Journal of Diabetes and Its Complications - Articles in Press

High-dose insulin in experimental myocardial infarction in rabbits: protection against effects of hyperglycaemia - Corrected Proof

Vincent W. Wong, Mahidi Mardini, N. Wah Cheung, Anastasia S. Mihailidou — 2010-03-08

Abstract: Introduction: Hyperglycaemia at the time of acute myocardial infarction (AMI) is a predictor of survival and is associated with increased mortality and morbidity in patients with or without diabetes mellitus. On the other hand, insulin has been shown to reduce myocardial injury in experimental studies but its benefits have not been confirmed in clinical studies.Methods: The isolated perfused heart model was used to examine the direct effect of incremental doses of insulin and varying degrees of hyperglycaemia on infarct size and cardiomyocyte apoptosis in rabbit hearts. The rabbit hearts were subjected to 30-min ischaemia and 2.5-h reperfusion.Results: Insulin, given alone just before reperfusion, dramatically reduced infarct size in a dose-dependent manner (75–300 μU/ml) during experimental myocardial infarction (46%±2% to 10.9%±3%, P<.001). Acutely elevated glucose levels (33 mmol/L) induced a significantly greater infarct size and cardiomyocyte apoptosis compared to hearts subjected to normal glucose levels. On the other hand, high-dose insulin (300 μU/ml) given 5 min before reperfusion attenuated the extent of infarction and reduced apoptosis in hearts that were exposed to high glucose levels.Conclusion: Acutely elevated levels of glucose induced larger infarct area during ischaemia-reperfusion, and this is mediated through proapoptotic pathways. Insulin, when given just before reperfusion, confers cardioprotection in a dose-dependent manner and reverses the detrimental effect of acute hyperglycaemia. High-dose insulin as well as maintaining normoglycaemia remain important factors that improve outcomes following myocardial infarction.

Change from oral antidiabetic therapy to insulin and risk of urinary tract infections in Type 2 diabetic patients: a population-based prescription study - Corrected Proof

2010-03-02

Abstract: Background: Diabetes is a risk factor for urinary tract infections (UTI), but the impact of insulin treatment and glycaemic control on UTI risk is not clear.Methods: We determined the risk of antibiotic-treated UTI episodes in a population-based cohort of 2737 Type 2 diabetic patients who switched from oral antidiabetic drug (OAD) to insulin therapy. Each patient was observed for 365 days before and after the switch date, excluding a 120-day time window around this date. Episodes of UTI were defined as filled prescriptions for a UTI-specific antibiotic. We used conditional logistic regression to estimate the relative risk (odds ratio) of having one or more UTIs in the insulin vs. OAD period overall and stratified by glycaemic change.Results: After the switch to insulin, 53% of all patients experienced a decrease in individual mean hemoglobin A1c (median decrease=1.5%, interquartile range 0.9%-2.3%). Episodes of treated UTIs occurred in 446 (16.3%) Type 2 diabetic patients in the insulin period and 437 (16.0%) in the OAD period (relative risk 1.04, 95% CI 0.86–1.26). Stratified analyses showed no consistent association between levels of glycaemic improvement and decreased UTI risk during insulin treatment.Conclusions: Among patients with Type 2 diabetes, no evidence was found that switch to insulin therapy with or without tightened glycaemic control decreased their high annual risk of antibiotic-treated UTI episodes.

Association between hemoglobin A1c, carotid atherosclerosis, arterial stiffness, and peripheral arterial disease in Korean type 2 diabetic patients - Corrected Proof

