Caroline Jane Magri

The role of tubular injury in diabetic nephropathy

Diabetic nephropathy is associated with increased mortality in diabetic patients and is a major cause of end-stage renal disease in most countries. Understanding its pathogenesis is important as it may equip us with novel ways in its prevention and in slowing its progression. To date, attempts to unravel the complex pathogenesis and pathophysiology of diabetic nephropathy have mostly focused on the glomerulus. However, recently a lot of data has accumulated that implicates the tubules as playing a key role. This article reviews these data and the light they throw on the role of renal tubules in the pathogenesis of diabetic nephropathy.

Red blood cell distribution width and diabetes-associated complications.

AIM Red blood cell distribution width (RDW) is a marker of cardiovascular morbidity and mortality. However, there is little data on the relationship between RDW and diabetes-associated complications. The aim was to investigate whether there is any association between RDW, nephropathy, neuropathy and peripheral arterial disease (PAD) in a type 2 diabetic population. METHODS This study included 196 diabetic patients with proliferative diabetic retinopathy. All subjects were investigated for diabetic nephropathy, diabetic neuropathy and PAD. Participants underwent 24-h blood pressure monitoring and were analysed for markers of the metabolic syndrome, inflammation, and insulin resistance. RESULTS 57% of the participants had diabetic nephropathy, 46% had diabetic neuropathy while 26% had PAD. No significant association was found between RDW, diabetic neuropathy and PAD (p=NS). However, RDW was strongly associated with diabetic nephropathy (p=0.006), even following adjustment for potential confounding variables. Multivariate logistic regression analysis showed RDW (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.15-2.35, p=0.006), estimated glomerular filtration rate (OR 0.98, 95% CI 0.96-0.99, p<0.001), night-time diastolic blood pressure (OR 1.07, 95% CI 1.03-1.11, p=0.001) and erythrocyte sedimentation rate (OR 1.03, 95% CI 1.004-1.05, p=0.019) to be independently associated with diabetic nephropathy. CONCLUSIONS This is the first study to report lack of association between RDW, neuropathy and PAD in subjects with type 2 diabetes mellitus. More importantly, RDW was shown to be significantly associated with diabetic nephropathy in a type 2 diabetic population with advanced proliferative retinopathy independent of traditional risk factors, including diabetes duration and glycaemic control.

Non-Dipping Heart Rate and Microalbuminuria in Type 2 Diabetes Mellitus

Objectives: The aim of this study was to identify factors which are independently associated with non-dipping heart rate (HR) in a type 2 diabetic population at high risk of cardiovascular disease. Methods: The study recruited 179 type 2 diabetic subjects with a mean diabetes duration of 18.3 years and with proliferative retinopathy. All underwent 24-hour blood pressure and HR monitoring, and were assessed for markers of inflammation, insulin resistance, albuminuria, presence of peripheral neuropathy and peripheral vascular disease. Subjects whose night-time HR did not decrease by more than 10% as compared to daytime readings were classified as non-dippers. Results: Univariate analysis revealed that non-dippers had significantly higher logarithmic albumin-creatinine ratio (ACR; p = 0.001) and higher platelet count (p = 0.014). Also, non-dippers were more likely to be on β-blockers (p = 0.037). Binary logistic regression analysis showed that logarithmic ACR (p = 0.001) and platelet count (p = 0.026) were independent predictors of non-dipping HR, even when correcting for β-blocker use. Conclusions: In this high-risk type 2 diabetic population, non-dipping HR was independently associated with ACR and platelet count, suggesting that non-dipping HR might give an indication of underlying generalised atherosclerosis in diabetic patients. Also, non-dipping HR may represent a novel mechanism explaining the association of nephropathy with cardiovascular events. This merits further study.

Peroxisome proliferator-activated receptor-γ and the endothelium: implications in cardiovascular disease

Peroxisome proliferator-activated receptors-γ (PPARγs) are ligand-activated transcription factors that play a crucial regulatory role in the transcription of a large number of genes involved in lipid metabolism and inflammation. In addition to physiological ligands, synthetic ligands (the thiazoledinediones) have been developed. In spite of the much publicized adverse cardiovascular effects of one such thiazoledinedione (rosiglitazone), PPARγ activation may have beneficial cardiovascular effects. In this article we review the effects of PPARγ activation on the endothelium with special emphasis on the possible implications in cardiovascular disease. We discuss its possible role in inflammation, vasomotor function, thrombosis, angiogenesis, vascular aging and vascular rhythm. We also briefly review the clinical implications of these lines of research.

Heart Failure with Preserved Ejection Fraction and Diabetes Mellitus

Heart failure with preserved ejection fraction (HFpEF) constitutes approximately 50% of heart failure patients. The prevalence of diabetes mellitus in HFpEF is high at 30-40%. The paper provides a systematic review of the pathophysiological features underlying HFpEF in diabetes mellitus. The importance of mechanisms other than left ventricular diastolic dysfunction underlying this important condition is emphasised. Thus, ventricular-arterial coupling & vascular dysfunction together with chronotropic incompetence & cardiovascular reserve dysfunction play an important role. The various morphologic and molecular features occurring in the myocardium and vasculature in diabetes secondary to hyperglycaemia and other metabolic disturbances are also discussed. These include microangiopathy, myocardial fibrosis, increased oxidative stress, impaired calcium homeostasis, activation of the cardiac renin-angiotensin system, autonomic neuropathy, endothelial dysfunction, re-expression of foetal gene response as well as stem cell involvement. Nonetheless, a lot is still unknown and further studies are needed to establish the underlying pathophysiological mechanisms with the hope that novel pharmacotherapies targeting this disease will be developed. In the meantime, cardiometabolic factors, including hyperglycaemia, hypertension and dyslipidaemia should be targeted and aggressively treated.

