Showing papers in "Journal of Diabetes and Its Complications in 2013"

Lower circulating irisin is associated with type 2 diabetes mellitus.

Abstract: Aims Irisin is a novel myokine secreted in response to PPAR-γ co-activator-1α (PGC-1α) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients. Methods In this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression. Results Circulating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204 ± 72 ng/ml vs. non-diabetic control 257 ± 24 ng/ml, p Conclusions Circulating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes.

Antioxidant, anti-diabetic and renal protective properties of Stevia rebaudiana

Abstract: article i nfo Background: Stevia rebaudiana Bertoni has been used for the treatment of diabetes in, for example, Brazil, although a positive effect on antidiabetic and its complications has not been unequivocally demonstrated. This herb also has numerous therapeutic properties which have been proven safe and effective over hundreds of years. Streptozotocin is a potential source of oxidative stress that induces genotoxicity. Objective: We studied the effects of stevia leaves and its extracted polyphenols and fiber on streptozotocin induced diabetic rats. We hypothesize that supplementation of polyphenols extract from stevia to the diet causes a reduction in diabetes and its complications. Design/Methods: Eighty Wistar rats were randomly divided into 8 groups; a standard control diet was supplemented with either stevia whole leaves powder (4.0%) or polyphenols or fiber extracted from stevia separately and fed for one month. Streptozotocin (60 mg/kg body weight, i.p) was injected to the diabetic groups on the 31st day. Several indices were analyzed to assess the modulation of the streptozotocin induced oxidative stress, toxicity and blood glucose levels by stevia. Results: The results showed a reduction of blood glucose, ALT and AST, and increment of insulin level in the stevia whole leaves powder and extracted polyphenols fed rats compared to control diabetic group. Its feeding also reduced the MDA concentration in liver and improved its antioxidant status through antioxidant enzymes. Glucose tolerance and insulin sensitivity were improved by their feeding. Streptozotocin was also found to induce kidney damage as evidenced by decreased glomerular filtration rate; this change was however alleviated in the stevia leaves and extracted polyphenol fed groups. Conclusion: The results suggested that stevia leaves do have a significant role in alleviating liver and kidney damage in the STZ-diabetic rats besides its hypoglycemic effect. It might be adequate to conclude that stevia leaves could protect rats against streptozotocin induced diabetes, reduce the risk of oxidative stress and ameliorate liver and kidney damage.

Obesity and hyperlipidemia are risk factors for early diabetic neuropathy.

Abstract: The Utah Diabetic Neuropathy Study (UDNS) examined 218 type 2 diabetic subjects without neuropathy symptoms, or with symptoms of 0.02 and 3.0 p<0.004 respectively). Multivariate analysis found obesity and triglycerides were related to loss of small unmyelinated axons based on IENFD whereas elevated hemoglobin A1c was related to large myelinated fiber loss (motor conduction velocity). These findings indicate obesity and hypertriglyceridemia significantly increase risk for peripheral neuropathy, independent of glucose control. Obesity/hypertriglyceridemia and hyperglycemia may have differential effects on small versus large fibers.

Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin.

Abstract: Background Vulvovaginitis, balanitis, and related genital infections are common in patients with type 2 diabetes. Glucosuria, which is an outcome of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors, is among the possible causes. Dapagliflozin, an SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes, has been studied across a broad spectrum of patients. Analysis of multi-trial safety data may better define the relationship between glucosuria and genital infection. Methods Safety data were pooled from 12 randomized, placebo-controlled Phase 2b/3 trials to analyze the association of glucosuria with genital infection in patients with suboptimally controlled diabetes (HbA1c > 6.5%–12%). Patients were randomized to receive dapagliflozin (2.5 mg, 5 mg, or 10 mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12–24 weeks. The incidence of clinical diagnoses and of events suggestive of genital infection was evaluated. Results The pooled safety data included 4545 patients: 3152 who received once-daily dapagliflozin (2.5 mg [n = 814], 5 mg [n = 1145], or 10 mg [n = 1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5 mg, 5 mg, 10 mg, and placebo, diagnosed infections were reported in 4.1%, 5.7%, 4.8%, and 0.9%, respectively. Most infections were mild or moderate and responded to standard antimicrobial treatment. Discontinuation due to these events was rare. No clear dose–response relationship between dapagliflozin and genital infection was demonstrated. Conclusions Treatment with dapagliflozin 2.5 mg, 5 mg, or 10 mg once daily is accompanied by an increased risk of vulvovaginitis or balanitis, related to the induction of glucosuria. Events were generally mild to moderate, clinically manageable, and rarely led to discontinuation of treatment.

