C Olivetti

Association of obstructive sleep apnoea with the presence and severity of non‐alcoholic fatty liver disease. A systematic review and meta‐analysis

Obstructive sleep apnoea syndrome (OSAS) and non‐alcoholic fatty liver disease (NAFLD) are common in clinical practice. NAFLD encompasses simple steatosis and non‐alcoholic steatohepatitis (NASH): both confer an increased risk of cardiovascular disease and diabetes; NASH increases also liver‐related risk. Growing experimental evidence connects chronic intermittent hypoxia of OSAS to NAFLD. We reviewed English and non‐English articles and international meeting abstracts through December 2012. Observational studies were included if they assessed OSAS by polysomnography and NAFLD by histological, radiological or biochemical criteria. Two reviewers evaluated retrieved articles by appropriate quality scores. Main outcomes were pooled using random‐ or fixed‐effects models. The effect of age, sex and body mass index (BMI) on effect estimates was assessed by meta‐regression. Eighteen cross‐sectional studies (2,183 participants) were included. Pooled odds ratios (ORs) of OSAS for the presence of NAFLD, as defined by histology, radiology, and AST or ALT elevation, were 2.01(95% CI: 1.36–2.97), 2.99(1.79–4.99), 2.36(1.46–3.82) and 2.60(1.88–3.61), respectively. Pooled ORs of OSAS for NASH, fibrosis‐any stage, or advanced fibrosis in biopsy‐proven NAFLD patients were 2.37(1.59–3.51), 2.16(1.45–3.20) and 2.30(1.21–4.38). The magnitude and direction of effects were unaffected by age, sex and BMI. In conclusion, OSAS is associated with an increased risk of NAFLD, NASH and fibrosis. OSAS patients should be screened for the presence and severity of NAFLD.

Obstructive sleep apnea-hypopnea syndrome and nonalcoholic Fatty liver disease: emerging evidence and mechanisms.

Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are common conditions, frequently encountered in patients with metabolic disorders. OSAS has been associated with an increased risk of cardiovascular and metabolic complications. It has been recently suggested that the chronic intermittent hypoxia of OSAS may also affect the presence and severity of NAFLD. We will critically review experimental and human evidence connecting OSAS to NAFLD pathogenesis, trying to dissect the effect of intermittent hypoxia from that of obesity and associated comorbidities, and examine molecular mechanisms connecting OSAS to liver and metabolic disease in NAFLD, including hypoxia inducible factor (HIF), nuclear factor-kappa B, unfolded protein response, hypoxic adipose tissue inflammation, and their therapeutic potential for NAFLD and its complications, including cirrhosis and hepatocellular carcinoma. Finally, we will provide suggestions for the management of NAFLD patients with suspected OSAS and recommendations for future research.

ACE, PAI-1, Decorin and Werner Helicase Genes are not Associated with the Development of Renal Disease in European Patients with Type 1 Diabetes

Genetic factors are involved in the development of diabetic nephropathy in Type 1 diabetes. We have examined the association of four candidate genes, angiotensin converting enzyme (ACE): insertion/deletion (I/D) polymorphism, plasminogen activator inhibitor‐1 (PAI‐1): 4G/5G polymorphism, decorin: 179/183/185 polymorphism and Werner syndrome helicase: C/R polymorphism, with the presence of diabetic nephropathy in Type 1 diabetic patients.

Activated Protein C Resistance in Type I Diabetes

OBJECTIVE To compare activated protein C (aPC) sensitivity in 37 type I diabetic patients and 33 healthy control subjects. RESEARCH DESIGN AND METHODS In this study, 37 type I diabetic patients and 33 healthy control subjects without personal or familial history of venous thrombosis and coagulation disorders, infections, intercurrent conditions, serum lupus anticoagulant, clinical cardiovascular complications, or drugs were examined. RESULTS The aPC ratio (aPTT [activated partial thromboplastin time] with and without aPC) was significantly lower in the type I diabetic patients than in the control subjects (P = 0.005). CONCLUSIONS These results suggest that the final steps of the protein C/S inhibiting system could be abnormal in type I diabetes.

Prothrombin Fragment 1 + 2 and Antithrombin III‐Thrombin Complex in Microalbuminuric Type 2 Diabetic Patients

In microalbuminuria there is an increased cardiovascular risk not fully explained by the excess of conventional risk factors. To investigate whether or not microalbuminuria is associated with haemostatic abnormalities in Type 2 diabetic patients, we measured the prothrombin fragment 1 + 2, a marker of thrombin generation, and the thrombin‐antithrombin complex, a marker of thrombin neutralization. Plasma levels of prothrombin fragment 1 + 2 and thrombin‐antithrombin complex were assayed in 17 microalbuminuric patients (albumin excretion rate, AER 20–200 μg min−1) and in 17 comparable normoalbuminuric (AER < 20 μg min−1) Type 2 diabetic patients. Plasma prothrombin fragment 1 + 2 was significantly higher in microalbuminuric than in normoalbuminuric patients (1.09 ± 0.06 vs 0.86 ± 0.04 nM, p = 0.003). Individual values of F1 + 2 were above the upper limit of the normal range in 8/17 microalbuminuric and in none of the normoalbuminuric Type 2 diabetic patients. Plasma thrombin‐antithrombin complex values were not significantly different in the two groups and were not correlated with AER. These results suggest that microalbuminuria is associated with a prethrombotic state and a relatively defective thrombin neutralization. Coagulation abnormalities might be part of the cardiovascular risk in microalbuminuric patients.

