**5. Metabolic syndrome**

248 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

hyperrelaxed accesory muscles and upper-airway dilators and, finally, because lung residual capacity is reduced during sleep and so the pharyngeal traction is. Then, normally decreased nocturnal oxygen saturation becomes a challenge in COPD and SAHS patients. A more blunted chemical response to hypoxic drive is seen in both diseases. A diminished ventilation/perfusion quotient results from an hyperinflated lung, less activity of intercostal muscles and a dissociated diaphragmatic and intercostal activity in COPD patients. A collapsible pharynx is the main cause of hypoxia and sleep disturbance in SAHS. Associated symptoms, comorbid diseases, drugs and sedentary lifestyle also reduce sleep efficacy.

Evidence from extent population-based prospective and experimental studies links short and/or poor sleep and type 2 diabetes (Tasali et al., 2008). The sleep-related diabetes is not necessarily explained by apneas (Ayas et al., 2003; Mallon et al., 2005). Two laboratory studies performed in healthy young lean adults obtained an enhanced insulin resistance and a diminished insulin secretion related to sleep deprivation (Knutsonet al., 2007; Spiegel et al., 1999). Measurements of insulin-glucose homeostasis were based on intravenous glucose overload and minimal model technique respectively. Minimal model (Bergman, 2005) resulted in a glucose disposition index (DI) 40% lower than after sleep recovery. A low DI reflects an insulin secretion that is insufficient to compensate for insulin resistance. A low DI indicates a high risk for type 2 DM. Subjects underwent a relative short sleep restriction (4 h for 6 or 2 nights) however inducing a pre-diabetic state similar to the habitual in older adults. Reduction of slow-wave sleep and sleep fragmentation were assessed in another laboratory set-up (Tasali et al., 2008), resulting a similar marked decrease in insulin sensitivity without a balanced insulin secretion. The decrease in insulin sensitivity was correlated with a rise in heart rate variability as a measure of the daily sympathetic activity. In addition, insulin resistance was more related to sleep slow wave suppression than to sleep fragmentation. These experimental procedures have not been reproduced in specific

We conclude that, in addition to hypoxia, sleep curtailment enhances sympathetic activation. Noradrenalin is a counter-regulatory hormone that reduces insulin release and function. There is also a decreased glucose uptake by muscle cells favored by high evening cortisol levels and extended duration of elevated growth hormone (GH) levels at night. Another relevant effect of short sleep is upregulation of appetite. A hormonal deregulation of appetite has been observed in the mentioned laboratory studies (Knutson et al., 2007). Ghrelin and leptin are hormones that exert respective hunger and satiety effects. Leptin inhibits appetite, modulates fat distribution and increases energy expenditure. Sleep debt shortens the adequate time that leptin levels require to balance the previous onset of a ghrelin peak. The ghrelin peak occurs during the first half of the night. An attenuated function of leptin due to leptin-CRP boundage has also been hypothesized (Chen et al.,

In diabetic patients, sleep duration and quality was associated with a poorer glycemic control in data from a cross-sectional study on African-American adults with type 2 DM (Knutson et al., 2006). Sleep characteristics were self-reported. Interestingly, sleep quality was associated with poorer glycemic control only in patients with chronic complications of diabetes. A theoretical explanation would be an impaired autonomic response at the background of those diabetic subjects. They would be more susceptible to a less-quality sleep. The cited results were adjusted for age, gender, insulin treatment and BMI. Central

2006). It is plausible in an inflammatory scene such sleep debt.

SAHS and COPD settings.

We can consider three group of factors in COPD patients: respiratory exacerbations and lung function, nutritional and muscle disorders and finally metabolic syndrome. There are several definitions of MS, but a common element is that all the components are related to the existence of insulin resistance, which will lead to glucose intolerance, abdominal obesity, elevated triglycerides, decreased HDL cholesterol and hypertension. It is estimated that 40- 50% of individuals over 60 years have MS in industrialized countries. In Europe there is a prevalence of 15% (Hu et al., 2004; Botros et al., 2009). In a study of 170 patients with COPD and 30 with chronic bronchitis, Sicras et al. (Sicras et al., 2007) observed that the frequency of MS was 53%, 50%, 53% 37% and 44% in patients with chronic bronchitis, COPD I, II, III and IV respectively. They explained the lower incidence in the latter stages of the disease would be related to weight loss.

As previously mentioned, insulin resistance and the development of type 2 diabetes is the key point of MS. In this sense, we have discussed that hypoxia, obesity and sleep disturbances reduce the insulin sensitivity. We could say that the association between SAHS and DM resembles the clustering of metabolic diseases found in MS. The components of MS keep bidirectional links, such insulin resistance and obesity, that are plausible between SAHS and DM. Similarly, the sum of SAHS and DM may result in multiplied cardiovascular effects.

We discussed that the association between COPD and MS is far less clear than the parallel course of SAHS and MS. Due to hypoxia, a change towards multiple firing of vasoconstrictor neurons will increase noradrenalin levels, so we could expect at least arterial hypertension in COPD. Surprisingly, patients were not hypertensive in data by Ashley et al. (Ashley et al., 2010), and the authors posed tempering vascular factors that might balance the hypertensive drive. The links between COPD, metabolic syndrome and cardiovascular disease are largely unknown. Most of the data available deals with the association between SAHS, endothelial dysfunction and subsequent cardiovascular morbidity (Zamarron et al., 2008). There is also recent evidence of an increased mortality in overlap patients without CPAP therapy as compared to COPD (42.2 vs. 24.2%, p < 0.001) (Marin et al., 2010). Death was most commonly due to cardiovascular disease. A poorer quality of life was also demonstrated, even in patients without diurnal sleepiness.