Urinary tract infections in patients with diabetes treated with dapagliflozin

Abstract: Aims Urinary tract infection is common in patients with type 2 diabetes. Possible causative factors include glucosuria, which is a result of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors. Dapagliflozin is an investigative SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes. Data from dapagliflozin multi-trial safety data were analyzed to clarify the association between glucosuria and urinary tract infection. Methods Safety data from 12 randomized, placebo-controlled trials were pooled to evaluate the relationship between glucosuria and urinary tract infection in patients with inadequately controlled diabetes (HbA1c >6.5%–12%). Patients were treated with dapagliflozin (2.5, 5, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12–24weeks. The incidence of clinical diagnoses and events suggestive of urinary tract infection were quantified. Results This analysis included 3152 patients who received once-daily dapagliflozin (2.5mg [ n =814], 5mg [ n =1145], or 10mg [ n =1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 3.6%, 5.7%, 4.3%, and 3.7%, respectively. Urinary glucose levels, but not the incidence of urinary tract infection, increased progressively with dapagliflozin dosage. Most identified infections were those considered typical for patients with diabetes. Discontinuations due to urinary tract infection were rare: 8 (0.3%) dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient. Most diagnosed infections were mild to moderate and responded to standard antimicrobial treatment. Conclusions Treatment of type 2 diabetes with once-daily dapagliflozin 5 or 10mg is accompanied by a slightly increased risk of urinary tract infection. Infections were generally mild to moderate and clinically manageable. This analysis did not demonstrate a definitive dose relationship between glucosuria and urinary tract infection.

Observational research--opportunities and limitations.

Abstract: Medical research continues to progress in its ability to identify treatments and characteristics associated with benefits and adverse outcomes. The principal engine for the evaluation of treatment efficacy is the randomized controlled trial (RCT). Due to the cost and other considerations, RCTs cannot address all clinically important decisions. Observational research often is used to address issues not addressed or not addressable by RCTs. This article provides an overview of the benefits and limitations of observational research to serve as a guide to the interpretation of this category of research designs in diabetes investigations. The potential for bias is higher in observational research but there are design and analysis features that can address these concerns although not completely eliminate them. Pharmacoepidemiologic research may provide important information regarding relative safety and effectiveness of diabetes pharmaceuticals. Such research must effectively address the important issue of confounding by indication in order to produce clinically meaningful results. Other methods such as instrumental variable analysis are being employed to enable stronger causal inference but these methods also require fulfillment of several key assumptions that may or may not be realistic. Nearly all clinical decisions involve probabilistic reasoning and confronting uncertainly, so a realistic goal for observational research may not be the high standard set by RCTs but instead the level of certainty needed to influence a diagnostic or treatment decision.

Diabetic foot ulcer incidence in relation to plantar pressure magnitude and measurement location.

Abstract: Aims We prospectively examined the relationship between site-specific peak plantar pressure (PPP) and ulcer risk. Researchers have previously reported associations between diabetic foot ulcer and elevated plantar foot pressure, but the effect of location-specific pressures has not been studied. Methods Diabetic subjects (n = 591) were enrolled from a single VA hospital. Five measurements of in-shoe plantar pressure were collected using F-Scan. Pressures were measured at 8 areas: heel, lateral midfoot, medial midfoot, first metatarsal, second through fourth metatarsal, fifth metatarsal, hallux, and other toes. The relationship between incident plantar foot ulcer and PPP or pressure–time integral (PTI) was assessed using Cox regression. Results During follow-up (2.4 years), 47 subjects developed plantar ulcers (10 heel, 12 metatarsal, 19 hallux, 6 other). Overall mean PPP was higher for ulcer subjects (219 vs. 194 kPa), but the relationship differed by site (the metatarsals with ulcers had higher pressure, while the opposite was true for the hallux and heel). A statistical analysis was not performed on the means, but hazard ratios from a Cox survival analysis were nonsignificant for PPP across all sites and when adjusted for location. However, when the metatarsals were considered separately, higher baseline PPP was significantly associated with greater ulcer risk; at other sites, this relationship was nonsignificant. Hazard ratios for all PTI data were nonsignificant. Conclusions Location must be considered when assessing the relationship between PPP and plantar ulceration.

Dry eye and its correlation to diabetes microvascular complications in people with type 2 diabetes mellitus.