Serum glucose, insulin and C-peptide response to oral glucose after intravenous administration of hydrocortisone and methylprednisolone in man

Glucocorticoid-induced glucose intolerance and insulin resistance are dependent on the type of steroid, its dose and route of administration. Although the intravenous (i.v.) route is used mainly, the effects of different steroids have so far been compared using the oral route. The present study was therefore planned to compare the effects on glucose metabolism of hydrocortisone (HC) and methylprednisolone (MP) administered i.v. at equivalent antiinflammatory doses in healthy subjects.Eighteen healthy volunteers with normal glucose tolerance, divided into three groups (A,B,C) matched for age, sex and body mass index were subjected to oral glucose tolerance tests (oGTT) 12 h after HC or MP i.v. injection. The two tests were performed at a 1-month interval and in random sequence. Group A received low doses (HC 100 mg, MP 20 mg), group B intermediate doses (HC 200 mg, MP 40 mg) and group C high doses (HC 400 mg, MP 80 mg). Serum glucose, insulin and C-peptide were measured during both fasting and oGTT.Serum glucose values were not significantly different after HC or MP, during both fasting and oGTT. However, there was a positive correlation between fasting serum glucose or the area under the glucose curve and the dose·kg−1 body weight of HC (r=0.748; r=0.462) and MP (r=0.708; r=0.736). Serum insulin values were significantly higher after MP than after HC when fasting (A: 115 vs 223; B: 95 vs 215, C: 158 vs 268 pmol·l−1) and as area under the oGTT curve (A: 57.8 vs 87; B: 48.5 vs 92.1; C: 57.8 vs 94.5 pmol·l−1·2 h). In contrast, serum C-peptide values were not significantly different after HC or MP, neither fasting nor as area under the insulin curve. Fasting C-peptide/insulin molar ratio was significantly lower after MP than HC at the three doses administered.In conclusion the dose-related decreases in glucose tolerance are more marked after a single i.v. injection of MP than HC at the same anti-inflammatory dose, MP 20 or 40 mg as well as HC 100 or 200 mg do not impair glucose tolerance, but the former is associated with higher serum insulin levels, suggesting insulin resistance. MP-induced hyperinsulinaemia seems to be mainly due to reduced hepatic insulin extraction.

Microalbuminuria in IDDM is associated with increased expression of monocyte procoagulant activity

Summary Microalbuminuria, the early phase of diabetic nephropathy, is associated with an increased risk of atherothrombosis. Monocytes play an important part in the pathogenesis of atherosclerosis and in the activation of haemostasis. However, procoagulant activity is poorly understood in Type I (insulin-dependent) diabetes mellitus, particularly in the presence of microalbuminuria. This study aimed to evaluate spontaneous and endotoxin-induced monocyte procoagulant activity in insulin-dependent diabetic patients with normoalbuminuria or microalbuminuria. Seventeen patients with microalbuminuria, 28 with normoalbuminuria and 26 healthy control subjects matched for age, sex, body mass index and smoking habit were studied. Mononuclear cells from peripheral venous blood were incubated with or without bacterial lypopolysaccharide. Spontaneous procoagulant activity and procoagulant activity after 3 h and 6 h of incubation were calculated. Spontaneous procoagulant activity values were similar in the three groups. After 3 h and 6 h incubation with bacterial lypopolysaccharide, procoagulant activity values were slightly, but not statistically significantly, higher in the normoalbuminuric diabetic group than in control group, and significantly higher in microalbuminuric diabetic group than in control group (p < 0.01). The increased endotoxin-induced monocyte procoagulant activity helps to explain the link between microalbuminuria and the increased risk of atherothrombosis in patients with Type I diabetes. [Diabetologia (1998) 41: 767–771]

Thrombomodulin levels in insulin-dependent diabetic patients with microalbuminuria

Thrombomodulin (TM) plays an important role in the regulation of blood coagulation at the endothelial surface. TM is also present in plasma, where an increase of its level seems to reflect endothelial damage. Since microalbuminuria is associated with an increased atherothrombotic risk and is considered an expression of widespread vascular damage, we evaluated plasma thrombomodulin levels, blood pressure, and plasma lipid values in Type 1 diabetic patients with micro‐ and normoalbuminuria. Thrombomodulin was measured in 12 microalbuminuric (albumin excretion rate 20–200 μg min−1 in 2 of 3 overnight urine collections) and in 12 normoalbuminuric (albumin excretion rate < 20 μg min−1) Type 1 diabetic patients matched for age, sex, body mass index, smoking habits, diabetes duration, and glycated haemoglobin. Mean thrombomodulin was significantly higher in micro‐ than in normalbuminuric group (59.34 ± 3.58 vs 43.56 ± 3.52 ng ml−1 p < 0.01). Systolic and diastolic blood pressure were significantly higher in micro‐ than in normoalbuminuric group (p < 0.05). There was a positive correlation between plasma thrombomodulin and albumin excretion rate (p = 0.013, r = 0.49), and between thrombomodulin and diastolic blood pressure (p = 0.023, r = 0.46) in diabetic patients as a whole but not in the individual groups. These findings suggest the presence of an endothelial injury in microalbuminuric patients.

Lipoprotein(a) after acute exercise in healthy subjects

Some acute-phase proteins increase during exercise, and lipoprotein(a) has been considered an acutephase protein on the basis of an increase in its serum level after acute cardiovascular episodes or surgery. We found no significant effect of acute physical exercise (600 kpm/min for 20 min) on lipoprotein(a) levels in ten healthy subjects [pre exercise 6.25 (0.1–14), median (range), mg/dl; at the end of exercise 6 (0.1–12) mg/dl; 30 min post exercise 5.9 (0.1–23) mg/dl; 60 min post exercise 5.95 (0.1–11) mg/dl. This suggest that activation of the adrenergic system does not induce changes in lipoprotein(a) levels.