2010-01-28

Abstract: Aims: To evaluate the association between hemoglobin A1c (HbA1c), carotid atherosclerosis, arterial stiffness, and peripheral arterial disease (PAD) in Korean type 2 diabetic patients.Methods: A total of 370 type 2 diabetic patients registered with the public health center in Gokseng-gun, Korea, participated in this study. Following an overnight fast, venous blood was collected and analyzed by high-performance liquid chromatography. The carotid intima-media thickness (IMT), amount of carotid plaque, brachial ankle pulse wave velocity (baPWV), and ankle-brachial index (ABI) of each patient were also assessed.Results: For categorical variables, we performed logistic regression after adjustment for other CVD risk factors. There was a significant association between HbA1c and carotid plaque [OR 2.66, 95% confidence interval (CI) 1.01 to 5.67 for the highest vs. the lowest tertile of HbA1c], and PAD (OR 3.75, 95% CI 1.30 to 10.81). For continuous variables, we performed analysis of covariance (ANCOVA) after adjustment for other covariates. The mean values of common carotid artery intima-media thickness (CCA-IMT) and baPWV were not significantly different according to the HbA1c tertiles.Conclusion: HbA1c was significantly associated with carotid plaque and PAD, but not CCA-IMT and baPWV in Korean type 2 diabetic patients.

Mutation H63D in the HFE gene confers risk for the development of type 2 diabetes mellitus but not for chronic complications - Corrected Proof

Máikel L. Colli, Jorge L. Gross, Luis H. Canani — 2010-01-25

Abstract: Purpose: To evaluate the frequency of mutations in the HFE gene (C282Y and H63D) in type 2 diabetes mellitus (DM) patients and their possible association with diabetic chronic complications.Methods: A case-control study with 723 subjects was performed. All diabetic subjects (n=519) underwent a clinical and laboratory evaluation. Diabetic retinopathy (DR) was evaluated by an ophthalmologist. Diabetic nephropathy (DN) was categorized by urinary albumin excretion (UAE) as normoalbuminuria (n=247), microalbuminuria (n=68), macroalbuminuria (n=70), or the presence of end-stage renal disease (dialysis; n=134). Data available for blood donors (n=204) were limited to age, sex, body mass index, and absence of previous diagnosis of diabetes and normal fasting plasma glucose. The mutations C282Y and H63D in the HFE gene were genotyped based on PCR protocols and digested with the restriction enzymes SnabI (C282Y) and MboI (H63D).Results: There was an association of type 2 DM with H63D polymorphism (genotypes HD/DD: OR=1.7, 95% CI=1.2–2.6), but not with C282Y polymorphism (OR=0.7, 955 CI=0.4–1.4). In respect to the chronic complications, there was no difference in the prevalence of DR, DN, or ischemic heart disease among the different genotypes.Conclusions: Mutation H63D in the HFE gene was associated with a higher risk of type 2 DM, but did not appear to confer risk for diabetic chronic complications. The mutation C282Y was not associated with diabetes or its chronic complications.

The response to antihypertensive therapy is dependent on renal structural changes. A 5-year prospective study of renal biopsy in type 2 diabetic patients with micro-macroalbuminuria - Corrected Proof

Ole Torffvit, Jan Tencer, Bengt Rippe — 2010-01-25

Abstract: A substantial fraction of patients with diabetes mellitus develop end-stage renal disease. We wanted to study the influence of renal structural changes on the response to treatment of the systemic blood pressure (BP) in type 2 diabetic patients with micro- or macroalbuminuria.Methods: A 5-year observational prospective study of 40 type 2 diabetic patients. Renal biopsy was performed on the indication micro-macroalbuminuria. Twenty-four-hour ambulatory BP and urine sampling were performed yearly. The goal for treatment was a nightly systolic BP below 140 mmHg. Glomerular filtration rate was examined early with plasma clearance of iohexol.Results: The nightly systolic BP goal <140 mmHg was achieved in 23 of 40 patients. The nightly systolic BP at start of study was correlated to the mean level of nightly systolic BP during the observation period. The glomerular basement membrane (GBM) thickness (BMT) was of prognostic significance for achieving the goal for antihypertensive treatment. Of the 12 patients with BMT below the median of 478 nm, 9 (75%) achieved the goal, while only 5 of 12 (42%) with BMT above 478 nm achieved a nightly systolic BP <140 mmHg. Also, the degree of interstitial fibrosis correlated to the nightly systolic BP.Conclusion: A thick basement membrane and the degree of interstitial fibrosis were associated with a lower number of patients achieving the goal of a nightly systolic BP <140 mmHg.

