Soy isoflavones improve cardiovascular disease risk markers in women during the early menopause.

BACKGROUND: Hormone replacement therapy may be beneficial for cardiovascular disease risk (CVR) in post-menopausal women. Soy isoflavones may act as selective estrogen receptor modulators. The aim of this study was to evaluate whether soy isoflavones had an effect on CVR markers. METHODS: The expected 10-year risk of cardiovascular disease and mortality were calculated as a secondary endpoint from a double blind randomised parallel study involving 200 women (mean age 55 years, Caucasian, Hull, UK, 2012) in the early menopause who were randomised to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (depleted of all isoflavones; SP) given as a snack bar between meals daily for 6 months. Age, diabetes, smoking, blood pressure and lipid profiles were used to calculate CVR using the Framingham CVR engine. RESULTS: SPI treatment resulted in a significant reduction in the metabolic parameters and systolic blood pressure compared to SP (p < 0.01). There were no changes in fasting lipid profile and diastolic blood pressure with either treatment. At 6 months, changes in these parameters with SPI treatment were reflected in a calculated 27% (p < 0.01) reduction in 10 year coronary heart disease risk, a 37% (p < 0.01) reduction in myocardial infarction risk, a 24% (p < 0.04) reduction in cardiovascular disease and 42% (p < 0.02) reduction in cardiovascular disease death risk. CONCLUSIONS: Supplementation with soy protein with isoflavones for 6 months significantly improved CVR markers and calculated CVR at 6 months during early menopause compared to soy protein without isoflavones. ISRCTN REGISTRY: ISRCTN34051237.

Platelet function following induced hypoglycaemia in type 2 diabetes.

AIM: Strict glycaemic control has been associated with an increased mortality rate in subjects with type 2 diabetes (T2DM). Here we examined platelet function immediately and 24hours following induced hypoglycaemia in people with type 2 diabetes compared to healthy age-matched controls. METHODS: Hyperinsulinaemic clamps reduced blood glucose to 2.8mmol/L (50mg/dl) for 1hour. Sampling at baseline; euglycaemia 5mmol/L (90mg/dl); hypoglycaemia; and at 24 post clamp were undertaken. Platelet function was measured by whole blood flow cytometry. RESULTS: 10 subjects with T2DM and 8 controls were recruited. Platelets from people with T2DM showed reduced sensitivity to prostacyclin (PGI2, 1nM) following hypoglycaemia. The ability of PGI2 to inhibit platelet activation was significantly impaired at 24hours compared to baseline in the T2DM group. Here, inhibition of fibrinogen binding was 29.5% (10.3-43.8) compared to 50.8% (36.8-61.1), (P<0.05), while inhibition of P-selectin expression was 32% (16.1-47.6) vs. 54.4% (42.5-67.5) (P<0.05). No significant changes in platelet function were noted in controls. CONCLUSION: Induced hypoglycaemia in T2DM enhances platelet hyperactivity through impaired sensitivity to prostacyclin at 24hours.

Effect of soy on bone turn-over markers in men with type 2 diabetes and hypogonadism - a randomised controlled study.

Type 2 diabetes (T2DM) is associated with increased risk of fractures. Soy supplementation has been shown to have a beneficial effect on bone turnover markers (BTM) in postmenopausal women. However, the effect of soy supplementation on BTM in T2DM and particularly in men is unclear. We performed an analysis of a randomized double blind parallel study of 200 men with T2DM treated with soy, either with or without isoflavones. Outcome measures were type I collagen crosslinked beta C-telopeptide (ßCTX), and type 1 procollagen-N-propeptide (P1NP). The men, with a total testosterone <12 nmol/L, were treated with 15 g soy protein containing 66 mg of isoflavones (SPI) or 15 g soy protein alone without isoflavones (SP) daily for three months. There was a 15% reduction in ßCTX after three months of SPI compared to SP supplementation. There was no significant difference in P1NP with either SPI or SP supplementation. There was a significant linear correlation between the reduction in ßCTX in the SPI group with the reduction in HbA1c (r2 = 0.42; p = 0.04) and HOMA-IR (r2 = 0.54; p = 0.02). Our study indicates that there was a significant reduction in bone resorption following 3 months of SPI supplementation that correlated with an improvement of glycemic control in men with T2DM.

