Sex Differences in Glutathione Peroxidase Activity and Central Obesity in Patients with Type 2 Diabetes at High Risk of Cardio-Renal Disease.

Women with type 2 diabetes (T2DM) have an increased susceptibility of developing cardio-renal disease compared to men, the reasons and the mechanisms of this vulnerability are unclear. Since oxidative stress plays a key role in the development of cardio-renal disease, we investigated the relationship between sex, plasma antioxidants status (glutathione peroxidase (GPx-3 activity), vitamin E and selenium), and adiposity in patients with T2DM at high risk of cardio-renal disease. Women compared to men had higher GPx-3 activity (p = 0.02), bio-impedance (p ≤ 0.0001), and an increase in waist circumference in relation to recommended cut off-points (p = 0.0001). Waist circumference and BMI were negatively correlated with GPx-3 activity (p ≤ 0.05 and p ≤ 0.01, respectively) and selenium concentration (p ≤ 0.01 and p ≤ 0.02, respectively). In multiple regression analysis, waist circumference and sex were independent predictors of GPx-3 activity (p ≤ 0.05 and p ≤ 0.05, respectively). The data suggest that increased central fat deposits are associated with reduced plasma antioxidants which could contribute to the future risk of cardio-renal disease. The increased GPx-3 activity in women could represent a preserved response to the disproportionate increase in visceral fat. Future studies should be aimed at evaluating if the modulation of GPx-3 activity reduces cardio-renal risk in men and women with T2DM.

Residual renal and cardiovascular disease risk in conventionally-treated patients with type 2 diabetes: the potential of non-traditional biomarkers.

Diabetes is a leading cause of chronic kidney disease (CKD) in the developed world. Promoters of the progression of kidney disease include the traditional profile of cardiovascular risk factors. However, the development of CKD and vulnerability to end-stage renal disease (ESRD) is highly variable. Determinants of the susceptibility to ESRD may include non-traditional risk factors such as gene-environment interactions, socio-geographic factors and/or treatment strategies. We review the conflicting clinical relevance of studies implicating pathways related to oxidative stress. These pathways are strongly implicated in the phenotype of some groups of high-risk patients and could assume importance in clinical care. Recent clinical trial evidence has shown that newer glucose-lowering agents also have beneficial effects on reducing the incidence of renal dysfunction and cardiovascular events in high-risk patients. Research is required to identify which patients will benefit most from newer approaches to managing diabetes. Understanding the relationship of non-traditional risk factors to renal and cardiovascular disease could help clinicians targeting new therapeutic approaches in the management of type 2 diabetes.

Sex differences in vascular stiffness and relationship to the risk of renal functional decline in patients with type 2 diabetes.

BACKGROUND: Recent data suggest that the higher risk of end-stage renal disease in women compared with men is associated with waist circumference. We investigated whether vascular stiffness which is linked to visceral fat accumulation is gender specific and associated with a loss in renal function. METHODS: We studied 166 patients with type 2 diabetes at high risk of progressive renal disease. A vascular stiffness index was derived from measurement of the peripheral arterial pulse waveform using infrared finger photoplethysmography. Multiple regression analysis was used to examine the relationship between vascular stiffness and traditional clinical and biochemical renal disease risk factors. RESULTS: Women were of similar mean (standard deviation) age [61.6 (6.8) vs 60.0 (8.3) years; p = 0.444] and duration of diabetes [9.8 (7.2) vs 10.9 (8.1) years; p = 0.885] compared to men. Waist circumference was significantly associated with vascular stiffness [regression coefficient B = 0.15 (95% confidence interval: 0.06-2.24); p = 0.001]. There was a negative slope parameter for the relationship between glomerular filtration rate and vascular stiffness [ B = -0.15 (95% confidence interval: -0.22 to -0.09); p < 0.001] in women only. CONCLUSION: In this cohort, early renal functional decline in women is linked to increased vascular stiffness which may be associated with visceral fat accumulation as determined by waist circumference.

