Low-carbohydrate diets in type 1 diabetes: balancing benefits and risks.

PURPOSE OF REVIEW: Interest in the use of calorie restriction with low-carbohydrate diets for patients with type 1 diabetes appears to be increasing despite physicians' discomfort about its longer term outcomes. A divergence in opinion regarding the balance of benefits and safety may lead to patient disengagement from conventional medical supervision. This review describes the current evidence regarding the benefits and risks of these diets and suggests a way forward to addressing this potential misalignment between the aims of patients and their physicians. RECENT FINDINGS: Benefits on glycaemia are observed in many studies, with improved HbA1c, time within target range and reduced glycaemic variability. A characteristic lipid profile with high LDL cholesterol is observed in many patients, but association with future cardiovascular events is undefined. A negative impact on growth has been identified in the paediatric population, and impact on mental health and disordered eating is of theoretical concern, without measurement in clinical studies. SUMMARY: Patients will continue to trial and, with immediate glycaemic benefits, potentially remain on lower carbohydrate diets irrespective of concern by treating physicians about potential longer term risks. A supportive multidisciplinary approach with greater nutritional supervision and more research is required, to allow these patients to achieve their desired glycaemic outcomes without compromising longer term safety.

Clinicians' perceptions of medical student teaching in a tertiary hospital.

Background: Medical student placements in teaching hospitals are a cornerstone for gaining clinical experience. However, the ever-evolving nature of health care has also changed the delivery of student education. Few studies have examined clinicians' perspectives toward teaching students in this setting. We sought to explore the attitudes of clinicians involved in teaching medical students at an Australian tertiary hospital. Methods: Clinicians were invited by email to complete an anonymous online survey developed using a combination of questions from previously validated surveys. The questions utilized 5-point Likert scale statements and were based around the themes of "personal purpose and enjoyment of teaching" and "barriers and challenges to teaching." Results for each question are presented as frequency and percentage. Results: Of 490 invited, 67 (13.7%) consultant clinicians from various specialties responded. The majority (>92%) enjoy teaching and see it as part of their work. However, approximately half thought that medical student teaching was under-recognized and half did not have adequate time to teach due to workload. Approximately 60% responded that there was insufficient time to get to know students to provide feedback and approximately 40% indicated that the scope of student knowledge and desired outcomes are not clearly defined by medical schools. Discussion: Our contemporary survey identifies modifiable factors which should be targeted. If these factors are addressed successfully, it may allow the hospital and university medical school to harness the valuable resource of clinical teachers. This could enhance the medical student experience and promote a culture of teaching and learning in hospitals.

The effect of Vitamin-K1 and Colchicine on Vascular Calcification Activity in subjects with Diabetes Mellitus (ViKCoVaC): A double-blind 2x2 factorial randomized controlled trial.

BACKGROUND: There is currently no treatment for attenuating progression of arterial calcification. 18F-sodium fluoride positron emission tomography (18F-NaF PET) locates regions of calcification activity. We tested whether vitamin-K1 or colchicine affected arterial calcification activity. METHODS: 154 patients with diabetes mellitus and coronary calcification, as detected using computed tomography (CT), were randomized to one of four treatment groups (placebo/placebo, vitamin-K1 [10 mg/day]/placebo, colchicine [0.5 mg/day]/placebo, vitamin-K1 [10 mg/day]/ colchicine [0.5 mg/day]) in a double-blind, placebo-controlled 2x2 factorial trial of three months duration. Change in coronary calcification activity was estimated as a change in coronary maximum tissue-to-background ratio (TBRmax) on 18F-NaF PET. RESULTS: 149 subjects completed follow-up (vitamin-K1: placebo = 73:76 and colchicine: placebo = 73:76). Neither vitamin-K1 nor colchicine had a statistically significant effect on the coronary TBRmax compared with placebo (mean difference for treatment groups 0·00 ± 0·16 and 0·01 ± 0·17, respectively, p > 0.05). There were no serious adverse effects reported with colchicine or vitamin-K1. CONCLUSIONS: In patients with type 2 diabetes, neither vitamin-K1 nor colchicine significantly decreases coronary calcification activity, as estimated by 18F-NaF PET, over a period of 3 months. CLINICAL TRIAL REGISTRATION: ACTRN12616000024448.

Is vitamin D testing at a tertiary referral hospital consistent with guideline recommendations?