Accuracy, determinants, and consequences of body weight self-perception in type 2 diabetes: the Fremantle Diabetes Study - Corrected Proof

Kylie Van Minnen, Wendy A. Davis, David G. Bruce, Timothy M.E. Davis — 2010-01-04

Abstract: Objective: To assess the accuracy, determinants, and consequences of body weight self-perception in type 2 diabetes.Methods: We studied 1272 community-based patients and a 518-patient overweight/obese subset who returned for ≥4 annual reviews. Multiple logistic regression was used to identify baseline predictors of correct weight self-perception and to determine whether correct weight self-perception predicted future weight loss. Overweight and obesity were defined as body mass indices of 25.0–29.9 and ≥30.0 kg/m2, respectively.Results: Of the patients who were overweight (40.0%) or obese (41.8%) at baseline, 52.8% and 83.7%, respectively, correctly self-identified their weight category. Overweight/obese participants who self-identified correctly were more likely to have been informed they were overweight (P<.001), predominantly by their general practitioner (80.1%). Overweight participants had less self-awareness if they were not abdominally obese, did not speak English fluently, were male, or had a low income. Obese participants were more likely to consider themselves overweight if they had better diabetes knowledge and higher educational attainment. Correct weight self-perception did not influence subsequent weight loss.Conclusions: Health care professionals can facilitate body weight self-awareness in type 2 diabetes. Education programmes should recognise the impact of gender and socio-demographic variables on accurate weight self-perception.

The heteroplasmic m.14709T>C mutation in the tRNAGlu gene in two Tunisian families with mitochondrial diabetes - Corrected Proof

2010-01-04

Abstract: Diabetes mellitus (DM) is a heterogeneous disorder characterized by the presence of chronic hyperglycemia. Genetic factors play an important role in the development of this disorder, and several studies reported mutations in nuclear genes implicated in the insulin function. Besides, DM can be maternally transmitted in some families, possibly due to the maternal mitochondrial inheritance. In fact, mitochondrial genes may be plausible causative agents for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells.Materials and Methods: In this report, we screened two Tunisian families with mitochondrial diabetes for the m.3243A>G and the m.14709T>C mutations, respectively, in the tRNALeu(UUR) and the tRNAGlu genes.Results: The polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and the sequence-specific primers by polymerase chain reaction (SSP-PCR) analysis in the leucocytes and the buccal mucosa in the members of the two families showed the absence of the m.3243A>G mutation and the presence of the heteroplasmic m.14709T>C mutation in the tRNAGlu gene in the two tested tissues.Conclusions: We conclude that the m.14709T>C mutation in the tRNAGlu gene could be a cause of mitochondrial diabetes in Tunisian affected families. In addition, the heteroplasmic loads correlated with the severity and the onset of mitochondrial diabetes in one family but not in the other, suggesting the presence of environmental factors or nuclear modifier genes.

Bone mass and sex steroids in postmenarcheal adolescents and adult women with Type 1 diabetes mellitus - Corrected Proof

2009-12-03

Abstract: Objective: The aim of this study was to compare the bone mass in young adolescents and adult women with Type 1 diabetes mellitus (T1DM) and determine its relationship with sex steroid and sex hormone-binding globulin (SHBG) levels.Design: Cross-sectional study.Patients: We studied a group of adolescents and adult women with T1DM (n=45) and 50 healthy controls (C) matched by gynecological age and body mass index in a case-control study. Girls with menarche within the last 18–40 months (n=17 T1DM and 32 C) and adult women (age=30.4+1.4 years; n=28 T1DM and 18 C) were recruited.Measurements: Bone mass was evaluated with a GE Lunar Prodigy densitometer. Sex steroid levels were measured by radioimmunoassay.Results: Bone mass was lower in adolescents with T1DM than in control adolescents, but was similar in both groups of postmenarcheal girls after adjusting for age, lean, and fat mass. However, adult T1DM women exhibited lower adjusted and unadjusted (P<.05) Z-femoral neck (−0.2±0.2 vs. 0.4±0.2) and bone mineral content (BMC) (2306±61 vs. 2645±79 g) than adult controls. Adult controls and T1DM adults showed higher whole body BMC than adolescent controls and T1DM adolescents, respectively. Bone mass in T1DM did not correlate with estradiol, free estradiol, testosterone, SHBG, or HbA1c levels.Conclusions: The diminished bone mass observed in adult T1DM women does not appear to be related to sex steroid levels. In young adolescents with T1DM, the observed decrease in bone mass appears to be related to differences in body composition and age.

