• Diabetes Mellitus
• Obesity
• Pulmonary Clinical Trials
• Sleep Disorders

• Diabetes Mellitus
• Pulmonary & Critical Care
• Obesity
• Pulmonary Clinical Trials
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• Sleep Disorders

Evidence supports an interaction between obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM). OSA is highly prevalent in persons with T2DM, with some estimates of the prevalence of moderate to severe OSA (defined as an apnea-hypopnia index [AHI] ≥5) as high as 61% [Einhorn D et al. Endocr Pract 2007], but the direction of causality is not yet clear.

Patrick Lévy, MD, PhD, University Joseph Fourier, Grenoble, France, gave an overview of the relationship between OSA and T2DM. In a consecutive series of 60 patients with T2DM, 77% had an AHI≥5, and adjusted HbA1C levels increased with increasing severity of OSA [Aronsohn RS et al. Am J Respir Crit Care Med 2010].

Data also suggest that OSA is independently associated with altered glucose metabolism to promote the development of T2DM. Adjusted odds ratios for the incidence of diabetes in moderate to severe OSA compared with no OSA range from 1.43 to 13.45 [Pamidi S, Tasali E. Front Neurol 2012].

Young lean men with OSA had reduced insulin sensitivity and higher total insulin secretion than controls despite similar glucose levels after an oral glucose tolerance test [Pamidi S et al. Diabetes Care 2012]. Increasing severity of AHI was independently associated with impaired glucose metabolism in a multicentric cohort of 1599 subjects without T2DM [Priou P et al. Diabetes Care 2012].

Sleep fragmentation and intermittent hypoxia can lead to insulin resistance and pancreatic β-cell dysfunction through sympathetic activation, alterations in the HPA axis (ie, increase in levels of cortisol), oxidative stress, activation of inflammatory pathways that promote the release of interleukin-6 and tumor necrosis factor-α, and adverse changes in adipokine profiles including a reduction in adiponectin.

Intermittent hypoxia causes reduced muscle glucose utilization in the soleus muscle in lean mice [Iiyori N et al. Am J Respir Crit Care Med 2007] and increased β-cell proliferation and cell death presumably due to oxidative stress [Xu J et al. Free Radic Biol Med 2009]. An increase in free fatty acid uptake by the liver induced by intermittent hypoxia may upregulate transcriptional pathways of lipid biosynthesis through HIF-1, leading to liver insulin resistance and nonalcoholic steatohepatitis conceivably through accelerated adipose tissue lipolysis [Mirrakhimov AE, Polotsky VY. Front Neurol 2012].

In morbidly obese people, chronic intermittent hypoxia is an independent predictor for nonalcoholic fatty liver disease (NAFLD), hepatic fibrosis, and fibroinflammation [Aron-Wisnewsky J et al. J Hepatol 2012]. Chronic intermittent hypoxia was found to have differential metabolic effects in lean and obese mice, inducing NAFLD, oxidative stress, and inflammation in only the obese mice [Drager LF et al. Obesity 2011].

In uncontrolled studies, it has been initially evidenced that long-term continuous positive airway pressure (CPAP) reduced HbA1C levels in diabetic individuals with sleep-disordered breathing [Babu AR et al. Arch Intern Med 2005]. Also, a rapid improvement in insulin sensitivity in patients with OSA obtained after initiation of CPAP may reflect a reduction in sympathetic activity [Harsch IA et al. Am J Respir Crit Care Med 2004]. The effect was smaller in obese patients, which suggests that in obese patients, insulin sensitivity is determined more by obesity than OSA.

Anthropometric variables (weight, body mass index, subcutaneous fat, visceral fat) improved significantly in a group of OSA patients who underwent 3 months of CPAP compared with sham CPAP [Sharma SK et al. N Engl J Med 2011]. This may explain the overall improvement in the metabolic profile in this study where the study group was highly selected (ie, untreated moderately obese subjects presenting with dysmetabolism). So far, this paper provided the most impressive results but most randomized controlled trials did not confirm this metabolic improvement during OSA treatment [Weinstock TG et al. Sleep 2012; Sivam S et al. Eur Respir J 2012; Hoyos CM et al. Thorax 2012]. Pepin et al. recently published a summary explaining the conflicting results [Thorax 2012]. The duration of CPAP, patient age, comorbidities, and the severity of OSA and intermittent hypoxia all appear to be critical factors in the relative success of CPAP in treating OSA.

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