To determine if 25 hydroxyvitamin D (25OHD) testing at our tertiary referral hospital is consistent with guideline recommendations concerning the clinical indications for testing, the timing of repeat testing and utilisation of the test result, we conducted a retrospective audit of electronic laboratory and patient case records. We included adult inpatients and outpatients who had serum 25OHD measured during a randomly selected one-week audit period and who had patient case records available for detailed review. The audit sample comprised 184 serum 25OHD measurements (134 initial and 50 repeat tests). There were 81 (60%) initial and 15 (30%) repeat tests [96 (52%) overall] that were consistent with guideline recommendations concerning clinical indication, timing of repeat testing and utilisation of result. Almost half the 25 hydroxyvitamin D tests audited were potentially unnecessary and/or not utilised clinically. Improved adherence to guideline recommendations for 25 hydroxyvitamin D testing, utilisation of test results and enforcement of new indications for testing due to be introduced by Medicare Australia could result in significant cost savings without adversely affecting patient outcomes.

Recent advances in pharmacotherapy for hypertriglyceridemia.

Elevated plasma triglyceride (TG) concentrations are associated with an increased risk of atherosclerotic cardiovascular disease (CVD), hepatic steatosis and pancreatitis. Existing pharmacotherapies, such as fibrates, n-3 polyunsaturated fatty acids (PUFAs) and niacin, are partially efficacious in correcting elevated plasma TG. However, several new TG-lowering agents are in development that can regulate the transport of triglyceride-rich lipoproteins (TRLs) by modulating key enzymes, receptors or ligands involved in their metabolism. Balanced dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists, inhibitors of microsomal triglyceride transfer protein (MTTP) and acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1), incretin mimetics, and apolipoprotein (apo) B-targeted antisense oligonucleotides (ASOs) can all decrease the production and secretion of TRLs; inhibitors of cholesteryl ester transfer protein (CETP) and angiopoietin-like proteins (ANGPTLs) 3 and 4, monoclonal antibodies (Mabs) against proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC-III-targeted ASOs, selective peroxisome proliferator-activated receptor modulators (SPPARMs), and lipoprotein lipase (LPL) gene replacement therapy (alipogene tiparvovec) enhance the catabolism and clearance of TRLs; dual PPAR-α/δ agonists and n-3 polyunsaturated fatty acids can lower plasma TG by regulating both TRL secretion and catabolism. Varying degrees of TG reduction have been reported with the use of these therapies, and for some agents such as CETP inhibitors and PCSK9 Mabs findings have not been consistent. Whether they reduce CVD events has not been established. Trials investigating the effect of CETP inhibitors (anacetrapib and evacetrapib) and PCSK9 Mabs (AMG-145 and REGN727/SAR236553) on CVD outcomes are currently in progress, although these agents also regulate LDL metabolism and, in the case of CETP inhibitors, HDL metabolism. Further to CVD risk reduction, these new treatments might also have a potential role in the management of diabetes and non-alcoholic fatty liver disease owing to their insulin-sensitizing action (PPAR-α/γ agonists) and potential capacity to decrease hepatic TG accumulation (PPAR-α/δ agonists and DGAT-1 inhibitors), but this needs to be tested in future trials. We summarize the clinical trial findings regarding the efficacy and safety of these novel therapies for hypertriglyceridemia.

New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease.

INTRODUCTION: Novel peroxisome proliferator-activated receptor (PPAR) modulators (selective PPAR modulators [SPPARMs]) and dual PPAR agonists may have an important role in the treatment of cardiometabolic disorders owing to lipid-modifying, insulin-sensitizing and anti-inflammatory effects. AREAS COVERED: This review summarizes the efficacy of new PPAR agonists and SPPARMs that are under development for the treatment of atherogenic dyslipidemia and non-alcoholic fatty liver disease (NAFLD). EXPERT OPINION: ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.

Calculated free and bioavailable vitamin D metabolite concentrations in vitamin D-deficient hip fracture patients after supplementation with cholecalciferol and ergocalciferol.

