Even moderately elevated insulin levels may increase the risk of developing Alzheimer’s disease, according to a small study by investigators at the University of Washington here.

They measured inflammatory markers in plasma and cerebrospinal fluid in 16 adult volunteers who were given infusions to mimic insulin resistance, and found that a moderate increase in peripheral insulin produced “striking” increases in central nervous system inflammatory markers.

“Our findings suggest that insulin-resistant conditions such as Diabetes mellitus and hypertension may increase the risk for Alzheimer’s disease, in part through insulin-induced inflammation,” wrote Mark A. Fishel, M.D. and colleagues in the online version of the Archives of Neurology. The study is scheduled for publication in the October print edition.

The results, if confirmed, suggest that the current epidemic of diabetes and insulin resistance syndromes could cause an upsurge in the prevalence of Alzheimer’s in the future, the authors contended.

Many researchers suspect that inflammation plays a key role in the development of Alzheimer’s disease, as suggested by the presence in CSF levels of Alzheimer’s patients of interleukin 6 (IL-6), an inflammatory cytokine, and F2-isoprostane, a lipid peroxidation marker. In addition, laboratory and animal studies have pointed to an interaction between inflammation and beta-amyloid processing and deposition. Abnormal accumulation of beta-amyloid protein is a diagnostic hallmark of Alzheimer’s.

To test whether insulin resistance could elevate markers of inflammation, the investigators recruited 16 cognitively normal adults ages 55 to 81 years. All were in good health and none were taking medications known to have CNS or gluco-regulatory effects.

On separate mornings one week or more apart, the fasting participants randomly received infusions of saline for a baseline and insulin with variable dextrose levels to raise their plasma insulin levels while maintaining normal glycemia. The result was an approximation of the physiologic state of patients with insulin resistance following a meal.

The investigators then measured changes in plasma and CSF levels of the inflammatory markers IL-1, IL-1, IL-6, F2-isoprostane, and tumor necrosis factor- (TNF-); inflammatory modulators (transthyretin, apolipoprotein E, and norepinephrine); and beta-amyloid.

They found that during hyperinsulinemia, there were increased CSF levels of all the interleukins, TNF-? and F2-isoprostane, but cytokine levels in plasma did not change reliably in response to insulin.

Insulin also increased both plasma and CSF levels of beta-amyloid42, and these changes were predicted by increased cytokine and F2-isoprostane, and by decreased transthyretin levels; transthyretin normally binds beta-amyloid and shuttles it out of the brain and into the periphery.

The increase in inflammatory markers that they observed was modulated by insulin-induced changes in CSF levels of apoE and norepinephrine.

The investigators hypothesize that insulin’s inflammatory effects may be due to its influence on CNS cells that express insulin receptors, such as the endothelial cells in the blood brain barrier, glial cells in the brain, and neurons.

Alternatively, insulin may have an indirect effect on CSF cytokine levels by modulation of CSF and beta-amyloid42 plasma levels.

“Although this model has obvious relevance for Diabetes mellitus, hyperinsulinemia and insulin resistance are widespread conditions that affect many nondiabetic adults with obesity, impaired glucose tolerance, cardiovascular disease, and hypertension,” wrote Dr. Fishel and colleagues. “Our results provide a cautionary note for the current epidemic of such conditions, which, in the context of an aging population, may provoke a dramatic increase in the prevalence of Alzheimer’s disease.”