LDL cholesterol variability in patients with Type 2 diabetes taking atorvastatin and simvastatin: a comparison of two formulae for LDL-C estimation.

BACKGROUND: A new formula was recently proposed by Cordovo et al. that was more highly correlated with low-density lipoprotein (LDL) measured directly than the Friedewald LDL formula. We conducted this prospective study to establish whether the new formula allows true variations in LDL within the same individual to be tracked more closely than that of the Friedewald formula. METHODS: A cross-over study of biological variation of lipids in 26 patients with Type 2 diabetes (T2DM) taking either a short half-life statin, simvastatin 40 mg (n=10), or a long half-life statin, atorvastatin 10 mg. After three months on one statin, fasting lipids were measured on 10 occasions over a five-week period. The same procedure was then followed for the other statin. The LDL was measured by a direct LDL immunoassay and was compared to the LDL estimated by the Friedewald and Cordova (0.7516) × (total cholesterol [TC]-high-density lipoprotein cholesterol [HDL-C]) formulae. RESULTS: As a group, the calculated or measured mean LDL was no different between statins. However, the biological coefficient of variation (CV) of directly measured LDL was far larger with simvastatin than atorvastatin. This difference was detected by Cordova LDL but not found with the Friedewald LDL formula. CONCLUSIONS: In contrast to Friedewald LDL, Cordova LDL estimation revealed LDL to be much more stable in T2DM patients taking atorvastatin rather than simvastatin that was in accord with LDL when measured directly. Therefore, Cordova LDL which is a measure of non-HDL-cholesterol is the simplest, cheapest and the most convenient measurement for assessment of response to statin treatment.

Postprandial effects of long-term niacin/laropiprant use on glucose and lipid metabolism and on cardiovascular risk in patients with polycystic ovary syndrome.

AIM: This study investigated the effect of long-term niacin/laropiprant therapy on CV risk and IR in obese women with PCOS. METHODS: In this double-blind randomized placebo-controlled trial, 13 and 12 PCOS women completed a 12 week course of niacin/laropiprant or placebo, respectively. Fasted subjects had an endothelial function test (EndoPat2000) and then consumed a mixed meal with blood sampled postprandially for 6 h before and after intervention. RESULTS: By 12 weeks, niacin/laropiprant lowered low-density lipoprotein cholesterol (LDL-c) (13%) and increased HDL-c (17%). Despite a reduction in fasting triglycerides (21%), the drug had no effect on their postprandial rise (2.69 ± 1.44 vs. 2.49 ± 1.14 mmol/l, p = 0.72). However, following the mixed meal, plasma glucose area under the response curve increased from 13.1 ± 2.9 to 14.0 ± 2.8 mmol/l, p = 0.05, as a consequence of both increased insulin resistance [HOMA-IR: 2.2 (1.2, 4.2) vs. 3.8(1.3, 5.5), p = 0.02] and a reduced acute insulin response to glucose [424 (211, 975) vs. 257(122, 418) pmol/mmol, p = 0.04]. Niacin/laropiprant did not improve RHI (1.97 ± 0.40 vs. 2.05 ± 0.58, p = 0.33) or hsCRP. CONCLUSIONS: In PCOS, niacin/laropiprant had a significant negative impact on postprandial glucose and no improvement in postprandial hypertriglyceridaemia, with at least the former mediated through increased IR and reduced ß-cell function. This data may help explain why the improvement in fasting lipids has not translated into improved CV risk markers in PCOS.

