One-third of all individuals with hyperglycemia admitted to an urban general hospital do not have a previous diagnosis of diabetes; in these patients, hyperglycemia is a risk factor for adverse outcomes during acute illness (1). For example, in patients presenting with acute myocardial infarction, glucose values in excess of 6.1–8.0 mmol/l were associated with a threefold increase in mortality and a higher risk of heart failure (2). Control of hyperglycemia with intensive insulin therapy during acute illness results in marked improvements of clinical outcomes (3).
Dandona et al. (4) put forward a working hypothesis linking in a feedback loop of glucose (and possibly other nutrients), insulin, and inflammation. According to this paradigm, hyperglycemia has a proinflammatory action that is normally restrained by the anti-inflammatory effect of insulin secreted in response to that stimulus. A likely corollary of this paradigm is that the proinflammatory effects of acute (stress) hyperglycemia may be implicated in the poor prognosis of hospitalized patients with or without diabetes (particularly death, disability after acute cardiovascular events, and infections). We have demonstrated that circulating levels of some proinflammatory cytokines are regulated by glucose levels in humans (5). Acute hyperglycemia (∼15 mmol/l) induced by glucose clamping in normal subjects and lasting 5 h determines a significant increase of interleukin (IL)-6, IL-18, and tumor necrosis factor-α (TNF-α) circulating levels. These effects were more sustained in patients with impaired glucose tolerance, as well as following consecutive pulses of intravenous glucose, and were annulled by glutathione, implicating an oxidative mechanism. Interestingly enough, these cytokines have been implicated in insulin resistance (TNF-α and IL-6), atherosclerotic plaque destabilization (IL-18), and future cardiovascular events (IL-6, IL-18, and TNF-α). So, an increased oxidative stress may be a likely mechanism linking stress hyperglycemia to cardiovascular events via an increased cytokine production.
Free fatty acids (FFAs) also induce proinflammatory changes. During illness, stress increases the concentration of counterregulatory hormones (mainly glucagon, an epinephrine). Given this background, it is plausible that in the presence of high concentrations of both glucose and FFA, inflammation is more prominent. We tested this hypothesis by giving type 2 diabetic patients two different meals: a high-carbohydrate meal (high glucose levels) and a high-fat meal (high glucose plus high FFA levels). In the latter condition, the serum concentrations of cytokines (TNF-α and IL-6) and adhesion molecules (intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) were at the highest level (6).
In conclusion, high circulating concentrations of glucose and FFAs may explain, at least in part, the oxidative and inflammatory derangements during acute illness; insulin may exert its anti-inflammatory action by ameliorating glucose and lipid parameters. However, any additional anti-inflammatory effect insulin may have of its own is welcome. The importance is to recognize that treatment of even trivial hyperglycemia during acute illness is fundamental to improve survival. Because insulin is the best choice to normalize glucose control during stress, accepting the premise will inevitably bring increased insulin use in intensive care units.
References
Address correspondence to Dario Giugliano, MD, PhD, Department of Geriatrics and Metabolic Diseases, Policlinico della Seconda Università di Napoli, Piazza L. Miraglia, 80138 Naples, Italy. Email: [email protected].
