Journal of Diabetes and Its Complications

2013-05-01

Proteinuria predicts 10-year cancer-related mortality in patients with type 2 diabetes

2013-01-21

Abstract: Background: We conducted a cohort study to determine if proteinuria predicts cancer-related mortality in type 2 diabetic subjects.Methods: Between July 1996 and June 2003, we enrolled 646 type 2 diabetic subjects. Participants were followed-up until December 31, 2008. The vital status was ascertained by linking records with computerized death certificates in Taiwan.Results: During a median follow-up of 10.4years, 158 subjects had died, including 59 from cancers. Subjects with proteinuria had a hazard ratio (HR) of 2.77 (95% CI 1.82–4.21) for all-cause mortality and 1.99 (95% CI 1.00–3.94) for cancer-related mortality after adjustment for demographic factors and medical conditions. Specifically, proteinuria showed a trend of increased colon cancer death. The presence of proteinuria significantly improved the predictive ability of cancer-related mortality (increase in concordance statistics or area under the ROC curve=0.03). Patients with both proteinuria and estimated glomerular filtration rate <60ml/min per 1.73m2 showed higher HR for all-cause mortality than patients with proteinuria only (adjusted HRs (95% CI), 4.01 (2.42–6.67) vs. 2.69 (1.51–4.79), both p<0.01).Conclusions: Proteinuria can predict 10-year all-cause and cancer-related mortalities independently in type 2 diabetic subjects, over and above the established risk factors associated with type 2 diabetes.

Impact of diabetes on inpatient mortality and length of stay for elderly patients presenting with fracture of the proximal femur

2013-01-11

Abstract: Introduction: Osteoporosis-related fractures of the proximal femur cause significant morbidity and result in an economic burden on societies. It remains debatable whether diabetic patients with proximal fracture of the femur demonstrate poorer outcomes in terms of hospital stay and mortality compared to non-diabetic controls.Methods: All patients over 65years old admitted to the University Hospital Birmingham during 2007–2010 with a diagnosis of a fracture of the proximal femur (total 1468 including 197 patients with diabetes) were analysed. Eligibility and case definitions were ascertained using electronic records. Multivariate analyses were conducted to control for the confounding effect of covariates, which may be associated with the outcomes of interest on the basis of biological plausibility and known risks.Results: In-patient mortality was estimated at 14.2% and 12% for the diabetic and non-diabetic patients respectively. Diabetes was not found to be a significant predictor of in-patient mortality, before and after adjustment for the covariates [Adjusted odds ratio 1.01 (95% CI 0.62–1.65)], in contrast to advancing age, male gender, co-morbidity score, low albumin and high creatinine concentrations. Similarly, median length of stay was greater in the diabetes patients, yet only by a day (20 versus 19days). This was not statistically significant in either the unadjusted (p=0.17) or in the multivariate analysis (p=0.06).Conclusions: Diabetic patients admitted with fracture of the proximal femur did not demonstrate significantly poorer outcomes in terms of in-patient mortality and length of stay compared to non-diabetic patients.

Comparison of annual variability in HbA1c and glycated albumin in patients with type 1 vs. type 2 diabetes mellitus

Masafumi Koga, Jun Murai, Shinya Morita, Hiroshi Saito, Soji Kasayama — 2013-01-11

Abstract: Objective: It has been suggested that plasma glucose (PG) levels per se and long-term variations in PG levels are associated with diabetic vascular complications. Glycated albumin (GA) reflects shorter-term glycemic control, as well as postprandial PG levels, as compared to HbA1c. In this study, we hypothesized that GA more strongly reflects long-term variations in PG levels than HbA1c, and compared the variability of HbA1c and that of GA in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).Methods: This study included 8 T1DM patients and 48 T2DM patients. Over a 1-year period, HbA1c and GA were measured every month and the mean values and coefficients of variation (CV) for each patient were calculated.Results: In both T1DM and T2DM patients, the CV of GA was significantly higher than the CV of HbA1c. Both the CV of HbA1c and the CV of GA were significantly higher in the T1DM patients than in the T2DM patients.Conclusion: The annual variability in GA was greater than that in HbA1c. In addition, the annual variability in HbA1c and that in GA in the T1DM patients were greater than in the T2DM patients. Our findings suggest that GA more accurately reflects long-term variations in PG levels than HbA1c.

