Muscle Lipid Oxidation Is Not Affected by Obstructive Sleep Apnea in Diabetes and Healthy Subjects.

The molecular mechanisms linking obstructive sleep apnea (OSA) with type 2 diabetes mellitus (T2DM) remain unclear. This study investigated the effect of OSA on skeletal muscle lipid oxidation in nondiabetic controls and in type 2 diabetes (T2DM) patients. Forty-four participants matched for age and adiposity were enrolled: nondiabetic controls (control, n = 14), nondiabetic patients with severe OSA (OSA, n = 9), T2DM patients with no OSA (T2DM, n = 10), and T2DM patients with severe OSA (T2DM + OSA, n = 11). A skeletal muscle biopsy was performed; gene and protein expressions were determined and lipid oxidation was analyzed. An intravenous glucose tolerance test was performed to investigate glucose homeostasis. No differences in lipid oxidation (178.2 ± 57.1, 161.7 ± 22.4, 169.3 ± 50.9, and 140.0 ± 24.1 pmol/min/mg for control, OSA, T2DM, and T2DM+OSA, respectively; p > 0.05) or gene and protein expressions were observed between the groups. The disposition index, acute insulin response to glucose, insulin resistance, plasma insulin, glucose, and HBA1C progressively worsened in the following order: control, OSA, T2DM, and T2DM + OSA (p for trend <0.05). No association was observed between the muscle lipid oxidation and the glucose metabolism variables. We conclude that severe OSA is not associated with reduced muscle lipid oxidation and that metabolic derangements in OSA are not mediated through impaired muscle lipid oxidation.

Visceral Fat Accumulation Is Related to Impaired Pancreatic Blood Perfusion and Beta-Cell Dysfunction in Obese Women.

AIMS/HYPOTHESIS: Beta-cell failure plays a fundamental role in type 2 diabetes mellitus (T2DM) development. It has been shown that the beta-cells are among the most sensitive to hypoxia. We aimed to analyze whether decrease in pancreatic perfusion relates to 1/decline in beta-cell function and 2/visceral fat accumulation in patients with T2DM. METHODS: Fifteen women with T2DM on metformin therapy alone and fifteen women of comparable age and BMI without prediabetes/diabetes were cross-sectionally examined: clinical and anthropometric examination, fast sampled intravenous glucose tolerance test (FSIVGTT), dynamic contrast-enhanced magnetic resonance imaging to assess pancreatic perfusion (area under the curve of postcontrast saturation, AUCTSIC), and visceral adiposity (VAT, calculated from transverse sections at the level L2-L5 vertebrae). RESULTS: Pancreatic blood perfusion (AUCTSIC) did not differ between groups (p = 0.273), but it negatively correlated with BMI (r = -0.434, p = 0.017), WHR (r = -0.411, p = 0.024), and VAT (r = -0.436, p = 0.016) in both groups. Moreover, AUCTSIC in the head of the pancreas negatively correlated with the level of fasting glycemia (r = -0.401, p = 0.028) and HOMA-IR (r = -0.376, p = 0.041). DISCUSSION/CONCLUSION: We showed that decreased pancreatic perfusion did not relate to beta-cell dysfunction in early stages of T2DM development, but it was related to VAT, insulin resistance, and higher fasting glycemia. Furthermore, lower pancreatic perfusion was related to VAT, insulin resistance, and higher fasting glycemia.

Obstructive sleep apnoea increases lipolysis and deteriorates glucose homeostasis in patients with type 2 diabetes mellitus.

Obstructive sleep apnoea (OSA) is associated with type 2 diabetes mellitus (T2DM). However, mechanisms mediating association between these two conditions remain unclear. This study investigated, whether the OSA-associated changes in adipose tissue lipolysis might contribute to impaired glucose homeostasis in patient with T2DM. Thirty-five matched subjects were recruited into three groups: T2DM + severe OSA (T2DM + OSA, n = 11), T2DM with mild/no OSA (T2DM, n = 10) and healthy controls (n = 14). Subcutaneous abdominal adipose tissue microdialysis assessed spontaneous, epinephrine- and isoprenaline-stimulated lipolysis. Glucose metabolism was assessed by intravenous glucose tolerance test. Spontaneous lipolysis was higher in the T2DM + OSA compared with the T2DM (60.34 ± 23.40 vs. 42.53 ± 10.16 µmol/L, p = 0.013), as well as epinephrine-stimulated lipolysis (236.84 ± 103.90 vs. 167.39 ± 52.17 µmol/L, p < 0.001). Isoprenaline-stimulated lipolysis was unaffected by the presence of OSA (p = 0.750). The α2 anti-lipolytic effect was decreased in T2DM + OSA by 59% and 315% compared with T2DM and controls (p = 0.045 and p = 0.007, respectively). The severity of OSA (AHI) was positively associated with spontaneous (p = 0.037) and epinephrine-stimulated (p = 0.026) lipolysis. The α2-adrenergic anti-lipolytic effect (p = 0.043) decreased with increasing AHI. Spontaneous lipolysis was positively associated with Insulin resistance (r = 0.50, p = 0.002). Epinephrine-stimulated lipolysis was negatively associated with the Disposition index (r = - 0.34, p = 0.048). AHI was positively associated with Insulin resistance (p = 0.017) and negatively with the Disposition index (p = 0.038). Severe OSA in patients with T2DM increased adipose tissue lipolysis, probably due to inhibition of the α2-adrenergic anti-lipolytic effect. We suggest that dysregulated lipolysis might contribute to OSA-associated impairments in insulin secretion and sensitivity.

