Sleep Apnea and Diabetes: A Possible Link?

Vol. 12 •Issue 6 • Page 10
Sleep Tracks

Sleep Apnea and Diabetes: A Possible Link?

Much attention has been focused recently on the role of sleep apnea in the development of metabolic dysfunction, including glucose intolerance, insulin resistance and overt diabetes.

Over the last decade, a number of studies have shown that self-reported history of habitual snoring, a common symptom of sleep apnea, is associated with an increased prevalence of glucose intolerance and is a risk factor for incident diabetes independent of obesity.1,2 Studies that have included a formal assessment of respiratory abnormalities during sleep with oximetry or full-montage polysomnography also have shown that sleep apnea is independently associated with metabolic dysfunction and may predispose to diabetes mellitus.3-12


Although definitive data to suggest a causal association between sleep apnea and metabolic dysfunction are still lacking, there’s good evidence that implicates intermittent hypoxemia and sleep loss as factors that could predispose to the development of metabolic dysfunction.

Literature from animal and human studies has shown that hypoxia can lead to development of insulin resistance. Previously healthy subjects manifest a state of acute insulin resistance when exposed to hypoxic conditions either in a hypobaric chamber or with rapid ascent to a high altitude.13,14 Experimental hypoxia in animal models also can increase serum levels of insulin and leptin, an adipocyte-derived factor that regulates glucose homeostasis.15,16

In addition to the detrimental effects of hypoxia, apnea-related sleep fragmentation and the resulting sleep loss may impose additional risk for the development of metabolic dysfunction. A recent study of normal subjects showed that a moderate level of acute sleep deprivation can exert a strong negative influence on glucose tolerance.17 Prospective data from the Nurses’ Health Study also has shown that sleep loss is a risk factor for incident diabetes independent of obesity.18

Collectively, the available animal and human data indicate that the pathophysiological consequences of intermittent hypoxemia and sleep fragmentation (with associated sleep loss) in sleep apnea could contribute independently to metabolic dysfunction. The question of how intermittent hypoxia and sleep fragmentation mediate their effects isn’t known.


Two intermediate pathways through which sleep apnea may disrupt glucose homeostasis include the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis.

Numerous studies have shown that patients with sleep apnea exhibit elevated levels of sympathetic neural traffic.19-23 Each episode of obstructive apnea is accompanied by transient periods of sympathoexcitation that resolve after termination of the event. Hypoxemia is the predominant stimulus for the sympathoexcitation with larger desaturations causing larger increases in sympathetic nerve activity.

However, other factors, including hypercarbia and arousal from sleep, also can increase transiently autonomic output. Sympathetic hyperactivity can influence glucose homeostasis by increasing glycogen breakdown and gluconeogenesis.

Further predisposition toward metabolic dysfunction in sleep may occur through its effects on the HPA axis. Experimental partial or total sleep deprivation has been shown to increase levels of plasma cortisol.24 This increase in serum cortisol levels can have marked effects on serum glucose and insulin levels and insulin secretion rate. Nonetheless, currently the data on the relationship between sleep apnea and altered HPA axis are limited.25

Cyclical hypoxia also may lead to metabolic dysfunction by promoting the release of inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a). Clinic-based studies have shown that plasma levels of IL-6 and TNF-a in patients with sleep apnea are higher compared to control subjects.8,26

IL-6 is a key inflammatory mediator that’s released by subcutaneous adipose tissue. Serum levels of IL-6 are correlated with indices of insulin resistance, and higher levels are associated with an increased risk for type II diabetes mellitus.27-29

Recent data also implicate TNF-a as a putative agent in the development of insulin resistance.30-33 Although the mechanisms through which inflammatory cytokines potentiate metabolic dysfunction need further clarification, there’s increasing acceptance that glucose intolerance, insulin resistance and diabetes mellitus are mediated, in part, by an inflammatory response.

A number of questions still remain on the association between sleep, glucose intolerance, insulin resistance and diabetes. Although studies have shown significant independent associations between these disorders, the role of central versus peripheral obesity hasn’t been rigorously addressed.

Central adiposity is a risk factor for sleep apnea, glucose intolerance, insulin resistance and diabetes. Thus, it’s possible that the observed relationship between sleep apnea and metabolic dysfunction is related to central adiposity though independent of body mass index itself. If it turns out that there’s a true causal association, then the magnitude of effect and its contribution in promoting cardiovascular disease in sleep apnea needs to be determined.

Lastly, whether treatment of sleep apnea with positive pressure therapy or with other alternatives can reverse the metabolic dysfunction also requires further study. While a number of questions remain unanswered, available data suggest the existence of a relationship between sleep apnea and metabolic dysfunction that’s independent of obesity.

Dr. Punjabi is an assistant professor of medicine and epidemiology in the division of pulmonary and critical care medicine, Johns Hopkins University, Baltimore.

For a list of references, please call John Crawford at (610) 278-1400, ext. 1499, or visit

This Sleep Tracks column is produced in conjunction with the American Sleep Apnea Association. The ASAA can help you help your patients. For brochures, newsletter reprints, articles and other materials, write to the staff at 1424 K St., N.W., Suite 302, Washington, D.C., 20005, call (202) 293-3650 or visit


Sleep apnea has been linked with glucose intolerance, insulin resistance and overt diabetes.

Glucose tolerance is a measure of an individual’s ability to metabolize glucose after a glucose challenge. Insulin resistance is a state involving a less than normal response to the actions of insulin — a hormone responsible for the regulation and maintenance of normal blood glucose levels. Glucose intolerance and insulin resistance precede the development of type II diabetes mellitus and can increase the risk of hypertension and cardiovascular disease.

It’s estimated that approximately 5 percent of adults in the United States have physician-diagnosed diabetes, and another 2.7 percent meet the criteria for diabetes yet remain undiagnosed.1

Diabetes mellitus is associated with adverse micro- and macro-vascular consequences, including coronary artery disease, peripheral artery disease, nephropathy and retinopathy.


1. Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care. 1998;21(4):518-24.

—Naresh M. Punjabi, MD, PhD