Journal of Diabetes and Its Complications

2011-11-01

The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial

2011-11-07

Abstract: Background: The goal of the VA Diabetes Trial (VADT) was to determine the effect of intensive glucose control on macrovascular events in subjects with difficult-to-control diabetes. No significant benefit was found. This report examines predictors of the effect of intensive therapy on the primary outcome in this population.Methods: This trial included 1791 subjects. Baseline cardiovascular risk factors were collected by interview and the VA record. The analyses were done by intention to treat.Findings: Univariate analysis at baseline of predictors of a primary cardiovascular (CV) event included a prior CV event, age, insulin use at baseline, and duration of diagnosed diabetes (all P 1.0) after which the HR is below 1.0. From 7 to 15 years' duration at entry, subjects have HRs favoring intensive treatment. Thereafter the HR approaches 1.0 and over-21-years' duration approaches 2.0. Duration over 21 years resulted in a HR of 1.977 (CI 1.77–3.320, P<.01). Baseline c-peptide levels progressively declined up to 15 years and were stable subsequently.Interpretation: In difficult-to-control older subjects with type 2 DM, duration of diabetes altered the response to intensive glucose control. Intensive therapy may reduce CV events in subjects with a duration of 15 years or less and may increase risks in those with longer duration.

Relationship of glycemia control to lipid and blood pressure lowering and atherosclerosis: the SANDS experience

2011-07-20

Abstract: Objectives: Cardiovascular disease prevention for patients with type 2 diabetes is accomplished through hypertension and dyslipidemia management. Although studies have established strategies for lowering low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP), none have examined whether glycemia influences ability to achieve lipid and BP targets. This post hoc analysis from the Stop Atherosclerosis in Native Diabetics Study examines the role of baseline glycemia in achieving standard and aggressive targets and outcomes after 36 months.Methods: Diabetic individuals aged >40 years with no cardiovascular events (n=499) were randomized to aggressive versus standard targets for LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C) and systolic BP (SBP). Management algorithms were used for both groups. Carotid ultrasound and echocardiography were performed at baseline and after 36 months.Results: No differences were observed in baseline hemoglobin A1c between treatment groups nor any significant change in A1c after 36 months in either group. Baseline A1c, however, was significantly and negatively related to achieving LDL-C (P=.007), non-HDL-C (P=.03) and SBP targets (P=.007) and to changes in LDL-C (P=.007), non-HDL-C (P=.03) and SBP (P=.001) in both groups. Baseline A1c failed to predict progression of carotid intima medial thickness (CIMT) (P=.42) or left ventricular mass index (LVMI) (P=.10), nor was it related to the effects of lipid and BP lowering on CIMT and LVMI over 36 months.Conclusions: In diabetic adults with no cardiovascular disease events, A1c was negatively associated with ability to achieve LDL-C, non-HDL-C and SBP goals but was not independently related to treatment-associated changes in CIMT or LVMI over 36 months.

High-sensitivity C-reactive protein: a novel cardiovascular risk predictor in type 2 diabetics with normal lipid profile

2011-11-07

Abstract: Background: India is the diabetic capital of the world. Coronary heart disease is a major cause of morbidity and mortality among diabetics. Type 2 diabetes mellitus and atherosclerosis are complex diseases sharing common antecedents like inflammation. High-sensitivity C-reactive protein (hs-CRP), an acute phase reactant protein, is a proinflammatory atherogenic circulating marker which can prove to be an independent cardiac risk predictor.Aim: The aim of the present study was to evaluate the role of hs-CRP as an independent cardiovascular risk marker among Indians with type 2 diabetes with normal lipid profile.Settings and Design: This was a case control study including 60 type 2 diabetics with normal lipid profile and 60 age- and sex-matched healthy controls.Materials and Methods: Twelve-hour fasting blood samples were collected from all the participants. Serum was assayed for hs-CRP and lipid profile.Statistical Analysis: Results were analyzed by unpaired t test.Results: We found elevated hs-CRP levels (4.8±0.2, P<.0001) among cases compared to controls (0.9±0.1). According to hs-CRP levels, seven cases were in the low-risk (<1 mg/l), 32 in the moderate-risk (1–3 mg/l), and 21 in the high-risk (3–10 mg/l) group with mean values of hs-CRP of 0.7±0.2, 1.75±0.7, and 5.8±1.4, respectively. Relative risk was 4.75 with odds ratio of 10.23 (95% confidence interval 8.8–11.23).Conclusion: The study suggests that hs-CRP is an independent cardiac risk predictor even with normal lipid profile and can help measure additional risk. The American Heart Association stated that patients in the intermediate- and high-risk group may benefit from therapeutic lifestyle change and that cardiovascular event may be prevented.

