Insulin Resistance In Obstructive Sleep Apnea Research Articles

Chronic Intermittent Hypoxia Induces Early-Stage Metabolic Dysfunction Independently of Adipose Tissue Deregulation.

Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O2) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O2) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism.

Body Fat Indices as Effective Predictors of Insulin Resistance in Obstructive Sleep Apnea: Evidence from a Cross-Sectional and Longitudinal Study : BFI as Predictors of IR in OSA.

Body fat indices serve as predictive markers of insulin resistance (IR) in metabolic diseases. IR is common in obstructive sleep apnea (OSA). However, whether body fat indices have utility as predictors of IR in OSA remain unknown. A longitudinal study was conducted in 46 patients undergoing bariatric surgery to explore the relationship between IR and body fat indices. Then, a cross-sectional study was performed to evaluate the relationships between body fat indices and IR, and receiver operating characteristic (ROC) curves were generated. Body indices, homeostasis model assessment index of insulin resistance (HOMA-IR), biological indicators, and polysomnographic variables were collected. In the longitudinal study, significant relationships were found between remission of IR and changes in visceral adiposity index (VAI) (r = 0.452, P < 0.05) and triglyceride-glucose index (TyG) (r = 0.650, P < 0.01). In the cross-sectional study, lipid accumulation product (LAP) (best cutoff value: 30.16, area under the curve (AUC) = 0.728, P < 0.001) and TyG (best cutoff value: 8.54, AUC = 0.740, P < 0.001) were indicators of IR in normal weight group. In overweight/obese group, body mass index (BMI) (best cutoff value: 27.69 AUC = 0.707, P < 0.001) and waist circumference (WC) (best cutoff value: 97.25, AUC = 0.708, P < 0.001) were markers of IR. TyG showed better ability to predict IR in normal weight females (best cutoff value: 8.39 AUC = 0.813, P < 0.001). Body fat indices are predictive markers of IR in patients with OSA.

Independent association of vitamin D and insulin resistance in obstructive sleep apnea

BackgroundVitamin D insufficiency and/or high levels of parathyroid hormone (PTH) seem to be associated with abnormal glucose metabolism, which is frequent in obstructive sleep apnea (OSA). The purpose of this study was to investigate vitamin D and PTH concentrations in OSA, and to explore potential links between vitamin D, PTH and insulin resistance (IR). MethodsA total of 112 subjects with suspected OSA were recruited consecutively, and evaluated by polysomnography (PSG) to determine the number of apnea and hypopnea episodes per hour of sleep (apnea/hypopnea index: AHI). OSA was diagnosed for AHI≥5. Average (APO2) and minimum pulse oxygen saturation (MPO2) were assessed during PSG as indices of nocturnal hypoxemia. After overnight fasting, a standard 75g oral glucose tolerance test was performed. Serum 25-hydroxyvitamin D, PTH, fasting glucose and fasting insulin were also measured. Homeostasis model assessment (HOMA) was used to evaluate IR: HOMA-IR=fasting plasma insulin×fasting plasma glucose/22.5, with “insulin resistance” defined as HOMA-IR>2.7. ResultsPatients were classified into 4 groups according to AHI: control group (AHI<5, n=8), mild OSA (5≤AHI<15, n=18), moderate OSA (15≤AHI<30, n=33), and severe OSA (AHI≥30, n=53). They were also classified, according to HOMA-IR, as insulin-resistant (HOMA-IR>2.7, n=59) or non-insulin-resistant (HOMA-IR≤2.7, n=45). There were no significant differences in vitamin D or PTH levels between AHI groups. HOMA-IR was significantly higher in severe OSA than in controls (P=0.019). Vitamin D concentration correlated negatively with AHI (r=−0.242, P=0.01) and with HOMA-IR (r=−0.338, P<0.001). PTH concentration correlated negatively with vitamin D concentration (P<0.001), but not with AHI or HOMA-IR. HOMA-IR correlated positively with AHI (r=0.368, P<0.001) and negatively with MPO2 (r=−0.414, P<0.001). Finally, stepwise linear multivariate regression showed that vitamin D concentration (β=−0.209, P=0.014) and MPO2 (β=−0.221, P=0.011) were independently associated with HOMA-IR. ConclusionSubjects with severe OSA may have a low vitamin D level associated with increased risk of IR. Vitamin D was independently associated with IR in OSA. Vitamin D insufficiency may play a role in the pathogenesis of IR in OSA.