Risk of type 2 diabetes and cumulative excess weight exposure in the Framingham Offspring Study

2013-01-14

Abstract: Aim: Mid-life obesity is associated with T2D risk. However, less is known about the cumulative effect of obesity during adulthood.Methods: Framingham Offspring Study participants who had an examination at 35±2years and were initially free of T2D were included in this study (N=1026). A cumulative excess weight (CEW) score (year*kg/m2) was calculated until T2D diagnostic or the end of follow-up.Results: Eighty-four individuals (8.2%) developed T2D over 20±6years. Mean CEW scores were 118.0±114.6year*kg/m2 in individuals who developed T2D and 30.2±91.4year*kg/m2 in those who did not develop T2D (P<0.01). T2D risk was doubled for each standard deviation increase in the CEW score (OR=1.99 [1.64-2.40]; P<0.001). However, CEW score was only significantly associated with T2D incidence for participants with a baseline BMI <25kg/m2 (OR =2.13 [1.36–3.36]; P <0.001).Conclusions: Accumulating weight between the mid-thirties to the mid-fifties increases the risk of developing T2D. However, BMI in mid-thirties remains a stronger predictor of T2D risk.

The impact of treatment non-compliance on mortality in people with type 1 diabetes

2012-11-15

Abstract: Aims: To determine if a diagnostic record of poor treatment compliance (medication non-compliance and/or non-attendance at medical appointments) was associated with all-cause mortality in people with type 1 diabetes.Methods: This is an observational cohort study of data extracted from The Health Improvement Network (THIN) database, comprising data on patients served by over 350 primary care practices in the UK. Participants were included in the study if they had diagnostic codes indicative of type 1 diabetes. Treatment non-compliance was defined as missing one or more scheduled appointment, or one or more codes indicating medication non-compliance.Results: Of 2946 patients with type 1 diabetes, 867 (29.4%) had a record of either appointment non-attendance or medication non-compliance in the 30month compliance assessment period. The crude, unadjusted mortality rate for those patients who were treatment non-compliant was 1.462 (95% CI 0.954–2.205). Following adjustment for confounding factors, treatment non-compliance was associated with increased all-cause mortality (HR=1.642; 95% CI 1.055–2.554).Conclusions: Treatment non-compliance was associated with increased all-cause mortality in patients with type 1 diabetes. Understanding and addressing factors that contribute to patient treatment non-compliance will be important in improving the life expectancy of patients with type 1 diabetes.

Increased arterial stiffness in subjects with impaired fasting glucose

2012-11-26

Abstract: Aims: The present study investigated the association between fasting glucose and arterial stiffness in subjects with normal fasting glucose (NFG) and impaired fasting glucose (IFG).Methods: The study group consisted of 1043 subjects, including 683 subjects with NFG and 360 subjects with IFG (100≤fasting glucose <126mg/dL). All subjects were evaluated for glucose, insulin, lipid profiles, high sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), 8-epi-prostaglandin F2α (8-epi-PGF2α) and brachial–ankle pulse wave velocity (ba-PWV).Results: MDA (P<0.001) and ba-PWV (P<0.001) in the IFG group were higher than those in the NFG group after adjustment for sex, age, BMI, smoking and drinking, waist, blood pressure, serum lipid profiles. Ba-PWV in the IFG group was still higher than that in the NFG group after further adjustment for hs-CRP, MDA, 8-epi-PGF2α (P=0.031). Through multiple linear regression analysis, ba-PWV was found to be independently and positively associated with fasting glucose, age, systolic blood pressure, triglyceride, hs-CRP and insulin and negatively associated with male:female ratio, BMI.Conclusion: Arterial stiffness was higher in the IFG group than in subjects with NFG even after adjustment for all confounding variables including hs-CRP and oxidative stress markers. In addition, fasting glucose and insulin were positively and independently associated with the ba-PWV in non-diabetic healthy adults.