We previously showed that oral cholecalciferol and ergocalciferol have comparable effects in decreasing circulating parathyroid hormone (PTH), despite a greater increase in total serum 25-hydroxyvitamin D (25OHD) concentration with cholecalciferol supplementation. However, the effects of cholecalciferol and ergocalciferol on total serum 1,25-dihydroxyvitamin D (1,25(OH)2D), vitamin D-binding protein (DBP), free 25OHD and free 1,25(OH)2D concentrations have not been previously studied. We randomized 95 hip fracture patients (aged 83±8 years) with vitamin D deficiency (serum 25OHD <50 nmol/L) to oral supplementation with either cholecalciferol 1000 IU/day (n=47) or ergocalciferol 1000 IU/day (n=48) for three months. All were given matching placebos of the alternative treatment to maintain blinding. We measured serum 25OHD (high-pressure liquid chromatography), 1,25(OH)2D (Diasorin radioimmunoassay), DBP (immunonephelometry), ionized calcium (Bayer 800 ion-selective electrode) and albumin (bromocresol green) concentrations before and after treatment. We calculated free and bioavailable concentrations of the vitamin D metabolites using albumin and DBP, and calculated free vitamin D metabolite indices as the ratios between the molar concentrations of the vitamin D metabolites and DBP. Seventy participants (74%) completed the study with paired samples for analysis. Total serum 1,25(OH)2D did not change significantly with either treatment (p>0.05, post-treatment vs baseline). Both treatments were associated with comparable increases in DBP (cholecalciferol: +18%, ergocalciferol: +16%, p=0.32 between groups), albumin (cholecalciferol: +31%, ergocalciferol: +21%, p=0.29 between groups) and calculated free 25OHD (cholecalciferol: +46%, ergocalciferol: +36%, p=0.08), with comparable decreases in free 1,25(OH)2D (cholecalciferol: -17%, ergocalciferol: -19%, p=0.32 between groups). In the treatment-adherent subgroup the increase in ionized calcium was marginally greater with cholecalciferol compared with ergocalciferol (cholecalciferol: +8%, ergocalciferol: +5%, p=0.03 between groups). There were no significant differences between the treatments in their effects on the calculated bioavailable concentrations or free indices of the vitamin D metabolites (p>0.05 between groups). In vitamin D-deficient hip fracture patients, oral supplementation with cholecalciferol and ergocalciferol had no effect on total serum 1,25(OH)2D, and comparable effects on DBP and free vitamin D metabolite concentrations. This is despite cholecalciferol having greater effects than ergocalciferol in increasing total 25OHD, and in increasing ionized calcium in treatment-adherent subjects. These findings may explain why cholecalciferol and ergocalciferol supplementation result in similar magnitudes of PTH reduction, but implicate potential differences in other vitamin D metabolites, such as 24,25(OH)2D, that could explain their different effects on ionized calcium.

Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells.

OBJECTIVE: Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients. METHODS AND RESULTS: FF impaired the capacity of transforming growth factor-ß to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-ß-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3ß phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1. CONCLUSIONS: FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity.

Prevalence and predictors of abnormal arterial function in statin-treated type 2 diabetes mellitus patients.

Arterial dysfunction (AD) in type 2 diabetes mellitus (T2DM) predicts cardiovascular events. The objective was to investigate the prevalence and predictors of AD in statin-treated T2DM patients. We measured flow-mediated (FMD) and nitrate-mediated (NMD) brachial artery dilatation in 86 statin-treated T2DM patients. Patients were classified into 2 groups: normal arterial function (FMD ≥3.7% with NMD ≥11.9%) or AD (FMD <3.7% with or without NMD <11.9%). Endothelial dysfunction without smooth muscle cell dysfunction (ED) was defined as FMD less than 3.7% with NMD of at least 11.9%, and endothelial dysfunction with smooth muscle cell dysfunction (ED/SMD) was defined as FMD less than 3.7% with NMD less than 11.9%. Predictors of arterial function were investigated using linear and logistic regression methods. The prevalence of AD was 33.7% (23.2% with ED and 10.5% with ED/SMD). In multivariate linear regression, history of hypertension (P < .01), statin dose (P < .05), and estimated glomerular filtration rate (eGFR) (P = .02) were significant predictors of FMD. Sex (P < .01) and creatinine (P = .03) or eGFR (P = .02) predicted NMD. In multivariate logistic regression, the independent predictors of AD were history of hypertension (odds ratio [OR], 8.79; 95% confidence interval, 2.14-36.12; P < .01), age (OR, 1.08; 1.01-1.17; P = .03), and statin dose (OR, 0.33; 0.12-0.87; P = .02). A history of hypertension (OR, 8.99; 1.87-43.26; P < .01) was the sole independent predictor of ED; eGFR (OR, 0.01; 0.00-0.26; P < .01) independently predicted ED/SMD. Our data suggest that one third of statin-treated diabetic patients have residual AD, mainly due to ED alone. Earlier identification and treatment of hypertension and renal impairment may improve AD and further decrease cardiovascular risk in such patients.