Modulation of endogenous antioxidant defense and the progression of kidney disease in multi-heritage groups of patients with type 2 diabetes: PRospective EValuation of Early Nephropathy and its Treatment (PREVENT).

BACKGROUND: Diabetes is the western world's leading cause of end-stage renal disease. Glucose-dependent, oxidative stress is linked to the development of renal inflammation and sclerosis, which, in animal models of diabetes, can be prevented by anti-oxidative treatment. Patients of non-Caucasian heritage have low activity of the selenoprotein, antioxidant enzyme, glutathione peroxidase (GPx) and its co-factor vitamin E, which may be linked to their increased propensity to developing end-stage renal disease. RESEARCH DESIGN AND METHODS: We have designed a double-blind, randomized, placebo controlled study with selenium and/or vitamin E versus placebo as the interventions for patients with type 2 diabetes and chronic kidney disease (CKD) stages 1-3. A 2 × 2 factorial design will allow a balanced representation of the heritage groups exposed to each intervention. The primary biochemical outcome is change in GPx activity, and clinical outcome measure is the actual, rate of-and/or percentage change in estimated glomerular filtration rate (eGFR) from baseline. Analysis will be with a marginal model for longitudinal data using Generalized Estimating Equations corrected for measures of baseline serum antioxidant enzyme activities (GPx, superoxide dismutase and catalase), micronutrient levels (vitamins E and C), measures of inflammation (interleukin 6, c-reactive protein and monocyte chemoattractant protein-1) and markers of oxidative damage (plasma 8-isoprostaglandin F2α and urinary 8-hydroxydeoxyguanosine). EXPECTED RESULTS: The study will assess the relationship between GPx activity, oxidative stress, inflammation and eGFR. It will test the null hypothesis that antioxidant therapy does not influence the activity of GPx or other antioxidant enzymes and/or alter the rate of change in eGFR in these patient groups. CONCLUSIONS: Outcome data on the effect of antioxidants in human diabetic renal disease is limited. Previous post hoc analyses have not shown a beneficial effect of vitamin E on renal function. A recent trial of a pharmaceutical antioxidant agent, improved eGFR, but in patients with advanced diabetes-related chronic kidney disease its use was associated with an increased incidence of cardiovascular events. We will explore whether the nutritional antioxidants, vitamin E and selenium alone, or in combination in patients at high risk of renal disease progression, forestalls a reduction in eGFR. The study will describe whether endogenous antioxidant enzyme defenses can be safely modified by this intervention and how this is associated with changes in markers of oxidative stress. Trial registration ISRCTN 97358113. Registered 21st September 2009.

An inter-professional education programme for diabetes care in London.

Over the years there has been a steady increase in avoidable referrals from primary to secondary care for newly diagnosed diabetic patients. Audits have shown that diabetes referral rates were rising yearly. Secondary care is becoming overwhelmed with the heavy workload and increasing cost, which also led to compromising care for complex patients. This led to the design and implementation of a diabetes based inter-professional education (IPE) programme. The IPE programme was taught in cycles. Each cycle consists of 10 sessions. One session was taught for one afternoon a week over 10 weeks. On the 11th week an OSCE style end of course assessment was performed. Health care professionals (HCPs) from different professions were taught in the same classroom, using the same material. A re-audit of diabetes referral rates showed a change in referral ratio post-programme. Qualitative interviews using Kirkpatrick and Barr's hierarchy were performed 2 years post-programme to assess learners' outcomes. Results show that the effects of the programme were sustained beyond 2 years and that these changes were carried into practice. There was a change in HCPs attitude and perception and more importantly it showed improvement in patient outcomes. This represents a novel IPE programme for diabetes care which has shown to be able to increase confidence, capacity and scope of care provided by HCPs in the community.

Mobile telemonitoring for achieving tighter targets of blood pressure control in patients with complicated diabetes: a pilot study.