Abstract: Aims This study was performed to investigate the correlation between dry eye disease and diabetes microvascular complications. Methods In this study 243 people with type 2 diabetes were enrolled. Tear osmolarity was measured using tear lab osmolarity system. All of the participants were evaluated for diabetes microvascular complications. The Michigan neuropathy screening instrument was used for detection of peripheral neuropathy, and the albumin/creatinine ratio in a spot urine sample was considered to diagnose diabetic nephropathy. Results The prevalence of dry eye disease was 27.7%. The mean value for tear osmolarity was 301.97 ± 13.52 mOsm/L. We found a significant correlation between dry eye disease and diabetic retinopathy (P = 0.01). However no significant correlation was found between dry eye disease, diabetic neuropathy, and diabetic nephropathy. Dry eye disease was more prevalent in people with proliferative diabetic retinopathy and/or clinically significant macular edema (0.006). In a binary logistic regression analysis model, there was a significant correlation between dry eye disease and retinopathy (OR = 2.29, CI = 1.16–4.52, P = 0.016). In addition, both dry eye and retinopathy had significant correlation with HbA1C. Conclusions Dry eye disease is common in people with type 2 diabetes, especially in those with diabetic retinopathy. In addition, it is more prevalent in people who suffer from advanced stages of diabetic retinopathy.

Diabetes mellitus and incidence and mortality of kidney cancer: a meta-analysis.

Abstract: Background: Diabetes is associated with increased risk of a spectrum of cancers, but there are few meta-analyses on the association between diabetes and kidney cancer. We performed a meta-analysis of case-control studies and cohort studies to address the incidence and mortality of kidney cancer in diabetes. Methods: Studies were identified by searching PubMed database and manual assessment of the cited references in the retrieved articles. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effect model. Study quality was assessed using the Newcastle-Ottawa scale. Results: A total of 24 studies were included. We found that diabetes was significantly associated with increased risk of kidney cancer (RR=1.40, 95% CI = 1.16 to 1.69), and the results were consistent between case-control and cohort studies. A slightly stronger positive relation was observed in women (RR = 1.47, 95% CI=1.18 to 1.83) than in men (RR=1.28, 95% CI=1.10 to 1.48). Additional analyses indicated that the increased risk of kidney cancer was independent of alcohol consumption, body mass index (BMI)/obesity and smoking. However, there was no association between diabetes and mortality of kidney cancer (RR=1.12, 95% CI=0.99 to 1.20), without heterogeneity (P = 0.419, I-2 = 1.8%). Conclusions: Diabetes mellitus may increase the risk of kidney cancer in both women and men.

Active- and placebo-controlled dose-finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus.

Abstract: Aim To evaluate the efficacy, safety, and tolerability of multiple doses of ipragliflozin. This novel selective inhibitor of sodium glucose co-transporter 2 is in clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM). Methods In a 12-week, multicenter, double-blind, randomized, active- and placebo-controlled dose-finding study, patients were randomized to one of four ipragliflozin treatment groups (12.5, 50, 150, and 300mg once daily), placebo, or active control (metformin). The primary efficacy outcome was the mean change from baseline to Week 12 of glycosylated hemoglobin (HbA1c) compared with placebo. Results Ipragliflozin showed a dose-dependent decrease in HbA1c of −0.49% to −0.81% at Week 12 compared with placebo ( P Proportions of patients experiencing treatment-emergent adverse events were similar across all groups: ipragliflozin (45.7–58.8%), placebo (62.3%), and metformin (59.4%). No clinically relevant effects were observed for other safety measures. Conclusions After 12weeks of treatment, ipragliflozin dose-dependently decreased HbA1c, with ipragliflozin ≥50mg/day in patients with T2DM; an effect comparable to metformin. No safety or tolerability concerns were identified.

Increased ratio of serum matrix metalloproteinase-9 against TIMP-1 predicts poor wound healing in diabetic foot ulcers.

Abstract: Objective Little is known about serum concentrations of Matrix Metalloproteinase-9 (MMP-9), MMP-2, TIMP-1 and TIMP-2 in diabetic patients with foot ulcers. This study demonstrates their relationship with wound healing. Methods Ninety-four patients with diabetic foot ulcers were recruited in the study. Serum MMP-9, MMP-2, TIMP-1 and TIMP-2 were measured at the first clinic visit and the end of 4-week treatment and followed up till 12weeks. According to the decreasing rate of ulcer healing area at the fourth week, we divided those cases into good and poor healers. Through analyses, we explore the possible relationship among those factors and degree of wound healing. Results The median level of serum MMP-9 in good healers was lower than poor healers at first visit (124.2μg/L vs 374.6μg/L, p vs −0.3251, r=−0.7096 vs −0.1231, respectively). Receiver Operator Curve (ROC) showed that the cutoff for MMP-9/TIMP-1 ratio at Conclusions Detecting serum MMP-9/TIMP-1 ratio on admission might be a predictor of healing and might provide a novel target for the future therapy in diabetic foot ulcers.

Irisin in obesity and type 2 diabetes.