Lupin and soya reduce glycaemia acutely in type 2 diabetes.

Addition of fibre or protein to carbohydrate-rich foods can reduce the glycaemic response to those foods. This may assist with glycaemic management in individuals with type 2 diabetes. Lupin is a legume rich in fibre and protein. We assessed the acute effects of lupin- and soya-based beverages on glucose and insulin responses in type 2 diabetic individuals. We hypothesised that the lupin and soya beverages would lower the acute glycaemic response compared with a control beverage containing no protein or fibre, and that lupin would reduce the postprandial glucose more than soya. In a randomised, controlled, cross-over trial, twenty-four diabetic adults (nineteen men and five women) attended three testing sessions, each 1 week apart. At each session, participants consumed a beverage containing 50 g glucose (control), 50 g glucose plus lupin kernel flour with 12·5 g fibre and 22 g protein (lupin), or 50 g glucose plus 12·5 g fibre and 22 g protein from soya isolates (soya). Serum glucose, insulin and C-peptide were measured periodically for 4 h following beverage consumption. Compared with the control beverage, the 4 h post-beverage glucose response was lower (P < 0·001), and the 4 h post-beverage insulin and C-peptide responses were higher (P < 0·001) for lupin and soya. Glucose (P = 0·25) and C-peptide (P = 0·07) responses did not differ significantly between lupin and soya, but lupin resulted in a lower insulin response compared with soya (P = 0·013). Adding lupin or soya to a carbohydrate-rich beverage reduces glycaemia acutely in type 2 diabetic individuals. This may have a beneficial role in glycaemic management.

Niacin improves small artery vasodilatory function and compliance in statin-treated type 2 diabetic patients.

We investigated the effect of niacin (nicotinic acid prolonged release) on forearm vasodilatory function and arterial compliance in statin-treated type 2 diabetic patients with endothelial dysfunction. In a parallel group study, we randomised 15 subjects, with LDL-cholesterol ≤2.5 mmol/L, to niacin (dose titrated to 1500 mg/day over 8 weeks, then maintained for a further 12 weeks) or no additional treatment. Niacin increased maximal post-ischaemic forearm blood flow (mean ± SEM 6.4±2.4 vs. -2.3±1.2 ml/100 ml/min, p = 0.001) and small artery compliance (1.3±0.8 vs. -2.3±1.1 ml/mmHg, p = 0.01) compared with no additional treatment, but did not alter large artery compliance, blood pressure nor heart rate. Niacin decreased serum triglycerides by 47% (p = 0.04), with no change in LDL-cholesterol, HDL-cholesterol, apolipoprotein (Apo) B-100 nor ApoA-I (p > 0.05). Adding niacin to statin therapy improves small artery vasodilatory function and compliance in type 2 diabetes. This may relate to a decrease in serum triglycerides and/or a direct benefit of niacin on vascular biology.

Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated Type 2 diabetic patients.

Dyslipidaemia contributes to endothelial dysfunction and CVD (cardiovascular disease) in Type 2 diabetes mellitus. While statin therapy reduces CVD in these patients, residual risk remains high. Fenofibrate corrects atherogenic dyslipidaemia, but it is unclear whether adding fenofibrate to statin therapy lowers CVD risk. We investigated whether fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. In a cross-over study, 15 statin-treated Type 2 diabetic patients, with LDL (low-density lipoprotein)-cholesterol <2.6 mmol/l and endothelial dysfunction [brachial artery FMD (flow-mediated dilatation) <6.0%] were randomized, double-blind, to fenofibrate 145 mg/day or matching placebo for 12 weeks, with 4 weeks washout between treatment periods. Brachial artery FMD and endothelium-independent NMD (nitrate-mediated dilatation) were measured by ultrasonography at the start and end of each treatment period. PIFBF (post-ischaemic forearm blood flow), a measure of microcirculatory endothelial function, and serum lipids, lipoproteins and apo (apolipoprotein) concentrations were also measured. Compared with placebo, fenofibrate increased FMD (mean absolute 2.1+/-0.6 compared with -0.3+/-0.6%, P=0.04), but did not alter NMD (P=0.75). Fenofibrate also increased maximal PIFBF {median 3.5 [IQR (interquartile range) 5.8] compared with 0.3 (2.1) ml/100 ml/min, P=0.001} and flow debt repayment [median 1.0 (IQR 3.5) compared with -1.5 (3.0) ml/100 ml, P=0.01]. Fenofibrate lowered serum cholesterol, triacylgycerols (triglycerides), LDL-cholesterol, apoB-100 and apoC-III (P < or = 0.03), but did not alter HDL (high-density lipoprotein)-cholesterol or apoA-I. Improvement in FMD was inversely associated with on-treatment LDL-cholesterol (r=-0.61, P=0.02) and apoB-100 (r=-0.54, P=0.04) concentrations. Fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. This may relate partly to enhanced reduction in LDL-cholesterol and apoB-100 concentrations.

Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol.

Vitamin D insufficiency is commonly associated with hip fracture. However, the equipotency of ergocalciferol and cholecalciferol supplementation in this patient group has not been studied in a randomized trial using high-performance liquid chromatography (HPLC) measurement of serum 25-hydroxyvitamin D (25OHD). The objective of this study was to determine if ergocalciferol and cholecalciferol are equipotent therapies in vitamin D-insufficient hip fracture patients. Ninety five hip fracture inpatients with vitamin D insufficiency (25OHD<50 nmol/L) were randomized, double-blind, to treatment with ergocalciferol 1000 IU/day (n=48) or cholecalciferol 1000 IU/day (n=47) for three months. All participants were also given a placebo matching the alternative treatment to maintain blinding of treatment allocation. The primary endpoint was total serum 25OHD measured by HPLC. Secondary endpoints included 25OHD measured by radioimmunoassay (RIA), intact parathyroid hormone (iPTH), and bioactive (1-84) whole PTH (wPTH). Seventy patients (74%) completed the study with paired samples for analysis. Cholecalciferol supplementation resulted in a 31% greater increase in total HPLC-measured 25OHD (p=0.010) and 52% greater rise in RIA-measured 25OHD (p<0.001) than supplementation with an equivalent dose of ergocalciferol. Changes in iPTH and wPTH were not significantly different between calciferol treatments (p>0.05). In vitamin D-insufficient hip fracture patients, supplementation with cholecalciferol 1000 IU/day for three months was more effective in increasing serum 25OHD than an equivalent dose of ergocalciferol. However, the lack of difference in PTH lowering between calciferol treatments raises questions about the biological importance of this observation.

Coenzyme Q10 improves endothelial dysfunction in statin-treated type 2 diabetic patients.

OBJECTIVE: The vascular benefits of statins might be attenuated by inhibition of coenzyme Q(10) (CoQ(10)) synthesis. We investigated whether oral CoQ(10) supplementation improves endothelial dysfunction in statin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a double-blind crossover study, 23 statin-treated type 2 diabetic patients with LDL cholesterol <2.5 mmol/l and endothelial dysfunction (brachial artery flow-mediated dilatation [FMD] <5.5%) were randomized to oral CoQ(10) (200 mg/day) or placebo for 12 weeks. We measured brachial artery FMD and nitrate-mediated dilatation (NMD) by ultrasonography. Plasma F(2)-isoprostane and 24-h urinary 20-hydroxyeicosatetraenoic acid (HETE) levels were measured as systemic oxidative stress markers. RESULTS: Compared with placebo, CoQ(10) supplementation increased brachial artery FMD by 1.0 +/- 0.5% (P = 0.04), but did not alter NMD (P = 0.66). CoQ(10) supplementation also did not alter plasma F(2)-isoprostane (P = 0.58) or urinary 20-HETE levels (P = 0.28). CONCLUSIONS: CoQ(10) supplementation improved endothelial dysfunction in statin-treated type 2 diabetic patients, possibly by altering local vascular oxidative stress.

Hemodynamic effects of fenofibrate and coenzyme Q10 in type 2 diabetic subjects with left ventricular diastolic dysfunction.