Increasing BMI and waist circumference and prevalence of obesity among adults with Type 2 diabetes: the National Health and Nutrition Examination Surveys - Corrected Proof

2009-11-16

Abstract: Objective: Obesity remains one of the most important modifiable risk factors for the prevention of Type 2 diabetes and its related comorbid conditions. The aim of this study was to examine trends in average body mass index (BMI), waist circumference, and obesity prevalence among adults with and without Type 2 diabetes.Methods: Information on BMI and waist circumference among 4162 adults with and 40,376 adults without Type 2 diabetes was obtained from the National Health and Examination Surveys completed during years 1976–2006. Mean BMI, waist circumference and prevalence of total obesity (BMI ≥30 kg/m2) and obesity stage III (BMI ≥40 kg/m2) were determined by survey periods after adjustment for the survey period weights and age standardization to the US 2000 Census. Means and proportions between first and last survey periods were compared using Z scores.Results: During this 20-year period, mean BMI increased from 29.2 kg/m2 to 34.2 kg/m2 among adults with Type 2 diabetes and from 25.2 kg/m2 to 28.1 kg/m2 among adults without diabetes (P<.0001 for both comparisons). Mean waist circumference increased substantially in all groups. Among adults with and without Type 2 diabetes, total obesity increased by 58% and 136%, respectively, while Class III obesity increased by 141% and 345%, respectively (P<.0001 for all comparisons).Conclusions: Obesity prevalence is rising rapidly among adults with and without Type 2 diabetes. This has important implications for the likely growth of the population with Type 2 diabetes and diabetes related comorbid conditions.

Hemoglobin Raleigh results in factitiously low hemoglobin A1c WHEN evaluated via immunoassay analyzer - Corrected Proof

Nina Jain, Mehmet Kesimer, James D. Hoyer, Ali S. Calikoglu — 2009-11-09

Abstract: Background: Glycosylated hemoglobin (HbA1c) is commonly used to assess long-term blood glucose control in patients with diabetes mellitus. Numerous conditions including hemoglobinopathies can alter HbA1c measurements and cause misleading results.Objective: To report a 13-year-old male with Type 1 diabetes mellitus who had low HbA1c measurements, despite persistent hyperglycemia.Design/Methods: HbA1c was initially measured by immunoassay. Hb electrophoresis was then employed to assess potential Hb variants. Electrospray ionization (ESI) tandem mass spectrometry of isolated Hb and gene sequencing of the Hbβ gene were used to specifically identify the Hb variant.Results: HbA1c measurement by immunoassay revealed an unusually low HbA1c of 3.9%. Hb electrophoresis revealed an aberrant Hb. The ESI mass spectrum of the intact Hb sample revealed a variant β-chain of 15,881 Da, 14 Da heavier than the mass of the normal Hb β-chain (15,867 Da). Sequence analysis of the 965.45 Da peptide suggested a substitution of valine (Val) to acetylated alanine (Ala). The DNA sequence of the patient's Hbβ gene revealed a single-base heterozygous mutation (GTG to GCG) at Base 2 of the codon of the first amino acid, producing a Val→Ala substitution, previously termed Hb-Raleigh. Because the acetylated N-terminal amino acid of the Hb-Raleigh β chain cannot be glycated, the HbA1c immunoassay will result in falsely low HbA1c levels.Conclusion: In managing diabetic patients, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential because hemoglobin variants may cause mismanagement of diabetes. Unusual results should prompt further analysis for a hemoglobinopathy as the potential cause of aberrant results.

