Publications

Inflammatory bowel disease (IBD) patients display elevated levels of intraluminal nitric oxide (NO). NO can react with other molecules to form toxic compounds, which has led to the idea that NO may be an important mediator of IBD. However, the cellular source of NO and how its production is regulated in the intestine are unclear. In this study we aimed to determine if intestinal myofibroblasts produce NO in response to the IBD-associated cytokines IL-1β, TNFα, and IFNγ. Intestinal myofibroblasts were isolated from mice and found to express inducible nitric oxide synthase (iNOS) mRNA, but not endothelial NOS or neuronal NOS. Individual treatment of myofibroblasts with IL-1β, TNFα, or IFNγ had no effect on NO production, but stimulation with combinations of these cytokines synergistically increased iNOS mRNA and protein expression. Treatment with TNFα or IFNγ increased cell surface expression of IFNγRI or TNFRII, respectively, suggesting that these cytokines act in concert to prime NO production by myofibroblasts. Impairment of NF-κB activity with a small molecule inhibitor was sufficient to prevent increased expression of IFNγRI or TNFRII, and inhibition of Akt, JAK/STAT, or NF-κB blocked nearly all NO production induced by combinatorial cytokine treatment. These data indicate that intestinal myofibroblasts require stimulation by multiple cytokines to produce NO and that these cytokines act through a novel pathway involving reciprocal cytokine receptor regulation and signaling by Akt, JAK/STAT, and NF-κB.

BACKGROUND

Diabetes complications account for significant worldwide morbidity and mortality. Improving glycemic control decreases microvascular complications, particularly among patients with the worst control. Current performance measures fail to prioritize such individuals. The categorization of glycemic control within a safety-net clinic population was compared using a common performance measure against one derived from a metric accounting for change in glycated hemoglobin (A1c) over time.

METHODS

Retrospective cohort analysis of all patients in a safety-net primary care clinic population quality registry with confirmed diabetes mellitus who had at least two A1c values between 2007 through 2011. Patients were stratified into five groups' on the basis of maximum and earliest A1c level (< 7%, 7% to < 8%, 8% to < 9%, 9% to < 10%, and > 10%). The change in Alc was assessed over time and compared with standard healthcare effectiveness data and information set (HEDIS) performance measures.

RESULTS

Some 1122 patients were included in the analysis, with mean A1c of 7.9%. There was a modest annual decrease in the average A1c, and > 19% of patients improved by 1% or more during each of the previous three years. For patients who had maximum A1c values > or = 10%, there was a significantly greater reduction in A1c (p < .01), which was not reflected in the standard performance measure.

CONCLUSIONS

It is feasible for safety-net clinics to analyze their patients with diabetes by level of disease control on the basis of change in A1c over time. Patients with the worst glycemic control tend to have the greatest improvement but are often overlooked by conventional performance measures. Improved performance measures should focus on longitudinal diabetes control and emphasize reducing risk of complications among patients at highest risk.