Glucagon-like peptide-1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been linked to polycystic ovary syndrome (PCOS) and carries an increased risk of liver cirrhosis. Procollagen type 3 amino-terminal peptide (PIIINP) is an independent predictor of liver cirrhosis. OBJECTIVE: To assess whether 6-month treatment with GLP-1 analogue, liraglutide, improves markers of liver fibrosis. DESIGN: A case-control study comparing women with PCOS to age- and weight-matched controls. PCOS was diagnosed according to the Rotterdam criteria. All participants underwent liver function tests and liver ultrasound scan to assess for fatty infiltration. Serum marker for liver fibrosis, PIIINP, was measured at baseline and after 6-month treatment with liraglutide 1·8 mg od. RESULTS: Nineteen women with PCOS and 17 controls were recruited, age 32·8 ± 7·2 vs 33·5 ± 6·7 years and weight 100·9 ± 16·7 vs 99·3 ± 14·7 kg, respectively. At baseline, the PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nm (P = 0·01), HOMA-IR 5·1 ± 2·6 vs 3·5 ± 1·3 (P = 0·03), AST 22·4 ± 5·2 vs 18·8 ± 3·4 u/l (P = 0·04), PIIINP 4·4 ± 0·8 vs 3·5 ± 0·8 ug/ml (P = 0·01) and NAFLD seven (35%) vs none (P = 0·005), respectively. Twenty-five (69%) participants completed the study (13 PCOS, 12 controls). Following treatment, weight was reduced by 3·0 ± 4·2 kg (P = 0·01) and 3·8 ± 3·4 kg (P = 0·001), respectively. Similarly, HOMA-IR, hsCRP, triglycerides and urinary isoprostane significantly reduced in both groups. PIIINP significantly reduced the in PCOS group 4·4 ± 0·8 vs 3·7 ± 0·9 ug/ml (P < 0·01), but not in controls 3·5 ± 0·8 vs 3·2 ± 0·7 ug/ml (P = 0·08). CONCLUSIONS: 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.

Use of complementary markers in assessing glycaemic control in people with diabetic kidney disease undergoing iron or erythropoietin treatment.

AIMS: HbA(1c) values are unreliable in patients with diabetes who have chronic kidney disease who receive iron and/or erythropoiesis stimulating agents. The study aimed to evaluate the utility of the complementary glycaemic markers glycated albumin, fructosamine and 1,5 anhydroglucitol in this group of patients. METHODS: A prospective study of patients with Type 2 diabetes and chronic kidney disease stage IIIB/IV undergoing intravenous iron or erythropoiesis-stimulating agent therapy. Glycaemic control was monitored using HbA(1c), seven-point daily glucose thrice weekly, continuous glucose monitoring, glycated albumin, fructosamine and 1,5 anhydroglucitol. RESULTS: Fifteen patients [9 men; median age 72 years (interquartile range 68-74), follow-up period (16.4 ± 3.7 weeks)] received parenteral iron; 15 patients [11 men; 70 years (interquartile range 62-75), (17.3 ± 3.3 weeks)] received erythropoiesis-stimulating agent. HbA(1c) fell following treatment with both iron [57 mmol/mol (7.4%) to 53 mmol/mol (7.0%), P < 0.001] and erythropoiesis-stimulating agent [56 mmol/mol (7.3%) to 49 mmol/mol (6.6%), P = 0.01] despite mean blood glucose remaining unchanged (iron: 9.55 to 9.71 mmol/l, P = 0.07; erythropoiesis-stimulating agent: 8.72 to 8.78 mmol/l, P = 0.89). Unlike HbA1c , the glycated albumin, fructosamine and 1,5 anhydroglucitol levels did not change following iron [glycated albumin (16.8 to 16.3%, P = 0.10); fructosamine (259.5 to 256 µmol/l, P = 0.89); 1,5 anhydroglucitol (54.2 to 50.9 µmol/l, P = 0.89)] or erythropoiesis-stimulating agent [glycated albumin (17.9 to 17.5%, P = 0.29), fructosamine (324.3 to 306.0 µmol/l, P = 0.52), 1,5 anhydroglucitol (58.2 to 46.7 µmol/l, P = 0.35)]. Despite this, HbA(1c) was consistently the marker most closely related to mean blood glucose before and after each treatment (R range 0.7-0.88). CONCLUSIONS: These data indicate that HbA(1c) was statistically most closely related to mean blood glucose, but clinical trends in glycaemia in patients undergoing iron or erythropoiesis-stimulating agent therapy are likely best assessed by including one of these additional glycaemic markers.

Biological variation of cardiovascular risk factors in patients with diabetes.

Biological variation refers to the natural fluctuations found when repeated measurements are made in a biological system. Generally, biological variation remains within narrow boundaries in health, but may differ in pathological states, with implications for the diagnosis and monitoring of disease processes. In disease, biological variation may alter such that any subsequent measurement may need to have a greater difference compared with a healthy control to be biologically relevant. Treatments such as insulin or anti-hypertensive therapy have been shown to reduce biological variability closer to normal levels and theoretically this may help prevent complication development or progression in conditions such as diabetes. This article reviews how biological variation can influence our identification and assessment of vascular risk factors in a person with diabetes. The role of biological variation in the diagnosis of diabetes (glucose and HbA1c) is then examined. Finally, the influence that common treatments in diabetes have in modifying biological variation is described.