Abstract: Insulin resistance plays an important role in the pathogenesis of type 2 diabetes and is associated with cardiovascular disease. Despite extensive research, the mechanisms underlying insulin resistance are not fully understood, and pharmacological treatment targeting insulin resistance is almost non-existing. As the largest organ in the body, skeletal muscle accounts for the majority of glucose uptake in response to insulin, and is quantitatively the most important site of insulin resistance. Accordingly, an improvement in insulin sensitivity is achievable by interventions that include increased physical activity. During the past decade, skeletal muscle has also been identified as a secretory organ, secretingmyostatin, IL-6, IL-15 andother factors,which may communicatewith other organs tomediate the beneficial effects of exercise on metabolism (Pedersen & Febbraio, 2012). It is increasingly being recognized that exercise-trainingandpreservationofmusclemass play an important role for health, and the prevention of type 2 diabetes and cardiovascular disease. The identification of therapeutic approaches that could enhance or even mimic the multiple health benefits of physical activity is therefore a field of great importance. Most recently, a novel myokine, named irisin, was identified in mice and human (Boström et al., 2012). Irisin is expressed in muscle as the type I membrane precursor protein FNDC5, which is proteolytically cleaved and secreted into the circulation. In mice, FNDC5 expression in muscle and circulating irisin increased in response to overexpression of PGC-1α as well as 3 weeks of aerobic exercise-training. Exogenous administration of irisin using adenoviral delivery triggered a programme of brown-fat-like development in specific depots of white adipose tissue (WAT), and resulted in increased energy expenditure, improved glucose tolerance, and a modest but significant weight loss (Boström et al., 2012). In obese, middle-aged healthy individuals, endurance-training for 10 weeks caused an increase in mRNA levels of FNDC5 and PGC-1α in skeletal muscle, and this was accompanied by a 2-fold increase in circulating irisin. However, a potential effect of this increase in irisin on the \"browning\" of WAT in human was not examined. These results provided evidence that irisin is a novel myokine that may mediate some of the positive effects of training, and have evoked a huge interest in defining the potential role of irisin in human. In the current issue of the Journal of Diabetes and its Complications, Liu and co-workers report that circulating irisin was significantly lower in patients with type 2 diabetes, and that in non-diabetic individuals circulating irisin correlated positively with age, BMI, total cholesterol, triglycerides, fasting blood glucose and diastolic blood pressure (Liu et al., 2013). After adjustment for multiple co-variates, the positive association of irisin with BMI and blood glucose persisted. The positive association of circulating irisin with BMI was also reported in two other non-diabeticpopulations, recently (Huhetal., 2012; Stengel et al., 2013).

Increased Gait Variability in Diabetes Mellitus Patients With Neuropathic Pain

Abstract: Aims Gait dysfunction in subjects with diabetes mellitus (DM) contributes to falling and subsequent injuries. Using a portable device (GaitMeter™), we measured gait parameters in DM patients with and without diabetic peripheral neuropathy (DPN) during flat surface walking. We hypothesized that DM patients with DPN and neuropathic pain (NeP) would have greater gait step variability than those with DPN without NeP. Methods Subjects with DPN and at least moderate NeP (DPN-P), DPN without NeP (DPN-NoP), DM without DPN, and control subjects without DM were assessed. Our outcome measure was gait variability for step length and velocity. DPN severity was quantified using the Toronto Clinical Scoring System and the Utah Early Neuropathy Score. Falls and their outcomes were retrospectively quantified. Results Each cohort contained≥20 subjects. Durations of DM and HbA1C were greatest amongst DPN cohorts. DPN-P participants had greater variability of step length and step velocity, except for DM only participants. DPN-P participants also reported greater risk of hospitalizations for fall-related injuries, and greater fear of falling. Modest negative relationships emerged for step length with step velocity, reported falls and pain severity. Conclusions NeP contributes to gait variability, potentially contributing to the risk of falling in DM patients.

Normoalbuminuric diabetic kidney disease in the U.S. population.

