Sleep-disordered breathing, glucose intolerance, and insulin resistance

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Abstract

Sleep-disordered breathing (SDB) is a common condition with prevalence estimates of 2–4% in the general population. Epidemiological data suggest that SDB is an independent risk factor for cardiovascular disease. Glucose intolerance and insulin resistance are also well-recognized risk factors for the development of cardiovascular disease. A number of recent clinic-based studies suggest that, independent of obesity, SDB may adversely affect glucose tolerance and insulin sensitivity. The purpose of this study was to systematically review the evidence for the link between SDB, glucose intolerance, and insulin resistance. A MEDLINE search for SDB and metabolic disorders was performed and 24 articles that met the inclusion criteria were identified. Population-based studies indicate that habitual snoring is independently associated with glucose intolerance and insulin resistance. Studies that have used objective measures of SDB (e.g. polysomnography) provide further support for an independent link between SDB, glucose intolerance, and insulin resistance. However, studies on the treatment of SDB with continuous positive airway pressure (CPAP) have yielded inconsistent results and overall do not reveal an improvement in the metabolic disturbance after treatment. Although population-based prospective data on the metabolic implications of SDB are still lacking, current data point to an independent association between SDB and impaired glucose homeostasis. Potential mediators of this association include altered adrenergic function, the direct effects of hypoxemia on glucose regulation, and release of proinflammatory cytokines that affect metabolism.

Introduction

Sleep-disordered breathing (SDB) is a disorder that is characterized by recurrent collapse of the upper airway during sleep. Population-based epidemiologic data indicate that 4% of adult men and 2% of adult women may have this chronic condition (Young et al., 1993). Patients with SDB often present with complaints of loud disruptive snoring, witnessed apneas, fatigue, and daytime sleepiness. SDB can disrupt nocturnal sleep continuity and lead to a number of adverse cardiovascular complications. Recent data from the Wisconsin Sleep Cohort Study and the Sleep Heart Health Study indicate that SDB is an independent risk factor for hypertension (Young et al., 1997, Nieto et al., 2000, Peppard et al., 2000) and prevalent cardiovascular disease (Shahar et al., 2001). Clinic based studies also suggest that SDB may lead to increased cardiovascular morbidity and mortality (Mooe et al., 2001).

Given the emerging data on the potential contribution of SDB to the occurrence of cardiovascular disease, a number of studies have examined intermediate mechanisms in the putative causal pathway. In particular, the effects of SDB on glucose tolerance and insulin sensitivity have received increasing attention in recent years. The focus on the metabolic implications of SDB is based on several studies that suggest an independent association between SDB, glucose intolerance, and insulin resistance. In light of the trends in the prevalence of obesity, glucose intolerance and insulin resistance are becoming increasing prevalent in the general population. Data from the Third National Health and Nutrition Examination Survey indicate that 5.1% of the adults in the United States have physician-diagnosed diabetes and an additional 2.7% meet the criterion for diabetes but remain undiagnosed (Harris et al., 1998). It is also estimated that 6.9% of the adults have impaired fasting glucose levels (≥110 mg/dl) and 15.6% have glucose intolerance (Harris et al., 1998). Since SDB and metabolic dysfunction share common etiologic risk factors (e.g. central obesity), rigorous control for such confounders is critical in establishing whether a causal link exists between the two disorders.

Although definitive evidence to support a causal association is still lacking, there are several lines of indirect evidence that have implicated SDB as an independent risk factor for glucose intolerance and insulin resistance. First, there is evidence that SDB is associated with an increase in sympathetic activity (Somers et al., 1995, Fletcher, 1997, Narkiewicz and Somers, 1997). Sympathetic hyperactivity can impair glucose homeostasis by increasing glycogen breakdown and gluconeogenesis. Second, data from animal models suggest that exposure to hypoxia can induce a state of insulin resistance (Cheng et al., 1997, Raff et al., 1999, Raff et al., 2001). Third, curtailment of sleep duration and secondary sleep debt, a common occurrence in SDB, can impair glucose tolerance in normal subjects (Spiegel et al., 1999). Although a number of previous studies have examined the relationship between SDB and metabolic dysfunction, the possibility of a causal link remains controversial given that the effects of obesity and other confounders have not been adequately addressed. The purpose of this study was to systematically review and critically appraise the evidence for the link between SDB, glucose intolerance, and insulin resistance.

Section snippets

Methods

A computerized bibliographic search of the MEDLINE database was performed to identify articles in the English language published between 1966 through June 2002. The following key words were used in the search: ‘insulin resistance’, or ‘glucose intolerance’, or ‘diabetes’ or ‘metabolic diseases’, and ‘sleep apnea syndromes’. Additional searches included use of the following exploded MeSH terms: ‘sleep apnea syndromes’ and ‘metabolic diseases’. Abstracts of each of the resulting articles were

Results

A total of 969 studies were identified through the computerized bibliographic search of the MEDLINE database. Abstracts of all the studies were reviewed independently by two of the authors and a final set of 24 articles that met the inclusion criteria were selected for the final review. These articles were classified into three categories: studies on the association between markers of SDB (e.g. snoring, witnessed apneas) and metabolic dysfunction (Table 1), studies of polysomnographically

Discussion

The results of this systematic review suggest SDB is independently associated with glucose intolerance and insulin resistance. The presence of habitual snoring, a marker for SDB, is associated with an increased prevalence of metabolic abnormalities and confers a higher risk for the development of type 2 diabetes mellitus independent of obesity and other covariates. Although studies on the relationship between snoring and metabolic dysfunction have been methodologically rigorous in accounting

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