Polymorphisms of myo-inositol oxygenase gene are associated with Type 1 diabetes mellitus - Corrected Proof

Bingmei Yang, Andrea Hodgkinson, Beverley A. Millward, Andrew G. Demaine — 2009-11-09

Abstract: Myo-inositol oxygenase (MIOX) is the first and rate-limiting enzyme in myo-inositol (MI) metabolism pathway. The increase in MIOX enzyme activity is in proportion to serum glucose concentrations and may be responsible for the MI depletion found in the diabetic complications. The aim was to investigate whether single nucleotide polymorphisms (SNPs) in the MIOX gene are associated with Type 1 diabetes mellitus (T1D) and its complications. Four hundred thirty Caucasian patients with T1D were recruited: 172 patients had diabetic nephropathy, 140 had diabetic retinopathy/neuropathy, 118 patients had diabetes for ≥20 years without microvascular complications and 224 were normal controls. Three SNPs, rs761745 (C/T), and rs2232873 (A/G) in the promoter and rs1055271 (C/G) in the 3′-untranslated were genotyped commercially. The frequencies of the CC genotype (0.36 vs. 0.44; P=.034) and C allele (0.60 vs. 0.68; P=.011) of rs761745 were significantly lower in patients with T1D compared with normal controls. Patients with T1D had a decreased frequency of the combination genotypes of CC (rs761745), GG (rs2232873) and GC (rs1055271) compared with the normal controls (0.13 vs. 0.22, P=.0027, Pc=0.014). The haplotypes with C/G/G and C/G/C were less common in patients with T1D compared to normal controls (0.59 vs. 0.70, P=.021) and the haplotypes with T/G/C and T/G/G ware more common in patients with T1D compared to normal controls (0.37 vs. 0.26; P=.021). In summary, our results demonstrated that the polymorphism (rs761745) in the promoter region of MIOX gene may be associated with the development of T1D in our studied population.

New diagnostic tests for diabetic distal symmetric polyneuropathy - Corrected Proof

Nikolaos Papanas, Dan Ziegler — 2009-11-09

Abstract: Neuropathy needs to be diagnosed early to prevent complications, such as neuropathic pain or the diabetic foot. It is obvious that diagnosis of neuropathy needs to be improved. New peripheral nerve function tests that appear to facilitate diagnosis are now emerging. This review outlines the new tests that have been proposed for the diagnosis of diabetic distal symmetric polyneuropathy, the commonest form of neuropathy in diabetes. New tests are classified into those mainly assessing large-fiber function (tactile circumferential discriminator, steel ball-bearing, and automated nerve conduction study) and those mainly assessing small-fiber function (NeuroQuick and Neuropad). Emerging tests are promising but must be evaluated in prospective studies. Moreover, their cost-effectiveness needs more careful appraisal. The clinician should, therefore, still rely on established modalities to diagnose neuropathy, but wider use of the new tests is expected in the near future.

Role of lipoic acid on insulin resistance and leptin in experimentally diabetic rats - Corrected Proof

2009-10-30

Abstract: Objective: We aimed to examine the changes in serum insulin and leptin levels in induced type 1 diabetes mellitus in relationship to glycemic state and lipid profiles and to clarify the role of lipoic acid (LA).Methods: Ninety-six male rats were equally divided into the following: a control group (normal, nondiabetic), a diabetic group induced by subcutaneous injection of alloxan (non-LA-treated), and an LA-treated diabetic group (for 4 weeks). Body weight, serum lipid profile, glucose, insulin, homeostasis model assessment–insulin resistance (HOMA-IR), and leptin were measured.Results: This study showed a significant increase in serum triacylglycerol (TG), total cholesterol, glucose levels, and HOMA-IR and a significant decrease in body weight gain, insulin, and leptin levels in the diabetic group compared to the control group. LA treatment induced a significant decrease in glucose, TG, and total cholesterol levels and significantly increased serum insulin and leptin levels in comparison with the diabetic group.Conclusion: Induced diabetes resulted in insulin resistance, hyperlipidemia, and hypoleptinemia, while LA ameliorates these changes and improves insulin sensitivity.