OBJECTIVE: To investigate the effects of fenofibrate and coenzyme Q(10) (CoQ) on diastolic function, ambulatory blood pressure (ABP), and heart rate (HR) in type 2 diabetic subjects with left ventricular diastolic dysfunction (LVDD). RESEARCH DESIGN AND METHODS: We randomized, double-blind, 74 subjects to fenofibrate 160 mg daily, CoQ 200 mg daily, fenofibrate 160 mg plus CoQ 200 mg daily, or matching placebo for 6 months. Echocardiography (including tissue Doppler imaging) and 24-h ABP and HR monitoring were performed pre- and postintervention. RESULTS: Neither fenofibrate nor CoQ, alone or in combination, altered early diastolic mitral annular myocardial relaxation velocity (E'), early-to-late mitral inflow velocity ratio (E/A), deceleration time, isovolumic relaxation time, or the ratio of early mitral flow velocity to early diastolic mitral annular myocardial relaxation velocity (E/E') compared with placebo (P > 0.05). Fenofibrate and CoQ interactively (P = 0.001) lowered 24-h systolic blood pressure (-3.4 +/- 0.09 mmHg, P = 0.010), with a prominent nocturnal effect (-5.7 +/- 1.5 mmHg, P = 0.006). Fenofibrate (-1.3 +/- 0.5 mmHg, P = 0.013) and CoQ (-2.2 +/- 0.5 mmHg, P < 0.001) independently lowered 24-h diastolic blood pressure. Fenofibrate reduced 24-h HR (-3.3 +/- 0.5 beats/min, P < 0.001), but CoQ had no effect on HR. CONCLUSIONS: In type 2 diabetic subjects with LVDD, neither fenofibrate nor CoQ, alone or in combination, improved diastolic function significantly. However, fenofibrate and CoQ independently and interactively lowered 24-h blood pressure, and fenofibrate alone reduced 24-h HR.

Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus.

Endothelial dysfunction is universal in diabetes, being intimately involved with the development of cardiovascular disease. The pathogenesis of endothelial dysfunction in diabetes is complex. It is initially related to the effects of fatty acids and insulin resistance on 'uncoupling' of both endothelial nitric oxide synthase activity and mitochondrial function. Oxidative stress activates protein kinase C (PKC), polyol, hexosamine and nuclear factor kappa B pathways, thereby aggravating endothelial dysfunction. Improvements in endothelial function in the peripheral circulation in diabetes have been demonstrated with monotherapies, including statins, fibrates, angiotensin-converting enzyme (ACE) inhibitors, metformin and fish oils. These observations are supported by large clinical end point trials. Other studies show benefits with certain antioxidants, L-arginine, folate, PKC-inhibitors, peroxisome proliferator activated receptor (PPAR)-alpha and -gamma agonists and phosphodiesterase (PDE-5) inhibitors. However, the benefits of these agents remain to be shown in clinical end point trials. Combination treatments, for example, statins plus ACE inhibitors and statins plus fibrates, have also been demonstrated to have additive benefits on endothelial function in diabetes, but there are no clinical outcome data to date. Measurement of endothelial dysfunction in cardiovascular research can provide fresh opportunities for exploring the mechanism of benefit of new therapeutic regimens and for planning and designing large clinical trials.

Revisiting the metabolic syndrome.

Metabolic syndrome (MS) refers to the clustering of cardiometabolic risk factors - including abdominal obesity, hyperglycaemia, dyslipidaemia and elevated blood pressure - that are thought to be linked to insulin resistance. MS is associated with increased risk of cardiovascular disease and type 2 diabetes. MS is common, affecting a quarter to a third of adults, and its prevalence is rising, in parallel with increasing obesity and population ageing. Operational definitions of MS have been proposed by the World Health Organization and the National Cholesterol Education Program. Recently, the International Diabetes Federation proposed a global definition that emphasised the importance of central adiposity. In cardiovascular risk assessment, MS encapsulates the contribution of non-traditional risk factors and provides a clinically useful framework for early identification of people at increased long-term risk. It should be used in conjunction with standard algorithms based on conventional risk factors, which better predict short-term risk. Management of MS should emphasise lifestyle interventions (eg, physical activity, healthy diet and weight reduction) to reduce long-term risk of cardiovascular disease and diabetes. Those at increased short-term risk should also have individual risk factors treated according to established guidelines.

Investigations of thyroid hormones and antibodies based on a community health survey: the Busselton thyroid study.