Differential effects of low-carbohydrate and low-fat diets on inflammation and endothelial function in diabetes

2011-10-31

Abstract: Objective: To characterize acute (postprandial) and chronic (after a 6-month period of weight loss) effects of a low-carbohydrate vs. a low-fat diet on subclinical markers of cardiovascular disease (CVD) in adults with type 2 diabetes.Design: At baseline and 6 months, measures of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule (sICAM) and soluble E-selectin were obtained from archived samples (n=51) of participants randomized in a clinical trial comparing a low-carbohydrate and a low-fat diet. In a subset of participants (n=27), postprandial measures of these markers were obtained 3 h after a low-carbohydrate or low-fat liquid meal. Endothelial function was also measured by reactive hyperemic peripheral arterial tonometry during the meal test. Paired t tests and unpaired t tests compared within- and between-group changes.Results: There were no significant differences observed in postprandial measures of inflammation or endothelial function. After 6 months, CRP (mean±S.E.) decreased in the low-fat arm from 4.0±0.77 to 3.0±0.77 (P=.01). In the low-carbohydrate arm, sICAM decreased from 234±22 to 199±23 (P=.001), and soluble E-selectin decreased from 93±10 to 82±10 (P=.05.) A significant correlation between change in high-density lipoprotein and change in soluble E-selectin (r=−0.33, P=.04) and with the change in ICAM (r=−0.43, P=.01) was observed.Conclusions: Low-carbohydrate and low-fat diets both have beneficial effects on CVD markers. There may be different mechanisms through which weight loss with these diets potentially reduces CVD risk.

Systemic resistin is increased in type 2 diabetic patients treated with loop diuretics

2011-08-03

Abstract: Increased serum resistin was found in rodent models of obesity and insulin resistance, whereas contradictory results have been obtained in human studies. In humans, resistin is primarily released by monocytes/macrophages, suggesting that soluble levels may be associated with macrophage activation. Here, systemic and monocyte-released resistin levels were found to be similar in type 2 diabetic (T2D) patients, overweight controls and normal-weight controls. When adjusted for body mass index and age, serum resistin modestly correlated with gamma-glutamyltransferase levels, fasting glucose and interleukin-6. Systemic resistin was marginally increased in T2D patients treated with beta-blockers or urate-lowering drugs and was considerably higher in patients treated with loop diuretics. Monocyte-released resistin was even reduced by the loop diuretic furosemide, excluding the possibility that this drug may directly stimulate resistin synthesis. In summary, the current data indicate that changes accompanying renal dysfunction but not obesity or type 2 diabetes are associated with increased serum resistin.

Risk factors for lower extremity amputation among patients with diabetes in Singapore

2011-10-10

Abstract: Background: Among other risk factors, renal disease and ethnicity have been associated with diabetic lower extremity amputation (LEA) in Western populations. However, little is known about risk factors for LEA among Asian patients.Objective: The objective was to assess the proportion of hospitalized patients with diabetes who have a LEA among all hospital patients with diabetes mellitus (DM) and to investigate risk factors for diabetic LEA (especially renal disease and ethnicity) using hospital discharge database.Method: A retrospective study of hospital discharge database (2004–2009) was performed to identify patients with DM, LEA and renal disease using the International Statistical Classification of Diseases and Related Health Problems, Ninth Revision, Australian Modification codes.Results: Of 44 917 hospitalized patients with DM during the 6 years, 7312 (16.3%) patients had renal disease, and 1457 (3.2%) patients had LEA. DM patients with renal disease had significant higher rates of LEA (7.1%) compared to DM patients without renal disease (2.5%, P<.001). The differences were present for foot (2.7% vs. 1.2%), ankle or leg (2.8% vs. 0.9%), and knee or above amputation (1.6% vs. 0.4%, all P<.001). Malays had the highest rate of diabetic LEA (5.1%), followed by Indians (3.0%), Chinese (3.0%), and others (2.3%, P<.001). In logistic regression analyses, renal disease and ethnicity were significant predictors of diabetic LEA (renal disease: odds ratio 3.2, 95% confidence interval 2.8–3.6; ethnicity: odds ratio, 1.6, Malays vs. Chinese, P<.001; 1.0, Indians vs. Chinese, P=.784) after adjustment for age, gender, and year of discharge.Conclusion: DM patients with renal disease and Malay ethnicity had higher rates of LEA in this Asian patient population. Malay patients with DM and diabetic patients with renal disease should be considered as high-risk groups for LEA and therefore screened and monitored systematically.