Polycystic ovary syndrome has no independent effect on vascular, inflammatory or thrombotic markers when matched for obesity.

INTRODUCTION: Previous studies investigating cardiovascular (CV) risk in obese women with polycystic ovary syndrome (PCOS) have been potentially confounded by not adequately accounting for body weight. OBJECTIVE: To assess if PCOS increases CV risk independently in young obese women by examining carotid intima-media wall thickness (cIMT) and platelet function. DESIGN: A case-control study comparing women with PCOS (n = 21) to age (32·8 ± 7·2 vs 33·5 ± 6·7 years), and weight (100·9 ± 16·7 vs 99·3 ± 14·7 kg)-matched controls (n = 19). Platelet function was examined by flow cytometry, clot structure and fibrinolysis by turbidimetric assays and endothelial function by ELISA and post ischaemic reactive hyperaemia. RESULTS: The PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nmol/l (P = 0·01), HOMA-IR 2·5 ± 1·7 vs 1·7 ± 1·0 (P = 0·08), impaired glucose regulation 33·3% vs 5·3% (P = 0·02), and urinary isoprostane 16·0 ± 4·4 vs 11·8 ± 7·1 ng/ml (P = 0·04) compared to controls. Mean cIMT 0·5 ± 0·05 vs 0·48 ± 0·06 mm (P = 0·36), and basal platelet surface expression (percentage of positive cells) of P-selectin 0·52 ± 0·3 vs 0·43 ± 0·23 (P = 0·40) and fibrinogen binding 0·97 ± 0·4 vs 0·83 ± 0·3 (P = 0·48) did not significantly differ between the PCOS and control groups respectively. Furthermore, platelets sensitivity to stimulation with adenosine-5'-diphosphate or inhibition with prostacyclin, clot structure and fibrinolytic efficiency ex vivo, endothelial reactive hyperaemic index (RHI), inflammation (hsCRP) and adhesion markers (sE-selectin, sP-selectin, sVCAM-1 and sICAM-1) were not significantly different between the two groups. CONCLUSIONS: PCOS appeared not to independently increase atherothrombotic risk when matched for obesity. It is likely that any excess CV risk in young obese women with PCOS can either be attributed to obesity or is not yet apparent at this early stage of the condition.

The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study.

The pleiotropic effect of statins may be mediated in part through raising 25 hydroxy vitamin D (25OHD) concentrations. It has also been shown that an increase in oxidative stress and inflammatory markers are a feature of the patients with type 2 diabetes (T2DM). A cross-over study of 26 patients with T2DM taking either simvastatin 40 mg or atorvastatin 10 mg was undertaken. After 3 months on one statin, lipids, C-reactive protein (hsCRP), 25OHD and malondialdehyde (MDA) were measured repeatedly. The same procedure was then followed taking the other statin. Despite similar lipid-lowering, the mean 25OHD was higher on atorvastatin compared with simvastatin and the mean MDA and hsCRP levels lower, irrespective of which statin the patients were taking before crossover. The changes in 25OHD predicted changes in CRP and MDA levels. Thus, compared with simvastatin, atorvastatin shows apparently beneficial pleiotropic effects with respect to 25OHD concentrations as well as markers of oxidative stress and inflammation in patients with T2DM.

High-polyphenol chocolate reduces endothelial dysfunction and oxidative stress during acute transient hyperglycaemia in Type 2 diabetes: a pilot randomized controlled trial.