Abstract: Background This study sought to compare the prevalence and modifying factors of normoalbuminuric (NA) versus albuminuric (ALB) CKD in the U.S. diabetic and nondiabetic populations. Methods NHANES 2001–2008 included 2798 diabetic and 15,743 nondiabetic participants. Age-specific prevalence of NA-CKD and ALB-CKD was calculated within each diabetes stratum and then stratified again according to gender, ethnicity, mean arterial pressure ≥ 105 mmHg and HbA1c ≥ 7%. Multivariate regression analyses were performed to determine odds ratios and 95% CI for NA-CKD. Results Prevalence of NA-CKD rose with age, with an overall mean of 9.7% in diabetic and 4.3% in nondiabetic participants. NA-CKD was less prevalent in diabetic men, OR = 0.58 (95% CI: 0.39, 0.87). In comparison with whites, blacks and ‘other’ ethnic groups had an OR for NA-CKD of 0.44 (95% CI 0.29, 0.68) and 0.57 (95% CI: 0.34, 0.96), respectively. Poorly controlled blood pressure and glycemia resulted in a decreased OR for NA-CKD (OR = 0.25, 95% CI: 0.13, 0.50) and (0.48, 95% CI: 0.31, 0.74), respectively. Similar results were obtained for nondiabetic participants. Conclusions NA-CKD is more common in people with diabetes, women, non-Hispanic whites, and in the setting of well controlled blood pressure and glycemia.

Association of biomarkers of inflammation and oxidative stress with the risk of chronic kidney disease in Type 2 diabetes mellitus in North Indian population.

Abstract: Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide. It results from diverse etiologies, diabetes being a frontrunner amongst them. Type 2 diabetes mellitus (DM) is being increasingly recognized as a proinflammatory state with increased oxidative stress which enormously increases the risk of micro and macro vascular diseases. This study was planned to explore the possible association between tumor necrosis factor-alpha (TNF-α), urinary monocyte chemoattractant protein-1 (uMCP-1), high-sensitivity C-reactive protein (hsCRP) and parameters of oxidative stress in patients with Type 2 diabetes mellitus (DM) and diabetic chronic kidney disease (DM–CKD). Fifty patients each were recruited in DM, DM–CKD and healthy control groups. Plasma TNF-α, hsCRP and uMCP-1 levels as inflammatory mediators were measured by ELISA, reduced glutathione (GSH), ferric reducing ability of plasma (FRAP) as parameters of antioxidant activity and malondialdehyde (MDA) as marker of oxidative stress, were measured spectrophotometrically. Plasma TNF-α, hsCRP and uMCP-1 were significantly higher in DM–CKD compared to DM and healthy controls. Lipid peroxidation, measured as MDA was significantly higher in patients with DM–CKD as compared to patients with DM and healthy controls. Further, antioxidant capacity of blood measured as FRAP and GSH was found to be significantly lower in patients with DM and DM–CKD as compared to healthy controls (p 1c (r=0.441, 0.643), hsCRP (r=0.400, 0.584) and MDA (r=0.423, 0.759) and significant negative correlation with GSH (R=−0.370, −0.800) and FRAP (r=−0.344, −0.684) Increased inflammatory markers viz. TNF-α, hsCRP and uMCP-1 and markers of oxidative stress i.e. increased MDA and decreased GSH and FRAP in DM–CKD suggest an important role of inflammation and oxidative stress in the pathogenesis of renal damage in diabetic patients.

Gender and ethnic differences in the prevalence of type 2 diabetes among Asian subgroups in California

Abstract: AimsTo investigate gender and ethnic type 2 diabetes (DM) prevalences among California Asian subgroups versus other ethnic groups and if risk factors explain these differences.MethodsWe identified the prevalence of DM and associated risk factors, stratified by gender, among Chinese, Filipino, South Asian, Japanese, Korean, Vietnamese, Mexican, Other Hispanic, African American, Caucasian, and Native American adults in a large survey conducted in 2009 (n=46,091, projected n= 26.6 mil).ResultsThe highest age-adjusted DM prevalence was seen in Native Americans (32.4%), Filipinos (15.8%), and Japanese (11.8%) among men and in Native Americans (16.0%) and African Americans (13.3%) among women. Caucasian and Mexican men had higher DM prevalences than women. Age and risk factor-adjusted logistic regression showed DM more likely (relative to Caucasians) among women in Koreans (OR=4.6, p<0.01), Native Americans (OR=3.0, p<0.01), and Other Hispanics (OR 2.9, p<0.01) and among men in Filipinos (OR=7.0, p<0.01), South Asians (OR=4.7, p<0.01), and Native Americans (OR=4.7, p<0.01). No specific risk factors accounted for the gender differences.ConclusionsEthnic and gender differences in DM prevalence persist, even after adjusting for lifestyle and other risk factors; prevalence is high among certain Asian American subgroups. Different diabetes prevention approaches may be needed across ethnic/gender groups.

Geographic variation in Medicare spending and mortality for diabetic patients with foot ulcers and amputations.