Red blood cell distribution width and myocardial scar burden in coronary artery disease

Introduction Red blood cell distribution width (RDW) is a novel independent marker of cardiovascular disease including heart failure, coronary artery disease and myocardial ischaemia. The aim of the study was to investigate a possible relationship between RDW and myocardial scar burden, as assessed by a MIBI viability scan. A secondary objective was to assess whether there is an association between RDW and left ventricular ejection fraction (LVEF). Methods The study comprised 123 subjects with ischaemic heart disease who underwent a myocardial viability scan between June 2008 and July 2014. Haemoglobin, mean corpuscular volume, RDW, platelet count, mean platelet volume (MPV), estimated glomerular filtration rate, fasting blood glucose, liver and lipid profiles were evaluated for all patients. The extent of myocardial scarring and LVEF were noted. Data were analysed using IBM SPSS Statistics 22.0. Univariate followed by multivariate analyses were performed to assess for independent predictors of myocardial scarring and LVEF, respectively. Results The mean age of the study population was 63.5 years; most of the subjects were men. The median LVEF was 31% and median percentage of myocardial scarring was 8.7%. Multivariate analyses revealed that RDW, HDL-cholesterol and alanine transaminase were independent predictors of myocardial scarring while RDW, MPV, LDL-cholesterol and gamma-glutamyl transpeptidase were independent predictors of LVEF. Conclusions Increased RDW is an independent predictor both of myocardial scar burden and of impaired left ventricular function in subjects with coronary artery disease.

Prediction of insulin resistance in type 2 diabetes mellitus using routinely available clinical parameters

AIMS To determine if insulin resistance (IR), an important predictor of cardiovascular risk in the general population and in type 2 diabetes mellitus, can be assessed using simple parameters which are readily available in clinical practice. METHODS This cross-sectional study included 194 patients with type 2 diabetes. Body mass index, waist index (WI), triglyceride levels, 1/HDL, triglyceride/HDL, uric acid and urine albumin:creatinine ratio were investigated as possible predictors of IR. RESULTS WI correlated more strongly than any other parameter with log insulin levels, log fasting glucose to insulin ratio (FGIR), log fasting glucose to insulin product (FGIP), homeostatic model assessment (HOMA-IR) and quantitative insulin check index (QUICKI). WI also emerged as the strongest independent predictor of IR indices studied in regression as well as in ROC analyses. At a cut-off of 1.115, WI had a 78% sensitivity and 65% specificity for predicting IR when HOMA-IR was used as indicator of IR, and 74% sensitivity and specificity when QUICKI was used as indicator of IR. Combining WI with other variables did not improve performance significantly. CONCLUSIONS In our cohort of patients with type 2 diabetes, WI was the parameter with the strongest association with, and the best predictor of, IR.

Female gender and cardiovascular disease

Despite a generalized belief that women are protected from cardiovascular disease, this remains the leading cause of death in women. This review focuses on differences in symptomatology, diagnostic modalities and therapeutic strategies in women with regard to cardiovascular disease.

Predictors of vibration perception threshold in type 2 diabetic patients with proliferative retinopathy

Purpose of the study Distal peripheral neuropathy (DPN) is a troublesome complication of diabetes mellitus (DM). The factors associated with the disease are still incompletely understood. The purpose of this study was to investigate factors associated with vibration perception threshold (VPT) as a marker of DPN in a type 2 diabetic population with advanced microvascular disease. Methods The study included 203 diabetic patients (117 male, 86 female) with proliferative diabetic retinopathy. Subjects were investigated by questionnaires, clinical examinations, blood and urine sampling, and review of medical records in the period from November 2008 through April 2009. Presence of DPN was defined as VPT ≥25 V. Results The mean (±SD) age was 65.2 (±9.9) years and median (IQR) diabetes duration was 18 (10–25) years. Forty-six per cent of subjects were found to have DPN, defined as a VPT ≥25 V by neurothesiometer testing. Prevalence of DPN was found to be associated with age (p=0.038), male gender (p=0.046), low haemoglobin (p<0.001), high erythrocyte sedimentation rate (p=0.03), uric acid values (p=0.034), and peripheral vascular disease (PVD) (p=0.003) in univariate analysis. Multivariate logistic regression analysis revealed male gender (OR 5.52; p<0.001) and low haemoglobin values (B=−0.58; p<0.001) to be independent predictors of VPT ≥25 V in subjects with proliferative retinopathy, while linear regression analysis revealed male gender (p<0.001), haemoglobin (p=0.001), age (p=0.04), and PVD (p=0.001) to be significant predictors of VPT. Conclusions This study reports a novel independent association of DPN with low haemoglobin values. In the study population with type 2 DM and proliferative retinopathy, DPN was also independently associated with male gender, age, and PVD. Further studies are needed to confirm the association with low haemoglobin and identify the underlying mechanism.

Rhinocerebral Mucormycosis Complicated by Diabetes Insipidus: A Case Report and Literature Review

Rhinocerebral mucormycosis (RCM) is an increasingly common infection in immunocompromised subjects. We report a case of RCM in an immunosuppressed gentleman known to suffer from sigmoid colon adenocarcinoma stage D and presenting with diabetic ketoacidosis, complete ptosis, and orbital cellulitis. During his hospital stay, the patient developed cranial diabetes insipidus. In spite of extensive surgical debridement and high-dose liposomal amphotericin, the disease had a fatal outcome. This case emphasizes the need for increased awareness of mucormycosis as a potentially lethal fungal infection requiring a high index of suspicion in subjects at risk. The case also illustrates a rare complication of RCM, namely diabetes insipidus.