Sitagliptin treatment of patients with type 2 diabetes does not affect CD4+ T-cell activation - Corrected Proof

Perrin C. White, Heidi Chamberlain-Shea, Maria-Teresa de la Morena — 2009-10-26

Abstract: Dipeptidyl peptidase IV (DPP4) inhibitors have recently become widely used for treating type 2 diabetes, but in meta-analyses are associated with a mildly increased risk of all-cause infections. CD26 is a cell-surface form of DPP4 which can costimulate T-cell proliferation, raising the possibility that DPP4 inhibitors might adversely affect immune function. To address this issue in an observational study, two groups of 20 subjects each were recruited from a private endocrinology practice; one group consisted of type 2 diabetes patients treated for at least 6 months with the DPP4 inhibitor, sitagliptin, whereas patients in the other group had never been treated with this agent. The groups were similar with regard to sex and racial composition, body mass index, hemoglobin A1c, and use of other medications for diabetes, but the sitagliptin group was slightly older. A blood sample from each patient was analyzed for CD4+ T-cell activation in response to phytohemagglutinin using adenosine triphosphate (ATP)-stimulated bioluminescence. There was not a significant difference in T-cell activation between the treatment groups (median, 419 and 481 ng/ml ATP in the groups that were and were not treated with sitagliptin, respectively). Thus the observed increased rate of infection in diabetic patients treated with sitagliptin cannot be explained by a major effect on T-cell activation. Randomized studies, preferably using several assays of immune function, should be performed to confirm and extend these findings.

Effectiveness of insoles used for the prevention of ulceration in the neuropathic diabetic foot: a systematic review - Corrected Proof

Joanne Paton, Graham Bruce, Ray Jones, Elizabeth Stenhouse — 2009-10-26

Abstract: Context: Ulceration can be a debilitating and costly complication of the neuropathic diabetic foot. Insoles inserted into footwear are routinely used in clinical practice to help to prevent ulceration.Aim and Scope of the Review: This review evaluated the effectiveness of insoles used for the prevention of ulcer in the neuropathic diabetic foot.Methods: Databases were searched from inception to 2008, supplemented by hand searching of references and grey literature. Data extraction and methodological quality assessment were independently conducted by two reviewers following the recommendations of the Centre for Reviews and Dissemination.Results: A total of five trials met the inclusion criteria: two randomised control trials (RCTs), two case control studies, and one follow-up study. The methodological quality of the majority of studies was poor. Omitted details regarding the generalisability of results made study comparison and inference to practice difficult. There is a small amount of limited evidence indicating that insoles are effective in reducing incidence of ulceration and reducing plantar peak pressures in the diabetic neuropathic foot. No study included economic analysis or patient-based outcome measures.Conclusions: Insoles appear of use for the prevention of neuropathic diabetic foot ulceration, although evidence is limited. Clinical recommendation regarding type and specification of insole is not possible at this time.There is an essential need for a large well-designed RCT comparing different types of commonly used insole for the prevention of ulceration in the diabetic neuropathic foot. Outcome measures should include patient perceptions of the effectiveness and cost-effectiveness analysis.

Effect of bovine amniotic fluid on intra-abdominal adhesion in diabetic male rats - Corrected Proof

Behnam Abbasian, Hamidreza Kazemini, Abolghasem Esmaeili, Shahriyar Adibi — 2009-10-15

Abstract: Background: Postsurgical adhesion formation is a significant clinical problem within every surgical specialty. In type I diabetic patients, the problem is more severe and wound healing is slow. A wide variety of treatments have been proposed to deal with the problems that adhesion causes. One of the modalities that have not been studied extensively yet is the use of amniotic fluid. The purpose of the present study was to evaluate the clinical value of bovine amniotic fluid (BAF) efficacy in the treatment of postsurgical adhesion formation in diabetic male rats.Materials and methods: Fifty male Wistar rats in five groups were used for our study, with animal identification being facilitated by a microchip implant system. Diabetes was induced in all groups except for the control group by intraperitoneal alloxan injection (120 mg/kg). Based upon blood glucose concentration, rats received either one third of the required insulin (two groups) or all the required insulin (remaining groups). After 2 weeks, a laparotomy was performed on each rat and adhesions were scaled. Bovine amniotic fluid was then applied to two groups, and, as a control, sterilized water was applied to the other groups. After 2 weeks, a laparotomy was again performed on each rat and adhesion was rescored.Results and Conclusion: Significant reductions (P<.05) in adhesions were seen with BAF only in those diabetic rats that had received the required insulin. The results of our study suggest that BAF could be effective in the treatment of adhesion formation during diabetes.

Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice - Corrected Proof

Thomas Høi-Hansen, Ulrik Pedersen-Bjergaard, Birger Thorsteinsson — 2009-10-05

Abstract: Aim: No consensus exists on classification of hypoglycemia awareness. We compared three methods for assessment of hypoglycemia awareness in a clinical setting.Methods: A questionnaire including the three methods was filled in by 372 outpatients with Type 1 diabetes [43% women, age 51±14 years (mean±S.D.)], duration of diabetes 24±13 years, and hemoglobin A1c 8.2±1.0%). Method A (Diabetes Care, 17, 697–703) and B (Diabetes Care, 18, 517-522) classify into two degrees of awareness, while Method C (Diabetes/Metabolism Research and Reviews, 19, 232-240) includes three classes.Results: Normal awareness was reported in 75%, 51%, and 41% (A, B, C); 25% and 28% had impaired awareness (A, B); and 13% were unaware (C); 46% belonged to the intermediate class of impaired awareness (C), while 21% were not classifiable (B). Higher rates of severe hypoglycemic events were reported by patients with impaired awareness (A, B) and unawareness (C) compared to aware patients. Patients with impaired awareness (C) had more severe hypoglycemia than aware patients and less severe hypoglycemia than unaware patients. A lower rate of severe hypoglycemia was reported by aware patients classified by Method C than A. Fractions of patients with normal awareness without an event of severe hypoglycemia were 0.81, 0.86, and 0.91 (A, B, C).Conclusion: All three methods for assessment of hypoglycemia awareness are feasible in clinical practice since the degree of awareness is associated with risk of severe hypoglycemia. The trisected method (C) identifies an intermediate group with impaired awareness and with a risk of severe hypoglycemia that is significantly different from those of aware and unaware patients.

Transforming growth factor beta 1 as a biomarker of diabetic peripheral neuropathy: cross-sectional study - Corrected Proof

Juan Ybarra, Josep M. Pou, June Hart Romeo, Javier Merce, Jeroni Jurado — 2009-10-05

Abstract: Background: Simple and efficient screening methods are lacking for diabetic peripheral neuropathy (DPN), the most common and most difficult to treat of the long-term diabetic complications. Increased levels of transforming growth factor beta 1 (TGFβ1) in type 2 diabetic patients (T2DM) plays an immunomodulatory role in diabetic nephropathy and, possibly, in atherosclerotic evolution. Since preliminary interrelationships between experimental DPN and TGFβ1 have been observed, we sought to assess whether TGFβ1 could be a biomarker molecule for human DPN.Materials and Methods: Cross-sectional cohort study focused on the assessment of the interrelationships between TGFβ1 levels, cardiovascular disease (CVD), diabetic nephropathy (DNF), and neuropathy (DPN) in a group of T2DM patients (N=180; male 117, female 63) randomly selected from the North Catalonia Diabetes Study. DPN was diagnosed using clinical and neurophysiology evaluation. Incipient DNF was assessed by microalbuminuria (MAU). Total TGFβ1 (without acidification) was measured by immunoassay by ELISA (Promega).Results: DPN correlated with age, time of diabetes duration, MAU, CVD, and TGFβ1 (P<.0001). Log-transformed TGFβ1 (logTGβ1) was significantly higher in patients with DPN than in those without (P<.0005). LogTGFβ1 (OR=7.5; P=.006), age (OR=1.1; P<.0005), and logMAU (OR=2.0; P=.016) appear as significant estimators of the occurrence of DPN in our series. The integrated ROC curve evaluation with these three parameters expressed an important sensitivity (78.1%), specificity (76.0%), positive predictive value (79.2%), and negative predictive value (70.3%) in relation to DPN presence.Discussion: TGFβ1 stands as an important biomarker molecule for DFN and DPN screening in our series. Further prospective studies are warranted.