RAGE/NF-κB pathway mediates hypoxia-induced insulin resistance in 3T3-L1 adipocytes

There is growing evidence in support of an independent association between obstructive sleep apnea (OSA) and type 2 diabetes, and in which hypoxia may play an important role. Hypoxia is the hallmark feature and the most important pathophysiologic pathway of OSA. Recently, receptor for advanced glycation end products (RAGE) was found to be involved in the pathogenesis of insulin resistance (IR). However, whether RAGE contributes to the IR of adipocytes under hypoxia remains unknown. In the present study, we found that hypoxia reduced glucose consumption and upregulated RAGE expression in 3T3-L1 adipocytes in a time-dependent manner. RAGE knockdown efficiently attenuated hypoxia-induced IR, including inhibiting serine phosphorylation of insulin receptor substrate-1 (IRS-1), increasing the expression of phosphorylated Akt (Ser473), and improving insulin-stimulated glucose uptake. In addition, hypoxia activated nuclear transcription factor κB (NF-κB). However, RAGE knockdown inhibited hypoxia-induced NF-κB activity in adipocytes. Finally, an NF-κB inhibitor (PDTC) significantly reduced the hypoxia-induced upregulation of RAGE expression and IR. Therefore, this study indicates that the RAGE/NF-κB pathway mediates hypoxia-induced IR in 3T3-L1 adipocytes, and suggests that RAGE may be a potential therapeutic target for suppressing IR in OSA.

Intermittent hypoxia regulates vasoactive molecules and alters insulin-signaling in vascular endothelial cells

Vascular dysfunction and insulin resistance (IR) are associated with obstructive sleep apnea (OSA), which is characterized by frequent episodes of nocturnal intermittent hypoxia (IH). While it is recognized that the balance between vasoconstrictive (endothelin-1) and vasodilatory molecules (nitric oxide, NO) determine vascular profile, molecular mechanisms contributing to vascular dysfunction and IR in OSA are not completely understood. Caveolin-1 is a membrane protein which regulates endothelial nitric oxide synthase (eNOS) activity which is responsible for NO generation and cellular insulin-signaling. Hence, we examined the effects of IH on caveolin-1, eNOS, and endothelin-1 in human coronary artery endothelial cells in the context of IR. Chronic 3-day IH exposure up-regulated caveolin-1 and endothelin-1 expression while reducing NO. Also, IH altered insulin-mediated activation of AKT but not ERK resulting in increased endothelin-1 transcription. Similarly, caveolin-1 overexpression attenuated basal and insulin-stimulated NO synthesis along with impaired insulin-dependent activation of AKT and eNOS, with no effect on insulin-stimulated ERK1/2 phosphorylation and endothelin-1 transcription. Our data suggest that IH contributes to a vasoconstrictive profile and to pathway-selective vascular IR, whereby insulin potentiates ET-1 expression. Moreover, IH may partly mediate its effects on NO and insulin-signaling via upregulating caveolin-1 expression.

Serum advanced glycation end products are associated with insulin resistance in male nondiabetic patients with obstructive sleep apnea.

Advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic vascular complications. Recently, growing evidence has shown that AGEs could be involved in the pathogenesis of insulin resistance. It has also been suggested that circulating AGE are associated with insulin resistance in nondiabetic patients. This study investigated whether serum AGEs levels are associated with insulin resistance in nondiabetic patients with obstructive sleep apnea (OSA). A total of 139 male nondiabetic patients with OSA were recruited for participation in the study. Serum AGE levels were examined using an enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment index (HOMA-IR). There was a significant correlation between serum AGEs and the apnea-hypopnea index (AHI) (r = 0.281, p = 0.014), duration of SaO₂ < 90% (r = 0.267, p = 0.018), minimum SaO₂ (r = -0.188, p = 0.046), high-sensitivity C-reactive protein (hsCRP) (r = 0.274, p = 0.012), and HOMA-IR (r = 0.303, p < 0.001). Multiple regression analysis showed that serum AGEs (p = 0.011), AHI (p = 0.024), waist circumference (p = 0.040), and hsCRP (p = 0.046) were independently associated with HOMA-IR (R(2) = 0.392). In addition, the strength of the correlation between serum AGEs and HOMA-IR was related to the severity of OSA. The present study indicated that serum AGE levels were associated with insulin resistance in male nondiabetic patients with OSA. These findings suggest that AGEs may play a role in insulin resistance in OSA and may also be a biomarker for patients with OSA with high risk of developing type 2 diabetes.