Abstract: Aims The purpose of this study was to identify the presence or absence of geographic variation in Medicare spending and mortality rates for diabetic patients with foot ulcers (DFU) and lower extremity amputations (LEA). Methods Diabetic beneficiaries with foot ulcers (n=682,887) and lower extremity amputations (n=151,752) were enrolled in Medicare Parts A and B during the calendar year 2007. We used ordinary least squares (OLS) regression to explain geographic variation in per capita Medicare spending and one-year mortality rates. Results Health care spending and mortality rates varied considerably across the nation for our two patient cohorts. However, higher spending was not associated with a statistically significant reduction in one-year patient mortality ( P =.12 for DFU, P =.20 for LEA). Macrovascular complications for amputees were more common in parts of the country with higher mortality rates ( P P =.12). In contrast, macrovascular complications were associated with increased per capita spending for beneficiaries with foot ulcers ( P =.01). Rates of hospital admission were also associated with higher per capita spending and increased mortality rates for individuals with foot ulcers ( P P P =.01 for mortality). Conclusions Geographic variation in Medicare spending and mortality rates for diabetic patients with foot ulcers and amputations is associated with regional differences in the utilization of inpatient services and the prevalence of macrovascular complications.

A systematic review of predictive risk models for diabetes complications based on large scale clinical studies

Abstract: This work presents a systematic review of long-term risk assessment models for evaluating the probability of developing complications in diabetes patients. Diabetes mellitus can cause many complications if not adequately controlled; risk assessment models can help physicians and patients in identifying the complications most likely to arise and in taking the necessary countermeasures. We identified six large medical studies related to diabetes mellitus upon which current available risk assessment models are built on; all these studies had duration over 5 years and most of them included some common demographic and clinical data strongly related to diabetic complications. The most common predictions for long term diabetes complications are related to cardiovascular diseases and diabetic retinopathy. Our analysis of the literature led us to the conclusion that researchers and medical practitioners should take in account that some limitations undermine the applicability of risk assessment models; for example, it is hard to judge whether results obtained on a specific cohort can be effectively translated to other populations. Nevertheless, all these studies have significantly contributed to identify significant risk factors associated with the major diabetes complications.

Frontal gray matter atrophy in middle aged adults with type 1 diabetes is independent of cardiovascular risk factors and diabetes complications

Abstract: Aims To determine if regional gray matter volume (GMV) differences in middle-aged adults with and without type-1 diabetes (T1D) are localized in areas most vulnerable to aging, eg fronto-subcortical networks; and if these differences are explained by cardiovascular risk factors and diabetes complications Methods Regional GMV was computed using 3 T MRI of 104 adults with a childhood onset of T1D (mean age: 49 ± 7 and duration: 41 ± 6 years) and 151 adults without diabetes (mean age: 40 ± 6) A Bonferroni threshold (n = 45, p ≤ 0001) was applied to account for multiple between-group comparisons and analyses were repeated in an age- and gender-matched subset of participants with T1D and controls (n = 44 in each group, mean age [SD] and range: 440, [43], 174 and 446 [43], 170, respectively) Results Compared to controls, T1D patients had smaller GMV in the frontal lobe (6% to 19% smaller) and adjacent supramarginal and postcentral gyri (8% to 13% smaller) Between-group differences were independent of age, waist circumference, systolic blood pressure, fasting total cholesterol and smoking status and were similar in sensitivity analyses restricted to age- and gender-matched participants Associations between GMV and diabetes complications were not significant Conclusions These findings extend the notion of accelerated brain aging in T1D to middle-aged adults The pathophysiology of frontal gray matter atrophy and its impact on future development of disability and dementia need further study, especially as middle-aged T1D patients progress to older age

The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes

Abstract: Purpose We determined the association between novel and acid-labile skin collagen-linked advanced glycation endproducts (AGEs) and the progression of microvascular and neuropathic complications from baseline to near study closeout in the Diabetes Control and Complications Trial (DCCT). Methods From a skin biopsy obtained near the close of the DCCT, proteolytic collagen digests were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS) for glucosepane (GSPNE), glyoxal and methylglyoxal hydroimidazolones (G-H1 and MG-H1) and the glycation product fructose-lysine (FL) using isotope dilution method. Results GSPNE and MG-H1 correlated with age and diabetes duration (P 40 mg/24 h (OR = 5.3, P Conclusions Glucosepane is a novel AGE marker of diabetic complications that is robustly associated with nephropathic, retinopathic and neuropathic outcomes despite adjustment for A1c, suggesting that it could be one mediator of these complications with possible diagnostic implications.

New options for the treatment of obesity and type 2 diabetes mellitus (narrative review).

Abstract: Moderate weight loss (>5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1-2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes.

Association of reduced glyoxalase 1 activity and painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients.

