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To the Editor: Dr Pradhan and colleagues1 found that elevated levels of interleukin 6 (IL-6) were associated with the risk of developing type 2 diabetes mellitus in a large cohort of apparently healthy middle-aged women. Their data are consistent with the results of others.2 - 3 According to Pradhan et al, type 2 diabetes mellitus may be a manifestation of a long lasting and ongoing cytokine-mediated acute phase response involving IL-6. However, the mechanisms of the diabetogenic action of IL-6 are far from clear. Modulation of insulin secretion by IL-6 does not seem to be a major factor; on the other hand, there is recent evidence that IL-6 may produce insulin resistance.2 - 3 Cytokines can exert their effects either directly or indirectly, although a direct effect of IL-6 on the insulin–receptor transduction pathway has not been demonstrated. Indirect effects on insulin resistance have been attributed to the stimulatory action of IL-6 on the hypothalamic-pituitary-adrenal axis, hence to induction of a hypercortisolemic state.3 In fact, hypercortisolism leads to insulin resistance in a number of conditions.
We wish to focus on an additional mechanism by which IL-6 is able to enhance local glucocorticoid action even when levels of circulating cortisol are not elevated. We and others have shown that IL-6 increases the number of glucocorticoid receptors.4 - 5 We suggest that IL-6 upregulates not only secretion of glucocorticoids, but also sensitivity to them. Glucocorticoids, in turn, are well-known inhibitors of IL-6 expression. These effects create a feedback loop that restrains excess IL-6 production and prevents tissue damage in many inflammatory conditions. From the clinical viewpoint this could mean that, in patients with sustained IL-6 hyperproduction (even at low levels and whatever the cause of such conditions), glucocorticoid action could be more apparent, particularly in target cells in which such action is more closely related to the number of binding sites. We do not know whether this is the case for insulin-sensitive cells, and thereby whether the phenomenon eventually leads to insulin resistance. The time has come for research on abnormal cytokine production as a factor for abnormal hormone action.
This letter was shown to Drs Pradhan and Ridker, who declined to reply.—ED.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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