BACKGROUND: Hypertension is a major risk factor for the long-term complications of diabetes. Mobile, self-measurement of blood pressure is emerging as a method to manage blood pressure in general, but its impact in patients with diabetes is unclear. METHODS: We randomized 137 patients with diabetes and hypertension to either mobile telemonitoring (n = 72) or usual care (n = 65). Clinic blood pressure was recorded at baseline and after 6 months. Patients in the intervention arm transmitted weekly blood pressure readings wirelessly, using adapted sensors via mobile phones to a central server. Clinicians received the data in real-time and using a web-based application provided management advice to the patient and their physicians. RESULTS: Systolic blood pressure fell significantly in the patients in the intervention group (mean [95% confidence interval], -6.5 [-0.8 to -12.2] mm Hg; P = 0.027) and remained unchanged in the control group (2.1 [9.3 to -5.0] mm Hg; P = 0.57). Patients within the intervention arm of African origin seemed to benefit more from the intervention. In addition, those who achieved a systolic blood pressure of <120 mm Hg had lower average blood sugars than those with higher readings (7.8 [SD 1.6] vs. 8.9 [SD 2.2] mmol/L; P = 0.02). CONCLUSIONS: In patients with diabetes, mobile telemonitoring has potential for delivering intensified care to improve blood pressure control, and its use may be associated with reduced exposure to hyperglycemia.

Technical and compliance considerations for mobile health self-monitoring of glucose and blood pressure for patients with diabetes.

Self-monitoring of blood glucose is an integral part of diabetes care which may be extended to other biometrics. Cellular and short range communication technologies will be important for the routine usage of these systems. However, the issues of follow-up and patient compliance with these emerging systems have not been yet studied evaluated but could be critical to the adoption of these technologies. We evaluated the impact of mobile telemonitoring on the intensification of care on blood pressure control and exposure to hyperglycaemia in patients with diabetes. We randomised 137 patients with diabetes to either mobile telemonitoring (n = 72) or usual care patients (n = 65) for 9 months. In this paper we present some of the clinical results with focus on blood pressure control hypertension and highlight some of the technical and compliance issues that were encountered.

Evaluation of a mobile phone telemonitoring system for glycaemic control in patients with diabetes.

We conducted a randomized controlled trial using mobile health technology in an ethnically diverse sample of 137 patients with complicated diabetes. Patients in the intervention group (n = 72) were trained to measure their blood glucose with a sensor which transmitted the readings to a mobile phone via a Bluetooth wireless link. Clinicians were then able to examine and respond to the readings which were viewed with a web-based application. Patients in the control arm of the study (n = 65) did not transmit their readings and received care with their usual doctor in the outpatient and/or primary care setting. The mean follow-up period was 9 months in each group. The default rate was higher in the patients in the intervention arm due to technical problems. In an intention-to-treat analysis there were no differences in HbA(1c) between the intervention and control groups. In a sub-group analysis of the patients who completed the study, the telemonitoring group had a lower HbA(1c) than those in the control group: 7.76% and 8.40%, respectively (P = 0.06).

Nitric oxide bioavailability and its potential relevance to the variation in susceptibility to the renal and vascular complications in patients with type 2 diabetes.

OBJECTIVE: We compared the renal and systemic vascular (renovascular) response to a reduction of bioavailable nitric oxide (NO) in type 2 diabetic patients without nephropathy and of African and Caucasian heritage. RESEARCH DESIGN AND METHODS: Under euglycemic conditions, renal blood flow was determined by a constant infusion of paraminohippurate and changes in blood pressure and renal vascular resistance estimated before and after an infusion of L-Ng-monomethyl-L-arginine. RESULTS: In the African-heritage group, there was a significant fall in renal blood flow (Delta-46.0 ml/min per 1.73 m(2); P < 0.05) and rise in systolic blood pressure (Delta 10.0 mmHg [95% CI 2.3-17.9]; P = 0.017), which correlated with an increase in renal vascular resistance (r(2) = 0.77; P = 0.004). CONCLUSIONS: The renal vasoconstrictive response associated with NO synthase inhibition in this study may be of relevance to the observed vulnerability to renal injury in patients of African heritage.

