN, DPN participants were older, had higher HbA 1c , had longer duration of diabetes, were more likely to be female, and were less likely to have a college education and private insurance (all P < 0.001). DPN participants also were more likely to have cardiovascular disease (CVD) (P < 0.001), worse CVD risk factors of smoking (P 5 0.008), hypertriglyceridemia (P 5 0.002), higher BMI (P 5 0.009), retinopathy (P 5 0.004), reduced estimated glomerular filtration rate (P 5 0.02), and Charcot neuroarthropathy (P 5 0.002). There were no differences in insulin pump or continuous glucose monitor use, although DPN participants were more likely to have had severe hypoglycemia (P 5 0.04) and/or diabetic ketoacidosis (P < 0.001) in the past 3 months. CONCLUSIONSThe prevalence of DPN in this national cohort with type 1 diabetes is lower than in prior published reports but is reflective of current clinical care practices. These data also highlight that nonglycemic risk factors, such as CVD risk factors, severe hypoglycemia, diabetic ketoacidosis, and lower socioeconomic status, may also play a role in DPN development.Diabetic neuropathy is a prevalent complication in patients with diabetes and a major cause of morbidity and mortality (1). Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DPN) and diabetic autonomic neuropathies are by far the most studied (1).
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