Abstract: Aims The present study was undertaken to investigate the relationship between glyoxalase 1 (Glo1) enzyme activity and painful diabetic neuropathy (DN) in patients with diabetes mellitus. Methods Glo1 activity and biochemical markers were determined in blood samples from 108 patients with type 1 diabetes, 109 patients with type 2 diabetes, and 132 individuals without diabetes as a control. Painful and painless peripheral DN was assessed and multivariate regression analysis was used to determine independent association of Glo1 activity with occurrence of painful DN. Results In patients with type 1 and type 2 diabetes mellitus and painful DN compared to patients with painless DN, Glo1 activity was significantly reduced by 12 and 14%, respectively. The increase in Glo1 activity was significantly associated with reduced occurrence of painful DN after adjusting for confounders by multivariate analysis. Conclusions Our results demonstrate for the first time that Glo1 activity is lower in patients with both types of diabetes mellitus who were diagnosed with painful DN. These data support the hypothesis that Glo1 activity modulates the phenotype of DN and warrant further investigation into the role of Glo1 in DN.

Psychological trauma symptoms and Type 2 diabetes prevalence, glucose control, and treatment modality among American Indians in the Strong Heart Family Study

Abstract: article Aims: The aims of this paper are to examine the relationship between psychological trauma symptoms and Type 2 diabetes prevalence, glucose control, and treatment modality among 3776 American Indians in Phase V of the Strong Heart Family Study. Methods: This cross-sectional analysis measured psychological trauma symptoms using the National Anxiety Disorder Screening Day instrument, diabetes by American Diabetes Association criteria, and treatment modality by four categories: no medication, oral medication only, insulin only, or both oral medication and insulin. We used binary logistic regression to evaluate the association between psychological trauma symptoms and diabetes prevalence. We used ordinary least squares regression to evaluate the association between psychological trauma symptoms and glucose control. We used binary logistic regression to model the association of psychological trauma symptoms with treatment modality.

Prognostic implication of liver histology in patients with nonalcoholic fatty liver disease in diabetes.

Abstract: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist due to shared risk factors. Their rising prevalence parallels the growing epidemic of obesity and insulin resistance (IR). In patients with T2DM and biopsy-proven NAFLD, a significantly higher prevalence of nonalcoholic steatohepatitis (NASH) (63-87%), any fibrosis (22-60%), and advanced fibrosis (4-9%) is noted. Possible risk factors for more advanced liver disease include concomitant metabolic syndrome with three or more components, visceral obesity, older age, increased duration of diabetes, and family history of diabetes. Liver biopsy is strongly suggested in these patients. Cardiovascular disease (CVD) and malignancy are the leading causes of death in this population, but a growing body of evidence shows liver-related mortality as an important cause of death, including an increased rate of hepatocellular carcinoma (HCC) in diabetes. The presence of NAFLD in T2DM is also associated with increased overall mortality. We aim with this review to summarize the results from studies investigating NAFLD in T2DM and to outline the factors that predict more advanced liver histology as well as the impact of these hepatic changes on CVD, overall and liver-related mortality.

Prevalence and risk factors for diabetes-related foot complications in Translating Research Into Action for Diabetes (TRIAD)

Abstract: Aims The objective was to describe the prevalence of diabetes-related foot complications in a managed care population and to identify the demographic and biological risk factors. Methods We assessed the period prevalence of foot complications on 6992 patients using ICD-9 diagnosis codes from health plan administrative data. Demographic and biological variables were ascertained from surveys and medical record reviews. We defined four mutually exclusive groups: any Charcot foot, DFU with debridement, amputation ± DFU and debridement, and no foot conditions. Results Overall, 55 (0.8%) patients had Charcot foot, 205 (2.9%) had DFU with debridement, and 101 (1.4%) had a lower-extremity amputation. There were 6631 patients with no prevalent foot conditions. Racial/ethnic minorities were less likely to have Charcot foot (OR = 0.21; 95% CI: 0.10, 0.46) or DFU (OR = 0.61; 95% CI: 0.44, 0.84) compared to non-Hispanic Whites, but there were no racial/ethnic differences in amputation. Histories of micro- or macrovascular disease were associated with a two- to four-fold increase in the odds of foot complications. Conclusion In managed care patients with uniform access to health care, we found a relatively high prevalence of foot complications, but attenuation of the racial/ethnic differences of rates reported in the literature.

Advanced glycation end products-induced reactive oxygen species generation is partly through NF-kappa B activation in human aortic endothelial cells.