AIMS: To investigate the effects of high-polyphenol chocolate upon endothelial function and oxidative stress in Type 2 diabetes mellitus during acute transient hyperglycaemia induced following a 75-g oral glucose challenge. METHODS: Ten subjects with Type 2 diabetes underwent a double-blinded randomized controlled crossover study. A 75-g oral glucose load was used to induce hyperglycaemia, which was administered to participants 60 min after they had ingested either low (control) or high-polyphenol chocolate. Participants undertook testing at weekly intervals, following an initial cocoa-free period. Endothelial function was assessed by both functional [reactive hyperaemia peripheral artery tonometry (EndoPAT-2000) and serum markers (including intercellular adhesion molecule 1, P-selectin and P-selectin glycoprotein ligand 1]. Urinary 15-F2t-isoprostane adjusted for creatinine was used as an oxidative stress marker. Measurements were made at baseline and 2 h post-ingestion of the glucose load. RESULTS: Prior consumption of high-polyphenol chocolate before a glucose load improved endothelial function (1.7 ± 0.1 vs. 2.3 ± 0.1%, P = 0.01), whereas prior consumption of control chocolate resulted in a significant increase in intercellular adhesion molecule 1 (321.1 ± 7.6 vs. 373.6 ± 10.5 ng/ml, P = 0.04) and 15-F2t-isoprostane (116.8 ± 5.7 vs. 207.1 ± 5.7 mg/mol, P = 0.02). Analysis of percentage changes from baseline comparing control and high-polyphenol chocolate showed a significant improvement for high-polyphenol chocolate in both measures of endothelial function (P < 0.05) and for urinary 15-F2t-isoprostane (P = 0.04). CONCLUSION: High-polyphenol chocolate protected against acute hyperglycaemia-induced endothelial dysfunction and oxidative stress in individuals with Type 2 diabetes mellitus.

Diagnostic performance of using one- or two-HbA1c cut-point strategies to detect undiagnosed type 2 diabetes and impaired glucose regulation within a multi-ethnic population.

INTRODUCTION: We compared test performance and cost per case for strategies detecting diabetes on the oral glucose tolerance test (OGTT) using either (a) glycated haemoglobin (HbA1c) ≥ 6.5% (48 mmol/mol) or (b) two HbA1c thresholds where the first cut-point 'rules out' and the second 'rules in' diabetes. HbA1c values in between the thresholds require confirmatory glucose testing for diagnosis. MATERIALS AND METHODS: We conducted an analysis of adults aged 40-75 years from the Leicester Ethnic Atherosclerosis and Diabetes Risk (LEADER) cohort (Leicester, UK), from 2002 to 2008, who underwent oral glucose tolerance testing (OGTT) and HbA1c testing. RESULTS: From 8696 individuals (mean age 57.3 years, 73% white Europeans (WE) and 27% South Asians (SA)), HbA1c ≥ 6.5% produced sensitivity of 62.1% for detecting diabetes in WE and 78.9% in SA. Using two selected thresholds, HbA1c ≤ 5.8% (rule-in, 40 mmol/mol) and HbA1c ≥ 6.8% (rule-out, 51 mmol/mol) produced high sensitivity/specificity (> 91.0%) for detecting diabetes, however, 28.8% of the cohort with HbA1c 5.9%-6.7% required a subsequent glucose test. The two cut-point threshold produced a lower cost per case of diabetes detected in WE, compared to HbA1c ≥ 6.5% of £38.53 (1.89 to 86.81) per case, but was more expensive in SA by £84.50 (69.72 to 100.92) per case. Using a risk score to determine HbA1c testing, the same costs per case became £63.33 (23.33 to 113.26) in WE and £69.21 (55.60 to 82.41) in SA. CONCLUSION: Using a two-threshold strategy may have some benefits over a single cut-point; however, 28.8% of individuals required two blood tests.

Implications of new European Union driving regulations on patients with Type 1 diabetes who participated in the Diabetes Control and Complications Trial.

AIMS: Recurrent severe hypoglycaemia in a patient with diabetes is strongly associated with a crash risk while driving. To help ensure road safety, recent changes were made to European Union driving regulations for patients with diabetes. These included the recommendation that more than one episode of severe hypoglycaemia within 12 months would lead to the loss of a driving licence. This study has assessed the impact of this regulation if applied to patients who participated in the Diabetes Control and Complications Trial. METHODS: All patients in the Diabetes Control and Complications Trial were assumed to be drivers. Repeated hypoglycaemic episodes within a year were determined during the mean 6.5 years of the study. RESULTS: Of the 1441 patients in the Diabetes Control and Complications Trial, 439 (30%) had more than one severe hypoglycaemic episode during a 12-month period of their study participation. Amongst the study groups, 312/711 (44%) of intensively treated and 127/730 (17%) of conventionally treated patients would have lost their licence at some point during the trial. The risk of licence loss increased with lower mean HbA1c , longer duration of diabetes and younger age (all P < 0.001). CONCLUSIONS: More than one episode of severe hypoglycaemia within a year was a frequent event in subjects in the Diabetes Control and Complications Trial, especially in intensively treated patients. If applied to current practice, improving road safety through these changes to European Union regulations could have a substantial impact on drivers who have Type 1 diabetes. This emphasizes the need to take into account the potential effects of severe hypoglycaemia in those who rely on a driving licence.