The COPD, SAHS and DM shared inflammatory state perpetuates these chronic conditions and have a cardiovascular impact. Hypoxia induced factor (HIF-1) triggers inflammation and angiogenesis inside the atherosclerotic plaque this way facilitating the entry of phagocytes, red blood cells and lipoproteins. CRP is also directly related to atherosclerosis.

Chronic Obstructive Pulmonary Disease and Diabetes *Mellitus* 251

patients with DM 2 who used high-dose inhaled fluticasone (2 mg / day). Other study (Slatore et al., 2009), shows that high dose of inhaled corticosteroids are associated with small changes in glycemic control that are detectable but not clinically relevant as they

One shared mainstay of COPD and DM treatment is physical exercise. Physical activity improves lung function and provides a better tolerance of the obstructive disease. It also reduces the risk of type 2 DM (13) and improves glycemic control with a lower dose of

Weight loss can clearly be of benefit for patients with SAHS, obesity and/or DM. Probably, a benefit can be obtained in not advanced COPD stages with excessive weight. Weight loss improves SAHS but does not cure it. In a meta-analysis about bariatric surgery and SAHS, the baseline AHI was reduced from 54.7 to 15.8 events per hour, the latter indicating a moderate to severe SAHS still remaining (Greenburg et al., 2009). Patients should be alerted that they will probably need to continue SAHS treatment after surgery. Clinicians should also be aware that weight loss is associated with increased mortality in COPD. There is no

In an indirect way, the oxygen prescribed in advanced lung disease may also influence the management of diabetes. Unfortunately we lack solid studies to verify it. The hypothesis is that control of hypoxia may improve glucose tolerance and the associated MS. CPAP treatment of SAHS has not shown to improve metabolic syndrome in obese patients (Vgontzas

As we have described how hyperglycemia may worsen COPD outcome, we could pose if diabetes treatment can improve respiratory function. Being type 2 the most prevalent DM among COPD patients, insulin sensitizers could improve the lung function. This hypothesis was tested by Kim and colleagues (Kim et al., 2010) in a retrospective cohort study. After adjustment by weight, height and glycemic control, they found an improvement of FVC in subjects treated with insulin sensitizers compared to other DM treatments, with no

We wonder if the new anti-inflammatory drugs (anti-phosphodiesterase 4) may have an effect on control of DM trying to improve the chronic inflammation of COPD. Modulators of the oxidative process such as methyl-bardoxolona are a possibility to be explored in both

We think that we should estimate the risk of diabetes in a COPD patient and *vice versa,* given the frequent simultaneity of both conditions and the confluence of common related factors. Definitely, prospective population-based and experimental evidence is needed to elucidate the crucial pathways between chronic hypoxemic status, insulin resistance and their contributing factors, mainly tabaquism, adiposity and disordered sleep. Of note, the architecture of sleep is of growing importance in DM. Understanding the clustering of these disorders and its cardiovascular prognosis may have an epidemiological impact on the tandem increase of COPD, DM and related conditions. Probably, lifestyle interventions on tobacco, diet and sleep

habits are the key to keep the individual's health and long term well-being.

et al., 2008), whereas it reduces visceral fat in non obese patients (Chin et al., 1999).

would not be a criteria to stop or change the treatment.

evidence to recommend weight loss in overlap syndrome.

significant changes in FEV1 or in FEV1/FVC.

antidiabetic agents.

chronic conditions.

**7. Conclusion** 

CRP interaction with Fcgamma receptor (Fcγ R) possibly increases the monocyte chemokine MCP-1 production, leading to monocyte adherence on to the arterial wall (Sevenoaks & Stockley, 2006). CRP also facilitates the production of foam cells that give shape to the atherosclerotic plaque. The "Third National Health and Nutrition Examination Survey" (NHANES III) denoted an association between CRP and myocardial ischemia. CRP levels higher than 3 mg/dl are significantly related to future cardiovascular events (Pai et al., 2004). This level is commonly surpassed in COPD patients. NF-κβ and TNF-α pathways leading to cardiovascular disease deserve a thorough research in COPD, SAHS and overlap syndrome. TNF- α induces the expression of CRP in the liver, being at the core of the process. TNF- α also has an active effect on macrophages migration, adhesion and differentiation within the atheroma plaque (Sevenoaks & Stockley, 2006). During COPD acute exacerbations, a further rise in CRP levels is also followed by a rise in fibrinogen as the expression of a thrombosis risk. Of note, cardiovascular mortality is particularly enhanced within and following hospital admission for an acute exacerbation (Sevenoaks & Stockley, 2006; Smeeth et al., 2004).

Briefly, the common consequence of COPD, SAHS, MS and DM is an inflammatory status that culminates in endothelial dysfunction leading to cardiovascular events. A novel explanation for the convergent endothelial dysfunction is a depletion or low response of bone marrow stem-cells. This phenomenon determines a reduction of circulating endothelial progenitor cells (EPC). Hyperglycemia, obesity, hypertension and dyslipidemia have been associated with a reduction of circulating EPC. Moreover, a synergistic reduction of EPC has been associated to the clustering of metabolic disruptions (Fadini et al., 2007; Werner et al., 2005, as cited in Tiengo et al., 2008).