Circulating cholesterol as a modulator of risk for renal injury in patients with type 2 diabetes.

Amelioration of albuminuria may be related to specific constellations of risk factors including race and dyslipidaemia. Circulating cholesterol could mitigate the beneficial effect of antihypertensive therapy. We assessed whether cholesterol affected the remission of urinary albumin in patients with type 2 diabetes of white, Caucasian and non-white origin. We studied 100 patients (African and Asian: n=57 and Caucasian: n=43) with type 2 diabetes and newly diagnosed microalbuminuria who received intensified and structured care for a median (IQ range) of 41 (32-48) months. Microalbuminuria remitted in 20% and progressed in 12% of patients. In those with uncontrolled systolic hypertension (>140 mmHg) systolic blood pressure fell by a mean (95% CI) of -9.4 (-3.8 to -15.11)mmHg; p=0.002. The change in urinary albumin excretion with time varied inversely with baseline systolic blood pressure (r=-0.25; p=0.04). At 3 years follow-up the decrement in blood pressure was significant for those patients in the regression group (-19.6[16.8]mmHg; p=0.005). In patients of African origin, systolic blood pressure was higher than in the other groups and correlated with cholesterol concentrations (r=0.44; p=0.04). Baseline systolic blood pressure and total cholesterol (odds ratio [95%CI]) were independent determinants of remission and progression of microalbuminuria (1.04[1.006-1.064]; p=0.02 and 1.75[1.03-2.95]; p=0.04). Patients with higher total cholesterol and baseline urinary albumin excretion were less likely to go into remission. Blood pressure correlated with cholesterol concentrations in patients of African origin. Specific cholesterol lowering strategies may benefit certain patients groups at high risk of renal disease.

Race-specific differences in antioxidant enzyme activity in patients with type 2 diabetes: a potential association with the risk of developing nephropathy.

OBJECTIVE: Lipid hydroperoxide, a marker of oxidative stress, is linked to the development of nephropathy and is reportedly higher in patients of African origin compared with Caucasians. This may be relevant to race-specific differences in susceptibility to nephropathy. We investigated whether alterations in antioxidant enzyme activity could account for this biochemical phenotype and examined the relationship with conventional markers of renal disease. RESEARCH DESIGN AND METHODS: Two hundred seventeen individuals were studied. Patients with type 2 diabetes (n = 75) of African and Caucasian origin were matched by sex and racial origin with healthy control subjects (n = 142). Plasma total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity were spectrophotometrically measured, and total cholesterol and triglycerides were measured by enzymatic methods. RESULTS: SOD activity was higher and GPx activity lower in patients with diabetes than in healthy control subjects (573 +/- 515 vs. 267 +/- 70 units/l, P < 0.001 and 150 +/- 93 vs. 178 +/- 90 units/l, P = 0.019, respectively). Patients of African origin with diabetes had lower GPx and higher SOD activity compared with Caucasian patients (126 +/- 82 vs. 172 +/- 97 units/l, P = 0.03 and 722 +/- 590 vs. 445 +/- 408 units/l, P = 0.002, respectively). Patients of African origin with normal urinary albumin excretion had significantly higher plasma creatinine concentrations (100.7 +/- 14.2 vs. 88.1 +/- 14.9 micromol/l, P = 0.007) and lower GPx activity (99.0 +/- 72.4 vs. 173.7 +/- 107.4 units/l, P = 0.02) compared with those of Caucasian origin. African origin was an independent predictor of elevated SOD (P = 0.007) and reduced GPx activity (P = 0.02) in regression analysis. CONCLUSIONS: SOD and GPx enzyme activities vary according to race and could account for differences in lipid hydroperoxide. In patients of African origin, susceptibility to renal disease may be associated with lowered GPx activity.

Circulating vitamin E, transforming growth factor beta1, and the association with renal disease susceptibility in two racial groups with type 2 diabetes.