Ongoing treatment with renin-angiotensin-aldosterone-blocking agents does not predict normoalbuminuric renal impairment in a general type 2 diabetes population

2012-12-14

Abstract: Aim: To examine the prevalence and the clinical characteristics associated with normoalbuminuric renal impairment (RI) in a general type 2 diabetes (T2D) population.Methods: We included 94 446 patients with T2D (56% men, age 68.3±11.6years, BMI 29.6±5.3kg/m2, diabetes duration 8.5±7.1years; means±SD) with renal function (serum creatinine) reported to the Swedish National Diabetes Register (NDR) in 2009. RI was defined as estimated glomerular filtration (eGFR)<60ml/min/1.73m2 and albuminuria as a urinary albumin excretion rate (AER)>20μg/min. We linked the NDR to the Swedish Prescribed Drug Register, and the Swedish Cause of Death and the Hospital Discharge Register to evaluate ongoing medication and clinical outcomes.Results: 17% of the patients had RI, and 62% of these patients were normoalbuminuric. This group of patients had better metabolic control, lower BMI, lower systolic blood pressure and were more often women, non-smokers and more seldom had a history of cardiovascular disease as compared with patients with albuminuric RI. 28% of the patients with normoalbuminuric RI had no ongoing treatment with any RAAS-blocking agent. Retinopathy was most common in patients with RI and albuminuria (31%).Conclusions: The majority of patients with type 2 diabetes and RI were normoalbuminuric despite the fact that 25% of these patients had no ongoing treatment with RAAS-blocking agents. Thus, RI in many patients with type 2 diabetes is likely to be caused by other factors than diabetic microvascular disease and ongoing RAAS-blockade.

Genetic variation in the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH) and their influence on weight loss and insulin resistance under a high monounsaturated fat hypocaloric diet

2013-01-18

Abstract: Background and Aims: The C385A polymorphism of FAAH gene (rs324420C>A) has been associated with obesity. We investigate the role of this polymorphism on anthropometric and metabolic responses after an enriched monounsaturated fat hypocaloric diet.Methods: A sample of 95 obese individuals was analyzed at baseline and after 3months of an enriched monounsaturated fat hypocaloric diet.Results: Sixty two patients (65.3%) had the genotype C385C and 33 (34.7%) patients had C385A genotype (30 patients, 31.6%) or A358A (3 patients, 3.2%) (A carriers group). In subjects with C385C genotype, insulin (−1.9±5.3mUI/l) and HOMA-R (−0.48±0.75 U) decreased. In A carriers subjects, the decreases in weight were 3.7±3.4kg (decrease in C385C genotype group 4.4±3.6kg), fat mass 2.7±3.2kg (decrease in C385C genotype group 3.4±3.2kg) and waist circumference 3.1±3.4cm (decrease in C385 genotype group 4.4±4.6cm). These changes were significantly higher in the C385C genotype group than the A carriers subjects.Conclusion: After weight loss, noncarriers of the allele A385 of FAAH had an improvement on insulin and HOMA-R levels with an enriched monounsaturated fat hypocaloric diet. A better response of weight, fat mass and waist circumference was observed in C385 genotype subjects than A carriers participants.

The impact of common variation in the definition of diabetic sensorimotor polyneuropathy on the validity of corneal in vivo confocal microscopy in patients with type 1 diabetes: a brief report

2012-12-20

Abstract: The consensus definition for diabetic sensorimotor polyneuropathy allows for subtle variation in specific diagnostic criteria. In 89 type 1 diabetes participants, we found that common variations in these criteria do not impact the diagnostic validity of corneal nerve fiber length, a parameter of corneal in vivo confocal microscopy.

High triglyceride-to-HDL cholesterol ratio associated with albuminuria in type 2 diabetic subjects

I-Te Lee, Chih-Yuan Wang, Chien-Ning Huang, Chen-Chung Fu, Wayne H.-H. Sheu — 2013-05-01

Abstract: Objective: Emerging evidence indicates that metabolic syndrome (MetS) predisposes diabetic subjects to nephropathy. Aside from hypertension and hyperglycemia, it is unclear which component of MetS also contributes to increased urinary albumin excretion (UAE). We compared the MetS profiles of subjects divided into two groups based on their UAE.Methods: The Asia Pacific Real-Life Effectiveness and Care Patterns of Diabetes Management (AP RECAP-DM) study is a cross-sectional survey in which type 2 diabetic subjects using oral anti-hyperglycemic drugs were enrolled. We analyzed the data of 162 type 2 diabetic subjects with normotension or taking antihypertensive medications.Results: There were 123 subjects with normal UAE (<30mg/g) and 39 with abnormal UAE (≥30mg/g). MetS was more prevalent in the abnormal UAE group (79.5%) than in the normal UAE group (58.5%) (P=0.018). Hypertriglyceridemia (odds ratio=8.65, P<0.001) and reduced high-density lipoprotein (HDL) cholesterol (odds ratio=3.27, P=0.022) were both independently associated with abnormal UAE. Using 3.4 as a cut-off value, a high triglyceride-to-HDL cholesterol ratio was a useful marker (odds ratio=15.05, P<0.001) for abnormal UAE.Conclusions: A high triglyceride-to-HDL cholesterol ratio was found to be an important risk factor for nephropathy in type 2 diabetic subjects.