Insulin resistance in obstructive sleep apnea

OSA is a common condition that is primarily characterized by intermittent and recurrent pauses in respiration results in multiple cycles of hypoxia/reoxygenation with an increased production of reactive oxygen species (ROS). Aim of work: Is to assess serum insulin level &insulin resistance in obese patients with & without OSA. Study was performed on 51 obese subjects who had been referred to Chest Department of Kasr Alaini Hospital with clinical suspicion of OSA in order to perform Polysomnography. They were classified into two groups; Cases: consists of 33 obese patients who were diagnosed as obstructive sleep apnea (OSA) & Controls: consists of 18 obese subjects, without OSA as a control group. The two groups were subjected to Full history taking, Clinical examination, Epworth sleepiness scale (ESS), Anthrop-ometric measurements including body mass index (BMI in kg/m2) waist, hip circumferences, waist/hip ratio and neck circumference, Polysomno-graphic study, Serum Insulin by ELISA & Assessment of insulin resistance by calculation of HOMA index. It was found that cases included 10 females (30.3%) & 23 males (69.7%), while controls included 14 females (77.8%) & 4 (22.2%).There was statistically highly significant increase in Epworth slee-piness scale (ESS) among cases compared to controls. As regards the Polysonographic data, there was statistically highly significant increase in AHI, desaturation index & duration of desaturation <90%. among cases compared to control subjects. Regarding minimal O2 sat% & average O2 sat% were lower in cases than in the control subjects and this reduction was statistically significant also there was statistically significant increase in arrhythmias index among cases than control subjects & there was significant increase in snoring index among cases than control subjects. There was statistically highly significant increase in serum insulin, HOMA index among cases as compared to controls. Insulin resistance in OSA is related to sleep associated hypoxaemia & hypoxic stress. Chest Department, Faculty of Medicine Cai-ro University.

The Vicious Cycle of Leptin-Insulin Resistance Predicts Impaired Glucose Metabolism in Obese Adults with Obstructive Sleep Apnea

le tt e r t o t H e e d it o r S is an overlooked area of metabolic processes and an important modulator of endocrine function. Despite a large body of evidence suggesting that obstructive sleep apnea (OSA) is an independent risk factor for type 2 diabetes, the underlying pathogenesis of impaired glucose metabolism (IGM) in OSA remains less well understood. The recent fi ndings of Papaioannou and colleagues showed no clinically signifi cant abnormalities of appetite regulating hormones in OSA that would suggest a cause for IGM.1 While the study provides an important insight into the phenotypic spectrum of OSA, it also raises questions related to possible yet unexplored more complex pathomechanisms linking appetite hormones with IGM in OSA. From a pathophysiological point of view, insulin resistance (IR) and beta-cell dysfunction both play a role in the development of IGM. While research has documented that OSA can contribute to IR independent of obesity, there is a paucity of information on leptin resistance-related IR in OSA that may potentially impair glucose homeostasis. Leptin is a wellknown adipose tissue-derived hormone that binds to receptors in the brain and inhibits expression of neuropeptide Y (NPY). Most obese humans produce large quantities of leptin but are insensitive to its effects. The suggested mechanisms underlying leptin resistance include defective leptin receptors and/or post-receptor signal transduction, reduced numbers of leptin receptors, interactions between leptin and plasma circulating factors, and other factors that override the leptin satiety signal. It is plausible that OSA-stress-related release of NPY from sympathetic nerves and activation of its Y2 receptors in the adipose tissue might stimulate fat angiogenesis and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity, while closing a vicious cycle of increasing leptin-insulin resistance. Considering different receptor-mediated effects of NPY, the plasma level of NPY might not necessarily be the best parameter to assess NPY effects in peripheral tissues. In our study,2 we demonstrated that OSA is associated with specifi c cytokines that refl ect link between OSA and glucose metabolism. Specifi cally, nocturnal oxyhemoglobin desaturations in OSA were closely associated with interleukin-6 (IL-6) production in obese women with IGM, but not in controls with normal glucose metabolism matched individually for sex, age, adiposity, and apnea-hypopnea index. Moreover, cross-sectional data from our study showed additional close associations of IL-6 with leptin-to-leptin receptor ratio and markers of adiposity only in IGM. These fi ndings support the role that IL-6 plays in obesity and extend it to possible pathophysiological processes linking obesity to IGM via leptin resistance and hypoxic stress in OSA. Further prospective studies are needed to explore the dynamic interactions among appetite regulating hormones, their receptors, and glucose homeostasis in OSA to develop novel interventions to prevent metabolic sequelae of OSA.

Sleep apnea is a manifestation of the metabolic syndrome

Obstructive sleep apnea (OSA) is a prevalent disorder particularly among middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness.' In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNFalpha plasma levels and the body-mass-index (BMI). In subsequent studies, we showed that IL-6, TNFalpha, and insulin levels were elevated in sleep apnea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnea. Furthermore, our findings that women with the polycystic ovary syndrome (PCOS) (a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness, suggests a pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnea and sleepiness in obese patients may be manifestations of the Metabolic Syndrome, include: obesity without sleep apnea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity, and age; increased prevalence of sleep apnea in post-menopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA; lack of effect of continuous positive airway pressure (CPAP) in obese patients with apnea on hypercytokinemia and insulin resistance indices; and that the prevalence of the metabolic syndrome in the US population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnea in general random samples. Finally, the beneficial effect of a cytokine antagonist on EDS in obese, male apneics and that of exercise on SDB in a general random sample, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnea in humans. In conclusion, accumulating evidence provides support to our model of the bi-directional, feed forward, pernicious association between sleep apnea, sleepiness, inflammation, and insulin resistance, all promoting atherosclerosis and cardiovascular disease.