Disparities in diabetes self-management and quality of care in rural versus urban veterans

Cheryl P. Lynch, Joni L. Strom, Leonard E. Egede — 2011-10-10

Abstract: Background: There are distinct geographic differences in diabetes-related morbidity and mortality; however, data regarding self-management and clinical outcomes are limited. This study examined diabetes care among veterans residing in rural versus urban areas.Methods: A national data set was analyzed based on 10,570 veterans with type 2 diabetes. Residence was determined according to US census-based metropolitan statistical area. Primary outcomes were self-management behaviors (lifestyle and self-monitoring) and quality of care indicators (provider visits, laboratory monitoring and preventive measures). Multivariate analyses were done using STATA v10 to assess the independent effect of veteran residence on each outcome measure and to account for the complex survey design.Results: Among veterans with diabetes, 21.4% were rural residents. Compared to urban veterans, rural veterans had significantly lower education, less annual income and less received diabetes education (P=.002). The final regression model showed that daily foot self-check was the only self-management behavior significantly higher among rural veterans (odds ratio 1.36, 95% confidence interval 1.10–1.70). Provider-based quality of care was not significantly different between groups.Conclusions: Diabetes self-foot care was significantly better among rural veterans than their urban counterparts, but quality of care was equivalent. This suggests that clinical diabetes care among veterans is uniform; however, greater efforts for patient education and support in diabetes self-management are needed to improve outcomes.

Increased IL-6 levels are not related to NF-κB or HIF-1α transcription factors activity in the vitreous of proliferative diabetic retinopathy

Olli Arjamaa, Matti Pöllönen, Kati Kinnunen, Tuomas Ryhänen, Kai Kaarniranta — 2011-08-03

Abstract: Purpose: The purpose was to assess the activity of nuclear factor (NF)-κB and hypoxia inducible factor (HIF)-1α transcription factors and the expression levels of inflammation markers [interleukin (IL)-6 and IL-8] in the vitreous of patients suffering from proliferative diabetic retinopathy (PDR) scheduled for elective vitreous surgery in a single academic-based retina practice in a prospective clinical study.Methods: Twenty-seven patients with PDR were enrolled in the study. The severity of retinopathy was classified (0, 1, 2, 3, 4) and the activity of neovascularization was graded (0, 1, 2, 3, 4) by the surgeon intraoperatively. Samples of the vitreous were collected during surgery, and the activity of NF-κB and HIF-1α transcription factors and the expression levels of IL-6 and IL-8 were measured.Results: The majority of samples fell into the retinopathy class 3 (n=12) or 4 (n=13). The level of IL-6 increased from 68.9±46.8 pg/ml to 102.7±94.1 pg/ml, and IL-8 increased from 165.1±136.0 pg/ml to 521.0±870.9 pg/ml (mean±S.D., nonsignificant change: normality test followed with Mann–Whitney Rank Sum Test). According to the neovascularization activity, the samples fell into grade 1 (n=7), 2 (n=12) or 3 (n=7). In IL-6, there was a statistically significant increase (P<.05) from grade 2 to 3: 58.6±40.3 pg/ml and 158.4±102.5 pg/ml, respectively (Kruskal–Wallis One-Way Analysis of Variance on Ranks followed with Dunn's Method). The level of IL-8 was as follows: in grade 1: 118.0±62.4 pg/ml, in grade 2: 192.3±127.1 pg/ml and in grade 3: 884.3±1161.0 pg/ml (statistically nonsignificant change). There was a statistically significant linear regression between IL-6 and IL-8 (P<.001): IL-6=51.88 pg/ml+(0.092⁎IL-8), r=0.772. Increased activity of the NF-κB and HIF-1α transcription factors was not observed.Conclusion: Interleukin-6 is a candidate to indicate activity of neovascularization process in PDR. It might be a new molecular therapeutic target to regulate innate immunity response in vitreous.

Effects of a synthetic retinoid on skin structure, matrix metalloproteinases, and procollagen in healthy and high-risk subjects with diabetes

