Intensive diabetes control has been associated with increased mortality in type 2 diabetes (T2DM); this has been suggested to be due to increased hypoglycemia. We measured hypoglycemia-induced changes in endothelial parameters, oxidative stress markers and inflammation at baseline and after a 24-hour period in type 2 diabetic (T2DM) subjects versus age-matched controls. Case-control study: 10 T2DM and 8 control subjects. Blood glucose was reduced from 5 (90 mg/dl) to hypoglycemic levels of 2.8 mmol/L (50 mg/dl) for 1 hour by incremental hyperinsulinemic clamps using baseline and 24 hour samples. Measures of endothelial parameters, oxidative stress and inflammation at baseline and at 24-hours post hypoglycemia were performed: proteomic (Somalogic) analysis for inflammatory markers complemented by C-reactive protein (hsCRP) measurement, and proteomic markers and urinary isoprostanes for oxidative measures, together with endothelial function. Between baseline and 24 -hours after hypoglycemia, 15 of 140 inflammatory proteins differed in T2DM whilst only 1 of 140 differed in controls; all returned to baseline at 24-hours. However, elevated hsCRP levels were seen at 24-hours in T2DM (2.4 mg/L (1.2-5.4) vs. 3.9 mg/L (1.8-6.1), Baseline vs 24-hours, P < 0.05). In patients with T2DM, between baseline and 24-hour after hypoglycemia, only one of 15 oxidative stress proteins differed and this was not seen in controls. An increase (P = 0.016) from baseline (73.4 ng/mL) to 24 hours after hypoglycemia (91.7 ng/mL) was seen for urinary isoprostanes. Hypoglycemia resulted in inflammatory and oxidative stress markers being elevated in T2DM subjects but not controls 24-hours after the event.While type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease 1 , strict glycemic control does not result in obvious cardiovascular benefit in people with T2DM 2-4 . A link between strict glycemic control, hypoglycemia and increased cardiovascular morbidity and mortality has been observed in clinical studies 5,6 . Although the underlying mechanism remains unclear, increased inflammatory cytokines and a leukocytosis are reported after hypoglycemia 7,8 , suggesting a link between hypoglycemia and inflammation.It is well recognized that oxidative stress leads to damage of proteins and deoxyribonucleic acid (DNA) 9 and contributes to the diabetic complications of retinopathy, nephropathy, neuropathy and cardiovascular disorders 10-13 , and is directly linked to vascular inflammation, precipitating both endothelial cell dysfunction and vascular damage 14 . Oxidative stress results from excessive generation of free radicals and/or deficient defense mechanisms 15 , and leads to a disturbance of the physiological redox state 16 . The membrane associated 1

Treatment with liraglutide, and/or associated weight loss, significantly reduced PIIINP levels in obese women with PCOS. This may be an additional beneficial factor when considering the use of liraglutide in women with PCOS, obesity and NAFLD.

SummaryPolycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age. PCOS is associated with multiple comorbidities including, obesity, insulin resistance and type 2 diabetes, as well as mood disorders and impaired quality of life (QoL). Obstructive sleep apnoea (OSA) is also a common medical condition that is often undiagnosed, particularly in women. OSA is associated with a similar spectrum of comorbidities to that observed in PCOS, including manifestations of the metabolic syndrome and impaired QoL, whilst obesity frequently constitutes a common denominator in the pathophysiology of both OSA and PCOS. Hence, it is not surprising that OSA and PCOS may coexist in women of reproductive age, and the current clinical guidelines on the management of PCOS recommend screening for OSA symptoms in overweight/obese women with PCOS. In this review, we examine the relationship between OSA and PCOS and explore the potential underlying mechanisms that link these two conditions. K E Y W O R D Shyperandrogenism, insulin resistance, obesity, obstructive sleep apnoea, polycystic ovary syndrome | INTRODUCTIONPolycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age with a prevalence of 6%-15%. 1,2PCOS is associated with obesity, subfertility, insulin resistance (IR) and type 2 diabetes (T2DM), depression and impaired quality of life (QoL).3,4 However, despite its high prevalence and significant comorbidities, our understanding of its underlying pathophysiology remains poor; with limited treatment options available to manage this lifelong disorder in everyday clinical practice. Hence, there is a need to improve the understanding of the pathogenesis of PCOS, and the spectrum of factors that might contribute to the clinical manifestations and comorbidities of this very common condition.Obstructive sleep apnoea (OSA) is also an obesity-related disorder.OSA prevalence in the general population is estimated at 17%-26% in men and 9%-28% in women, but this difference varies depending on the definition and methods used to diagnose OSA. 5 OSA is characterized by recurrent episodes of partial (hypopnoea) or complete (apnoea)upper airway obstructions associated with recurrent oxygen desaturations and cyclical changes in heart rate, blood pressure, intrathoracic pressure and sympathetic activity. and/or of REM sleep. 6Patients with OSA may present with nocturnal symptoms, including snoring, witnessed apnoea episodes, choking or gasping, insomnia, nocturia, enuresis, frequent arousals, diaphoresis and impotence.7

BackgroundPolycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular (CV) risk markers. In this study our aim was to assess the effects of six months treatment with liraglutide 1.8 mg od on obesity, and CV risk markers, particularly platelet function, in young obese women with PCOS compared to controls of similar age and weight.MethodsCarotid intima-media wall thickness (cIMT) was measured by B-mode ultrasonography, platelet function by flow cytometry, clot structure/lysis by turbidimetric assays and endothelial function by ELISA and post-ischaemic reactive hyperemia (RHI). Data presented as mean change (6-month – baseline) ± standard deviation.ResultsNineteen obese women with PCOS and 17 controls, of similar age and weight, were recruited; baseline atherothrombotic risk markers did not differ between the two groups. Twenty five (69.4%) participants completed the study (13 PCOS, 12 controls). At six months, weight was significantly reduced by 3.0 ± 4.2 and 3.8 ± 3.4 kg in the PCOS and control groups, respectively; with no significant difference between the two groups, P = 0.56. Similarly, HOMA-IR, triglyceride, hsCRP, urinary isoprostanes, serum endothelial adhesion markers (sP-selectin, sICAM and sVCAM), and clot lysis area were equally significantly reduced in both groups compared to baseline. Basal platelet P-selectin expression was significantly reduced at six months in controls −0.17 ± 0.26 but not PCOS −0.12 ± 0.28; between groups difference, 95% confidence interval = −0.14 – 0.26, P = 0.41. No significant changes were noted in cIMT or RHI.ConclusionsSix months treatment with liraglutide (1.8 mg od) equally affected young obese women with PCOS and controls. In both groups, liraglutide treatment was associated with 3–4% weight loss and significant reduction in atherothrombosis markers including inflammation, endothelial function and clotting. Our data support the use of liraglutide as weight loss medication in simple obesity and suggest a potential beneficial effect on platelet function and atherothrombotic risk at 6 months of treatment.Trial registrationClinical trial reg. no. ISRCTN48560305. Date of registration 22/05/2012.