Increased gait variability in diabetes mellitus patients with neuropathic pain

2012-12-05

Abstract: Aims: Gait dysfunction in subjects with diabetes mellitus (DM) contributes to falling and subsequent injuries. Using a portable device (GaitMeterTM), 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.

Association of the genetic variants of endothelial nitric oxide synthase gene with angiographically defined coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus

2012-11-21

Abstract: Introduction: The polymorphic variants of endothelial nitric oxide synthase (eNOS) gene have been implicated in endothelial dysfunction and are highly relevant to macroangiopathies. We investigated the relationship between eNOS gene T-786C, G894T, intron 4a/b polymorphisms and coronary artery disease (CAD) in South Indian type 2 diabetic (T2DM) individuals.Methods: We screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with myocardial infarction (MI), 89 without MI and 121 T2DM individuals with no evidence of CAD for eNOS gene polymorphisms.Results: There appeared to be a significant difference in the genotype and allele distribution of eNOS T-786C polymorphism between T2DM groups with and without CAD (p=0.004), albeit no significant association with MI was observed. The frequencies of TC and CC genotypes and −786C allele were considerably higher in patients with triple vessel disease (TVD) as compared to those without CAD (p=0.003), thereby associating this polymorphism with severity of CAD. Genotype and allele distributions of G894T and intron 4a/b polymorphisms were not significantly different between T2DM subjects with and without CAD/MI. Significant linkage disequilibrium was observed between intron 4a/b and T-786C polymorphisms. Multiple logistic regression analysis revealed a significant and independent association of eNOS T-786C polymorphism and other putative risk factors with CAD/TVD in T2DM individuals.Conclusions: These findings reveal a significant association between eNOS T-786C polymorphism, CAD/TVD and coincident putative risk factors in T2DM individuals in South Indian population.

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

2013-01-25

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.

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

2013-05-01

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<0.001); a decrease of −0.72% was seen with metformin. Among the ipragliflozin groups there was also a dose-dependent reduction in body weight of up to 1.7kg.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.

Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: Pooled analysis of data from three placebo-controlled phase III trials

2013-02-11

Abstract: Aims: To evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response.Methods: Pooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo-controlled, parallel-group studies, who received oral linagliptin (5mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed.Results: Among 388 subjects with HbA1c ≥9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24weeks (P<.0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6mmol/l vs. 0.4mmol/l); treatment difference, 1.1mmol/l (95% CI, −1.7 to −0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (≤1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%).Conclusions: Linagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea.

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

Jan N. Basile — 2013-02-04

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.

Vanilloid receptors—do they have a role in whole body metabolism? Evidence from TRPV1

Andrea Zsombok — 2013-01-18

Abstract: With increasing lifespan, therapeutic interventions for the treatment of disorders such as type 2 diabetes mellitus are in great demand. Despite billions of dollars invested to reduce the symptoms and complications due to diabetes mellitus, current treatments (e.g., insulin replacements, sensitization) remain inadequate, justifying the search for novel therapeutic approaches or alternative solutions, including dietary supplementation, for the treatment of diabetes mellitus in every age group. The involvement of the vanilloid system in the regulation of metabolism has been identified, and the emerging role of its receptors, the transient receptor potential vanilloid type 1 (TRPV1), in diabetes was recently demonstrated. Indeed, beneficial effects of dietary capsaicin, an agonist of TRPV1 receptors, were identified for improving glucose, insulin and glucagon-like peptide-1 levels. Recent findings regarding TRPV1 receptors in association with whole body metabolism including glucose homeostasis will be reviewed in this article.

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

Iliana Doycheva, Niraj Patel, Michael Peterson, Rohit Loomba — 2013-01-11

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.