2011-11-07

Abstract: Background: In diabetes, foot ulceration may result from increased skin fragility. Retinoids can reverse some diabetes-induced deficits of skin structure and function, but their clinical utility is limited by skin irritation. The effects of diabetes and MDI 301, a nonirritating synthetic retinoid, and retinoic acid have been evaluated on matrix metalloproteinases (MMPs), procollagen expression, and skin structure in skin biopsies from nondiabetic volunteers and diabetic subjects at risk of foot ulceration using organ culture techniques.Methods: Zymography and enzyme-linked immunosorbent assay were utilized for analysis of MMP-1, -2, and -9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) and immunohistochemistry for type I procollagen protein abundance. Collagen structure parameters were assessed in formalin-fixed, paraffin-embedded tissue sections.Results: The % of active MMP-1 and -9 was higher and TIMP-1 abundance was lower in subjects with diabetes. Type 1 procollagen abundance was reduced and skin structural deficits were increased in diabetes. Three μM MDI 301 reduced active MMP-1 and -9 abundance by 29% (P<.05) and 40% (P<.05), respectively, and increased TIMP-1 by 45% (P=.07). MDI 301 increased type 1 procollagen abundance by 40% (P<.01) and completely corrected structural deficit scores. Two μM retinoic acid reduced MMP-1 but did not significantly affect skin structure.Conclusions: These data indicate that diabetic patients at risk of foot ulceration have deficits of skin structure and function. MDI 301 offers potential for repairing this skin damage complicating diabetes.

Reply to the “Comments on the article ‘Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations’”, by Avogaro (Journal of Diabetes and Its Complications 25 [2011] 352–353)

Raffaele Marfella, Giuseppe Paolisso — 2011-07-20

Comparative studies of vildagliptin and sitagliptin are limited. Although both drugs target dipeptidyl peptidase 4 (DPP-4), pharmacological differences have been described, with sitagliptin having greater potency and selectivity in DPP-4 inhibition per molecule and vildagliptin having a lower proportion of unmetabolized drug excreted in the urine (). In particular, the enzyme inhibitors of human DPP-4, such as sitagliptin and alogliptin, bind to the enzyme to form a DPP-4/inhibitor complex. However, vildagliptin is not strictly a DPP-4 inhibitor. It is a slow substrate of DPP-4, displaying tight-binding kinetics with very slow dissociation rates compared with GLP-1: the vildagliptin/DPP-4 complex dissociates slowly, giving a long duration of inhibition and excellent in vivo potency due to its strong binding to DPP-4 (). As a consequence of the tight-binding mechanism, a lower concentration of vildagliptin is needed for the same duration of inhibition as with a simple inhibitor. However, currently, these pharmacologic differences have not been linked to differences in clinical outcomes. In our nonrandomized parallel cohort study of vildagliptin and sitagliptin, we found no statistically significant difference in efficacy for decreasing glycosylated hemoglobin A1c (HbA1c) or fasting plasma glucose (FPG), but more consistent glycemic control with vildagliptin, as measured by a greater decrease in the mean amplitude of glycemic excursions (MAGE) (). In this context, we agree with the observation that more data are needed in assessing the therapeutic choice between vildagliptin and sitagliptin in controlling daily blood glucose excursions. However, Avogaro provided us with several speculative criticisms regarding the use of MAGE, assessed by continuous subcutaneous glucose monitoring (CSGM), as index of daily glycemic excursions. This approach to evaluate the MAGE was initially used by and subsequently by several other authors. Moreover, as suggested by a recent review (), the MAGE is most commonly used for CSGM data. On these basis, we used the glucose profiles obtained from continuous glucose monitoring system data on Study Days 1 and 2, i.e., from continuous monitoring for 48 h. This parameter was designed to quantify major swings of glycemia and to exclude minor ones. For this reason, only increases of more than 1 S.D. of the mean glycemic values were taken into account. Calculation of the MAGE was obtained by measuring the arithmetic mean of the differences between consecutive peaks and nadirs; measurement in the peak-to-nadir or nadir-to-peak direction was determined by the first qualifying excursion. The measurement of this parameter is of particular interest because when MAGE is greater, glycemic instability is higher ().

Journal of Diabetes and Its Complications

Contents

The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial

Relationship of glycemia control to lipid and blood pressure lowering and atherosclerosis: the SANDS experience

High-sensitivity C-reactive protein: a novel cardiovascular risk predictor in type 2 diabetics with normal lipid profile

Differential effects of low-carbohydrate and low-fat diets on inflammation and endothelial function in diabetes

Systemic resistin is increased in type 2 diabetic patients treated with loop diuretics

Risk factors for lower extremity amputation among patients with diabetes in Singapore

Disparities in diabetes self-management and quality of care in rural versus urban veterans

Increased IL-6 levels are not related to NF-κB or HIF-1α transcription factors activity in the vitreous of proliferative diabetic retinopathy

Effects of a synthetic retinoid on skin structure, matrix metalloproteinases, and procollagen in healthy and high-risk subjects with diabetes

Reply to the “Comments on the article ‘Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations’”, by Avogaro (Journal of Diabetes and Its Complications 25 [2011] 352–353)