BACKGROUND: End-stage renal disease caused by diabetes disproportionately affects patients of African origin. The biological mechanism(s) for this observation is unclear. Emerging data from cross-sectional studies suggest that increased oxidative stress and the cytokine, transforming growth factor beta(1), are associated with this phenomenon. Therefore, a pathway involving these factors could alter the vulnerability to renal disease and impact adversely on the rate of loss of renal function. METHODS: We assessed the relationship between renal function, oxidative stress, and transforming growth factor beta(1) in 58 patients with type 2 diabetes of African and Caucasian origin over 174 patient-years of follow-up. Oxidative stress was assessed by measuring plasma lipid hydroperoxide and vitamin E in the postprandial state. Creatinine clearance was calculated from the Cockcroft-Gault equation. Patients received standardized management of hypertension, hyperglycemia, and hypercholesterolemia. Data were adjusted by multiple regression analysis to account for potential confounders. RESULTS: Lipid hydroperoxide was higher and vitamin E lower, while there was no difference in fasting transforming growth factor beta(1) between the African (N= 22) and Caucasian (N= 36) patients [5.1(1.2) vs. 4.3 (1.8) micromol/L; P= 0.02 and 29.8 (10.8) vs. 41.3(19.7) micromol/L; P= 0.02 and 6.33 (5.5) vs. 6.84 (3.9) ng/mL; P= 0.73], respectively. The mean (95% confidence interval) of the difference in creatinine clearance between the patients of African and Caucasian origin was -12.5 (-23.4 to -1.7) mL/min; P= 0.015 at baseline, the magnitude of which increased to -17.5 (-28.4 to -6.5) mL/min; P= 0.002 after 3 years. The fall in creatinine clearance from baseline among the patients of African origin was greater for lower levels of vitamin E (rho = 0.48; P= 0.03). Final plasma creatinine was significantly higher in the African patients compared with the Caucasian patients [109.0 (25.8) vs. 94.0 (20.0) micromol/L; P= 0.0017]. In regression analysis, vitamin E was a significant and independent predictor of plasma creatinine (t -3.17, P= 0.003). CONCLUSION: In these patients with type 2 diabetes, vitamin E is a determinant of renal function, and may explain some of the racial differences in renal disease susceptibility that precedes the divergence in incidence of end-stage renal disease.

Management of uncontrolled hypertension in a nurse-led clinic compared with conventional care for patients with type 2 diabetes.

OBJECTIVE: To compare the effectiveness of a nurse-led hypertension clinic with conventional community care in general practice in the management of uncontrolled hypertension in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 120 men and women outpatient attendees (61% non-Caucasian) with type 2 diabetes and a seated blood pressure (BP) >or=140/80 mmHg. All patients were being treated for hypertension, and 71% had increased urinary albumin excretion (UAE). Patients were allocated to either a nurse-led hypertension clinic or conventional primary care. The primary outcome measure was a change in systolic BP. Secondary outcome measures were total cholesterol, HDL cholesterol, total triglycerides, HbA(1c), UAE, serum creatinine, and changes in absolute stroke and coronary heart disease (CHD) risk scores. RESULTS: The mean (95% CI) difference in the decrement of systolic BP was 12.6 mmHg (5.9-19.3) (P = 0.000) in favor of the nurse-led group, whose patients were three times more likely to a reach target systolic BP <140 mmHg compared with conventional care (P = 0.003). A significant fall in 10-year CHD (P = 0.004) and stroke risk (P = 0.000) scores occurred only in the nurse-led group. There were no significant differences in the reduction of diastolic BP or any of the other secondary outcome measures at 6 months. CONCLUSIONS: Compared with conventional care, a nurse-led hypertension clinic is a more effective intervention for patients with type 2 diabetes and uncontrolled hypertension. A target systolic BP <140 mmHg is more readily achieved and may be associated with significant reductions in 10-year cardiovascular disease risk scores.