OBJECTIVE: Overt or subclinical thyroid dysfunction is common within the community, yet the significance of subtle anomalies in thyroid function tests remains contentious. The aims of this study were to: (a) establish reference intervals for serum-free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid antibodies (antithyroperoxidase, TPOAb and antithyroglobulin, TgAb) in the Busselton community of south-western Western Australia; and (b) determine the prevalence of thyroid hormone anomalies in this community. SUBJECTS AND DESIGN: In 1981, 2115 adults residing in Busselton participated in a cross-sectional health survey that involved blood collection and a questionnaire on lifestyle and general health history. MEASUREMENTS: Serum samples were analysed for FT4, TSH, TPOAb and TgAb by immunochemiluminescent assays. RESULTS: Based on standard statistical approaches and using guidelines recommended by the National Academy of Clinical Biochemistry (NACB), reference intervals were derived for each analyte: 9-23 pmol/l for FT4, 0.4-4.0 mIU/l (TSH), < 35 KIU/l (TPOAb) and < 55 KIU/l (TgAb). The prevalence of elevated thyroid antibodies was 12.4% among subjects without a history of thyroid disease and is more common in women than in men. Elevated thyroid antibody levels were observed at both extremes of TSH abnormality, but were more commonly increased when TSH levels were above 4.0 mIU/l (63% subjects) than for those with TSH levels 0.4-4.0 mIU/l (7.8% subjects). CONCLUSIONS: This study establishes the prevalence of antibodies to thyroperoxidase and thyroglobulin in a community-based sample and reference intervals for free T4 and TSH. When the NACB decision limits are applied to older men or women, there is a markedly increased number with 'elevated' autoantibody levels compared to sex- and age-specific reference intervals.

Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy.

Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of diabetic vasculopathy. They are both powerful independent predictors of cardiovascular risk. Advances in non-invasive methodologies have led to widespread clinical investigation of these abnormalities in diabetes mellitus, generating a wealth of new knowledge concerning the mechanisms of vascular dysfunction, risk factor associations and potential treatment targets. Endothelial dysfunction primarily reflects decreased availability of nitric oxide (NO), a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilatation of the brachial artery and plethysmography measurement of forearm blood flow responses to vasoactive agents. Arterial stiffness may be assessed using pulse wave analysis to generate measures of pulse wave velocity, arterial compliance and wave reflection. The pathogenesis of endothelial dysfunction in type 2 diabetes is multifactorial, with principal contributors being oxidative stress, dyslipidaemia and hyperglycaemia. Elevated blood glucose levels drive production of reactive oxidant species (ROS) via multiple pathways, resulting in uncoupling of mitochondrial oxidative phosphorylation and endothelial NO synthase (eNOS) activity, reducing NO availability and generating further ROS. Hyperglycaemia also contributes to accelerated arterial stiffening by increasing formation of advanced glycation end-products (AGEs), which alter vessel wall structure and function. Diabetic dyslipidaemia is characterised by accumulation of triglyceride-rich lipoproteins, small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL)-cholesterol and increased postprandial free fatty acid flux. These lipid abnormalities contribute to increasing oxidative stress and may directly inhibit eNOS activity. Although lipid-regulating agents such as HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates) and fish oils are used to treat diabetic dyslipidaemia, their impact on vascular function is less clear. Studies in type 2 diabetes have yielded inconsistent results, but this may reflect sampling variation and the potential over-riding influence of oxidative stress, dysglycaemia and insulin resistance on endothelial dysfunction. Results of positive intervention trials suggest that improvement in vascular function is mediated by both lipid and non-lipid mechanisms, including anti-inflammatory, anti-oxidative and direct effects on the arterial wall. Other treatments, such as renin-angiotensin-aldosterone system antagonists, insulin sensitisers and lifestyle-based interventions, have shown beneficial effects on vascular function in type 2 diabetes. Novel approaches, targeting eNOS and AGEs, are under development, as are new lipid-regulating therapies that more effectively lower LDL-cholesterol and raise HDL-cholesterol. Combination therapy may potentially increase therapeutic efficacy and permit use of lower doses, thereby reducing the risk of adverse drug effects and interactions. Concomitant treatments that specifically target oxidative stress may also improve endothelial dysfunction in diabetes. Vascular function studies can be used to explore the therapeutic potential and mechanisms of action of new and established interventions, and provide useful surrogate measures for cardiovascular endpoints in clinical trials.