Abstract: Tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) are involved in the endothelial dysfunction and the progression of atherosclerosis. In the pathogenesis of diabetic micro- and macro-vascular complications, advanced glycation end products (AGEs) and their receptor signaling are thought to play pivotal roles. We have studied the interaction among AGEs, TNF-α and ROS production using human aortic endothelial cells (HAoEC), and elucidated the significance of transcription factor NF-κB in that interaction. Concentration of TNF-α as well as 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of ROS generation, in the culture medium was significantly elevated 24 h after treatment with glycolaldehyde-derived AGE3. Antioxidant TEMPOL almost completely inhibited AGE3-induced TNF-α secretion, whereas NF-κB inhibitor PDTC partly suppressed AGE3-induced 8-OHdG production. Since NF-κB, which induces TNF-α expression is activated by ROS and TNF-α itself, AGE3-induced ROS generation is partly through NF-κB activation and subsequent TNF-α production in these cells. Our findings suggest that sustained activation of NF-κB might be crucial for endothelial dysfunction in diabetes, and that inhibition of local NF-κB and/or TNF-α action could be one of therapeutic strategies for vascular complications.

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes

Abstract: Aims To assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥1500mg/day) and pioglitazone (≥30mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A 1c [HbA 1c ] ≥7.5% and ≤11%). Methods This placebo-controlled, double-blind study included 313 patients, mean baseline HbA 1c =8.7%, who were randomized to receive sitagliptin 100mg/day or placebo for 26weeks. Results The addition of sitagliptin led to significant ( P 1c (−0.7%), fasting plasma glucose (−1.0mmol/L), and 2-h post-meal glucose (−2.2mmol/L). In patients with baseline HbA 1c ≥9.0%, mean changes from baseline in HbA 1c were −1.6% and −0.8% for the sitagliptin and placebo groups, respectively (between-group difference −0.8%; P P =.786). Two patients, both in the placebo group, experienced an episode of hypoglycemia that required non-medical assistance. Conclusions In this 26-week study, addition of sitagliptin to combination therapy with metformin and pioglitazone improved glycemic control and was generally well tolerated.

The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM).

Abstract: Type 2 diabetes mellitus (T2DM) significantly increases morbidity and mortality from cardiovascular disease (CVD). Treatments for patients with T2DM have the potential to reduce cardiovascular (CV) risk. This review focuses on the potential of a new class of antidiabetic agents, the sodium glucose cotransporter 2 (SGLT2) inhibitors, to reduce CV risk in patients with T2DM through reductions in hyperglycemia, blood pressure (BP), and body weight. The results of clinical trials of SGLT2 inhibitors are summarized and discussed.

The effectiveness of footwear as an intervention to prevent or to reduce biomechanical risk factors associated with diabetic foot ulceration: A systematic review

Abstract: Aim Footwear interventions are used within clinical practice in an effort to reduce ulcerations however the effectiveness of these interventions is unclear. The aim of this paper was to conduct a systematic review which examined the effectiveness of footwear as an intervention for prevention of diabetic foot ulcers or the reduction of biomechanical risk factors for ulceration and to discuss the quality and interpret the findings of research to date. Methods The CINAHL, Medline and Cochrane Register of Controlled Trials databases were searched with 12 articles identified for review. Results The majority of these studies were cross sectional and examined the effect of different footwear conditions on plantar pressure measurements. Factors which influenced study findings such as participant selection, measurement and analysis techniques, footwear design and compliance are discussed and recommendations for future studies are provided. Conclusions No research to date has examined the effectiveness of footwear in preventing ulceration. Conflicting findings are reported on the effective of footwear interventions to prevent reulceration. While the use of rocker sole footwear and custom orthoses in plantar pressure reduction are supported in cross sectional studies, longitudinal studies are required to confirm their benefit.

Insulin sparing action of adenovirus 36 and its E4orf1 protein.

Abstract: Additional drugs are required to effectively manage diabetes and its complications. Recent studies have revealed protective effects of Ad36, a human adenovirus, and its E4orf1 protein on glucose disposal, which may be creatively harnessed to develop novel anti-diabetic agents. Experimental Ad36 infection improves hyperglycemia in animal models and natural Ad36 infection in humans is associated with better glycemic control. Available data indicate distinctive advantages for a drug that may mimic the action of Ad36/E4orf1. The key features of such a potential drug include the ability to increase glucose uptake by adipose tissue and skeletal muscle, to reduce hepatic glucose output independent of proximal insulin signaling, and to up-regulate adiponectin and its hepatic action. The effect of Ad36/E4orf1 on hepatocyte metabolism suggests a role for treating hepatic steatosis. Despite these potential advantages, considerable research is required before such a drug is developed. The in vivo efficacy and safety of E4orf1 in improving hyperglycemia remain unknown, and an appropriate drug delivery system is required. Nonetheless, Ad36 E4orf1 offers a research opportunity to develop a new anti-diabetic agent with multiple potential advantages and conceptually advances the use of a rather unconventional source, microbial proteins, for anti-diabetic drug development.