The Clinical Impact of Systematic Screening for Obstructive Sleep Apnea in a Type 2 Diabetes Population-Adherence to the Screening-Diagnostic Process and the Acceptance and Adherence to the CPAP Therapy Compared to Regular Sleep Clinic Patients.

Obstructive sleep apnea (OSA) is a common disorder in Type 2 diabetes (T2D) patients further increasing their already high cardiovascular risk. As T2D patients typically not report OSA symptoms, systematic screening for OSA in this population is warranted. We aimed to determine the readiness of T2D patients to undergo screening and to compare their adherence to continuous positive airway pressure (CPAP) therapy with "regular" sleep clinic patients who typically seek medical advice on their own initiative. We therefore recruited 494 consecutive T2D patients and offered them OSA screening using home sleep monitoring (type IV device). All participants in high risk of moderate-to-severe OSA were recommended home sleep apnea testing (HSAT) followed by CPAP therapy. Patients were followed-up for 12 months and outcomes compared to 228 consecutive sleep clinic patients undergoing HSAT. Among 307 screened T2D patients, 94 (31%) were identified at high risk of moderate-to-severe OSA. Subsequently, 54 patients underwent HSAT, 51 were recommended, and 38 patients initiated CPAP (acceptance 75%). Among 228 sleep clinic patients, 92 (40%) were recommended and 74 patients initiated CPAP (acceptance 80%). After 1 year, 15 (39%) T2D and 29 (39%) sleep clinic patients showed good CPAP adherence (use ≥ 4 h/night ≥ 70% nights). In conclusion, 20 T2D patients needed to be screened in order to obtain one successfully treated patient. OSA screening in T2D patients identified 31% with moderate-to-severe OSA. Once diagnosed, their CPAP acceptance and adherence did not differ from sleep clinic patients. However, the reasons for the high dropout during the screening-diagnostic process impacting the overall success of the screening program need to be identified and addressed.

Increased Incretin But Not Insulin Response after Oral versus Intravenous Branched Chain Amino Acids.

BACKGROUND/AIMS: Branched chain amino acids (BCAAs) are known to exert an insulinotropic effect. Whether this effect is mediated by incretins (glucagon like peptide 1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) is not known. The aim of this study was to show whether an equivalent dose of BCAA elicits a greater insulin and incretin response when administered orally than intravenously (IV). METHODS: Eighteen healthy, male subjects participated in 3 tests: IV application of BCAA solution, oral ingestion of BCAA and placebo in an equivalent dose (30.7 ± 1.1 g). Glucose, insulin, C-peptide, glucagon, GLP-1, GIP, valine, leucine and isoleucine concentrations were measured. RESULTS: Rise in serum BCAA was achieved in both BCAA tests, with incremental areas under the curve (iAUC) being 2.1 times greater for IV BCAA compared with those of the oral BCAA test (p < 0.0001). Oral and IV BCAA induced comparable insulin response greater than placebo (240 min insulin iAUC: oral 3,411 ± 577 vs. IV 2,361 ± 384 vs. placebo 961.2 ± 175 pmol/L, p = 0.0006). Oral BCAA induced higher GLP-1 (p < 0.0001) and GIP response (p < 0.0001) compared with the IV or placebo. Glucose levels declined significantly (p < 0.001) in the same pattern during both BCAA tests with no change in the placebo group. CONCLUSIONS: An equivalent dose of BCAA elicited a comparable insulin and greater incretin response when administered orally and not when administered through IV. We conclude that insulinotropic effects of BCAA are partially incretin dependent.