The rise and fall of HbA(1c) as a risk marker for diabetes complications.

It is still unclear whether short-term, within-day, variability in glycaemic control is contributory to the development of diabetes micro- or macrovascular complications. However, consistent and compelling data are emerging that longer term fluctuations in glucose, as evidenced by increases in HbA(1c) variability, do indeed add to the mean HbA(1c) value in predicting the risk of microvascular disease. Until now, studies have found this to be the case mainly in type 1 diabetes, but in this issue of Diabetologia (DOI: 10.1007/s00125-012-2572-7 ) an analysis of the Tsukuba Kawai Diabetes Registry in Japan has found that HbA(1c) variability also predicts the risk of nephropathy in type 2 diabetic patients. These observations raise the possibility that reducing rises and falls in HbA(1c) may help avoid hyperglycaemia-related vascular disease without running the same risk of hypoglycaemia that a strategy focusing purely on lower HbA(1c) might incur.

Short-term glucose variability in healthy volunteers is not associated with raised oxidative stress markers.

It is unknown whether glycaemic variability adds to the risk of microvascular complications of diabetes over and above the mean glucose value for a patient. We examined the effect of purposefully induced short-term glycaemic variability on oxidative stress markers. Eleven healthy subjects underwent three sequential glycaemic states; sustained hyperglycaemia, sustained euglycaemia and variable glycaemia, using glycaemic clamps for 3 h. Twenty-four hours urinary 8-isoprostane-PGF2α was measured before and after each glycaemic state to assess oxidative stress. The median and interquartile range of the urinary 8-iso-PGF2α in ng/24 h were (1373, 513), (996, 298) and (1227, 472) for the euglycaemic, hyperglycaemic and variable states, respectively. There was no significant difference in urinary isoprostanes between the three different states; mean ranks 20.9, 11.9 and 18.2 for the euglycaemic state, hyperglycaemic state and glycaemic variability state, respectively, p = 0.083. In conclusion, we did not see a significant increase in the urinary isoprostanes when glycaemic variability was induced under controlled conditions in healthy individuals.

Does severe hypoglycaemia influence microvascular complications in Type 1 diabetes? An analysis of the Diabetes Control and Complications Trial database.

AIMS: Severe hypoglycaemia may have a role in aggravating micro- and macrovascular disease in diabetes. Data from the Diabetes Control and Complication Trial have been reanalysed to ascertain whether the frequency of severe hypoglycaemia exerted an influence on the development and progression of retinopathy or nephropathy in people with Type 1 diabetes. METHODS: Using binary longitudinal multiple logistic regression, HbA(1c) at study baseline, mean HbA(1c) throughout the study and the number of severe hypoglycaemic episodes during the trial were compared to examine the risk of development/progression of retinopathy and nephropathy. RESULTS: Average HbA(1c) during the study and/or HbA(1c) at baseline were independently predictive of retinopathy and nephropathy both in the intensively and the conventionally treated patients (all P ≤ 0.001). However, the number of hypoglycaemic episodes did not add to HbA(1c) in predicting retinopathy [odds ratio (95% CI) 0.99 (0.96-1.01), P = 0.51 in intensively treated patients, 0.94 (0.89-1.00), P = 0.05, conventional] or nephropathy [odds ratio (95% CI) 0.98 (0.95-1.01), P = 0.48 intensive, 1.03 (0.98-1.10), P = 0.17 conventional]. CONCLUSIONS: The frequency of exposure to severe hypoglycaemia did not predict a different risk of developing retinopathy or nephropathy in either treatment group of the Diabetes Control and Complications Trial at any given HbA(1c) .

A comparison of methods for the measurement of 8-isoPGF(2α): a marker of oxidative stress.