[Obstructive sleep apnoea and type 2 diabetes mellitus]. / Obstrukcní spánková apnoe a diabetes mellitus 2. typu.

Obstructive sleep apnoea syndrome (OSA) is a disease very frequently occurring in people with type 2 diabetes, that significantly increases cardiovascular morbidity and mortality. In a number of studies, OSA has been identified as an independent risk factor for the development of insulin resistance, glucose intolerance and type 2 diabetes mellitus. Disorders of glucose homeostasis in patients with OSA are probably mediated by chronic intermittent hypoxia and/or sleep fragmentation through activation of the sympathetic nervous system, the hypothalamic-pituitary-adrenal stress axis, pro-inflammatory paths or oxidative stress. Despite the high prevalence of OSA among patients with type 2 diabetes as well as the proven benefit of the continuous positive airway pressure (CPAP) therapy on reduction of mortality, most patients with OSA remain undiagnosed. Active OSA screening should therefore be performed in all patients with type 2 diabetes, ideally through home monitoring of oxygen saturation and breathing during sleep. Although the effect of CPAP therapy on the improvement in diabetes control (decrease in glycated hemoglobin) has not been clearly proven in patients with type 2 diabetes so far, promising outcomes have been observed during the treatment of patients with prediabetes.Key words: CPAP - diabetes mellitus - glycemic control - intermittent hypoxia - obstructive sleep apnoea - screening - sleep fragmentation.

Screening for obstructive sleep apnea syndrome in patients with type 2 diabetes mellitus: a prospective study on sensitivity of Berlin and STOP-Bang questionnaires.

BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in patients with Type 2 diabetes mellitus representing an additional risk factor for already increased cardiovascular mortality. As cardiovascular diseases are the main cause of death in this population, there is a need to identify patients with moderate to severe OSA indicated for treatment. We aimed to evaluate the performance of the Berlin, STOP, and STOP-Bang screening questionnaires in a population of patients with Type 2 diabetes mellitus. METHODS: 294 consecutive patients with Type 2 diabetes mellitus filled in the questionnaires and underwent overnight home sleep monitoring using a type IV sleep monitor. RESULTS: Severe, moderate, and mild OSA was found in 31 (10%), 61 (21%), and 121 (41%) patients, respectively. The questionnaires showed a similar sensitivity and specificity for AHI ≥ 15: 0.69 and 0.50 for Berlin, 0.65 and 0.49 for STOP, and 0.59 and 0.68 for STOP-Bang. However, the performance of the STOP-Bang questionnaire was different in men vs. women, sensitivity being 0.74 vs. 0.29 (p < 0.05) and specificity 0.56 vs. 0.82 (p < 0.05). CONCLUSIONS: Even the best-performing Berlin questionnaire failed to identify 31% of patients with moderate to severe OSA as being at high risk of OSA, thus preventing them from receiving a correct diagnosis and treatment. Considering that patients with Type 2 diabetes mellitus are at high risk of cardiovascular mortality and also have a high prevalence of moderate to severe OSA, we find screening based on the questionnaires suboptimal and suggest that OSA screening should be performed using home sleep monitoring devices.

Adipogenesis, lipogenesis and lipolysis is stimulated by mild but not severe hypoxia in 3T3-L1 cells.

In-vitro investigation of the effects of hypoxia is limited by physical laws of gas diffusion and cellular O2 consumption, making prolonged exposures to stable O2 concentrations impossible. Using a gas-permeable cultureware, chronic effects of mild and severe hypoxia on triglyceride accumulation, lipid droplet size distribution, spontaneous lipolysis and gene expression of adipocyte-specific markers were assessed. 3T3-L1 cells were differentiated under 20%, 4% or 1% O2 using a gas-permeable cultureware. Triglyceride accumulation, expression of genes characteristic for advanced adipocyte differentiation and involvement of key lipogenesis enzymes were assessed after exposures. Lipogenesis increased by 375% under mild hypoxia, but dropped by 43% in severe hypoxia. Mild, but not severe, hypoxia increased formation of large lipid droplets 6.4 fold and strongly induced gene expression of adipocyte-specific markers. Spontaneous lipolysis increased by 488% in mild, but only by 135% in severe hypoxia. Inhibition of ATP-dependent citrate lyase suppressed hypoxia-induced lipogenesis by 81% and 85%. Activation of HIF inhibited lipogenesis by 59%. Mild, but not severe, hypoxia stimulates lipolysis and promotes adipocyte differentiation, probably through excess of acetyl-CoA originating from tricarboxylic acid cycle independently of HIF activation.