BACKGROUND: Oxidative stress describes the cellular damage caused by excess reactive oxygen species not adequately inactivated by antioxidants. Oxidative stress has been implicated in playing a role in many disorders. Lipid peroxidation end-products are employed as markers of oxidative stress, of which the isoprostane, 8-iso-PGF(2α), is widely used. 8-iso-PGF(2α) is measured in plasma or urine by gas chromatography-mass spectrometry (GC/MS), liquid chromatography-mass spectrometry (LC/MS), tandem-mass spectrometry or enzyme-linked immunosorbent assay (ELISA). However, discrepancies between the specificity of these methods means correlation is poor. METHODS: A tandem-mass spectrometric (LC/MS/MS) method, using immunoaffinity purification, for urinary 8-iso-PGF(2α) was developed and compared with two commercial ELISAs (A--Cayman Chemicals, B--Oxford Biomedical Research) in urine samples (n = 156). RESULTS: An LC/MS/MS method coupled to immunoaffinity purification was developed with satisfactory performance and comparison to ELISAs A and B. Spearman rank correlation demonstrated significant correlation between all methods (P = <0.0001); however, r² values ranged from 0.68 to 0.72. Bland-Altman plots revealed a proportional positive bias of ELISA B when compared with ELISA A and LC/MS/MS. Furthermore, the agreement between ELISA A and LC/MS/MS was poor. CONCLUSIONS: The poor agreement between methods for measurement of 8-iso-PGF(2α) highlights differences in selectivity. 8-iso-PGF(2α) is an isoprostane, a family of isomeric end-products of arachidonic acid peroxidation, which are produced by peroxidation or enzymatically. This makes avoiding cross-reactivity between 8-iso-PGF(2α) and related isomers challenging. When assessing oxidative stress studies, the selectivity of the methods used should be taken into account, particularly when comparing studies.

Insulin resistance variability in women with anovulatory and ovulatory polycystic ovary syndrome, and normal controls.

Women with polycystic ovary syndrome (PCOS) were found to have a higher biological variability in insulin resistance (IR) compared to controls, but it is unknown whether this variability in IR differs between PCOS who are anovulatory compared to those who have an ovulatory cycle. The primary aim of this study was to compare and contrast the variability of IR in women with ovulatory and anovulatory PCOS, in comparison to normal subjects. 53 Caucasian women with PCOS and 22 normal ovulating women were recruited. Fasting blood was collected each day on 10 consecutive occasions at 3-4 day intervals for analysis of insulin, glucose, progesterone, and testosterone. Analysis of progesterone levels showed 22 of 53 women with PCOS to have had an ovulatory cycle. Insulin resistance was calculated by HOMA method. Women with anovulatory PCOS had higher mean and variability of IR compared to those having an ovulatory cycle, and both were significantly higher than controls (mean ± SEM; HOMA-IR 4.14 ± 0.14 vs. 3.65 ± 0.15 vs. 2.21 ± 0.16, respectively) after adjustment or BMI. The mean BMI for individual PCOS patients correlated with mean HOMA-IR (p=0.009). Insulin resistance in women with anovulatory PCOS is both higher and more variable than in ovulatory PCOS. Since anovulatory PCOS therefore mimics the IR features of type 2 diabetes more closely, anovulation may be particularly associated with a higher cardiovascular risk compared to PCOS patients who ovulate.

The effect of extensive flooding in Hull on the glycaemic control of patients with diabetes.

AIMS: To examine the impact of extensive flooding in a UK city in 2007 on the glycaemic control of patients with diabetes mellitus. METHODS: This was a longitudinal study in patients with diabetes mellitus 12 months before and after the floods in Hull and East Yorkshire, UK. All patients registered with diabetes mellitus were sent questionnaires about their experiences during and after the floods. Glycaemic control for patients directly affected by the floods was compared against those unaffected. RESULTS: Of 1743 respondents, 296 patients had been affected by the floods (110 insulin treated, 186 lifestyle and oral agents) and 1447 unaffected (482 insulin treated, 965 lifestyle and oral agents). There was a rise in mean HbA(1c) of affected individuals comparing 12 months before the floods with 12 months after [mean (95% confidence interval), 7.6% (7.5-7.7) vs. 7.9% (7.7-8.0), P = 0.002], but not those unaffected [7.5% (7.4-7.6) vs. 7.5% (7.4-7.6), P = 0.46]. The difference was mainly in insulin-treated patients [8.6% (8.3, 8.9) affected vs. 8.2% (8.1, 8.3) unaffected, (P = 0.002)]. CONCLUSIONS: Glycaemic control deteriorated in diabetes patients following the floods but was almost exclusively confined to patients taking insulin and was worst at 6-9 months following the event. Insulin-treated patients may need specific targeting in the event of a natural disaster.