Concept paper: antihyperglycemic therapy and the diabetic heart—do we really know enough? - Corrected Proof

Jerzy W. Kolaczynski — 2009-09-25

Abstract: The purpose of this article is to provide reasons to start looking more critically at the existing glucose-lowering therapies in diabetes, from the point of their effect on cardiac metabolism. The presented arguments begin with the description of major differences between metabolism in myocardium and the skeletal muscle and of examples of myocardial metabolic inflexibility observed in heart failure and Type 2 diabetes. It is proposed that the metabolic inflexibility of diabetic myocardium should be taken into consideration as a factor to explain causes of unexpected cardiovascular mortality observed in the recently published outcome studies such as Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Feasibility Trial. The same reasoning was applied to challenge the “legacy effect” of the UK Prospective Diabetes Study and Steno-2 trials. A striking paucity of data on the effects of antihyperglycemic therapies on cardiac metabolism is brought to attention in spite of the fact that the technology to study human cardiac metabolism in vivo is available. It is hoped that increased focus on research in this area could contribute to improved cardiovascular safety monitoring of various antihyperglycemic regimens and thereby enhance our ability to save more lives of patients with Type 2 diabetes.

Investigation of glycemia recovery with oral administration of glycerol, pyruvate, and l-lactate during long-term, insulin-induced hypoglycemia - Corrected Proof

2009-09-14

Abstract: Aim: The acute effect of oral administration of isolated or combined glycerol, pyruvate, and l-lactate on glycemia recovery (GR) during long-term, insulin-induced hypoglycemia (IIH) was compared.Methods: Glycemia of 24 h-fasted rats that received intraperitoneal injection (1.0 U/kg) of regular insulin (IIH group) or saline (COG group) and, 15, 150, or 165 min later, oral saline (control IIH), glycerol (100 mg/kg), pyruvate (100 mg/kg), l-lactate (100 mg/kg), or combined glycerol+pyruvate+l-lactate (each 33.3 or 100 mg/kg) was compared. In addition, for comparative purposes, a group that received glucose (100 mg/kg) was included. Glycemia was measured 180 min after insulin or saline injection. To investigate the participation of the hepatic availability of gluconeogenic substrates to GR, livers from IIH and COG rats that received physiological or supraphysiological concentrations of isolated or combined glycerol, pyruvate, and l-lactate were compared. Liver experiments were done 180 min after insulin or saline injection.Results: Oral glycerol, pyruvate, and l-lactate (isolated or combined) or glucose promoted GR. Moreover, the best GR was obtained with combined glycerol+pyruvate+l-lactate (100 mg/kg). In agreement, livers that received supraphysiological concentrations of glycerol, pyruvate, and l-lactate (isolated or combined) showed higher glucose release than livers that received physiological concentrations of these substances (isolated or combined).Conclusion: The best GR obtained with combined administration of glycerol, pyruvate, and l-lactate (100 mg/kg) during long-term IIH was a consequence of the higher liver availability of these substances associated with a maintained liver ability to produce glucose from gluconeogenic substrates.

Patients' concepts and attitudes about diabetes - Corrected Proof

Amulya R. Sircar, Sudeep Sircar, Joydeep Sircar, Sheela Misra — 2009-09-14

Abstract: Objective: To evaluate the concepts and attitudes of patients and their immediate family members towards diabetes, its complications, and treatment.Research Design and Methods: A total of 654 patients with poorly controlled diabetes and 216 of their immediate family members were interviewed regarding their concept about diabetes, its complications, diet, exercise, drug therapy, and understanding about insulin.Results: There was lack of awareness about diabetes and its complications among the patients of diabetes. Majority of obese patients and their close family members failed to accept that they were obese. Child birth, menopause, and tubal ligation in female patients were wrongly attributed as a cause of obesity. There were major misconceptions about diet, exercise, and insulin therapy. More than 90% of study subjects had a misconception that all sweet fruits are prohibited and all bitter vegetables are beneficial. Temporary discontinuation of drug therapy was found in 189 cases. The lack of awareness and various misconceptions had no statistical relationship with the educational background of the patients.Conclusion: Among patients of poorly controlled diabetes and their close family members, there was a gross lack of knowledge of complications of diabetes, causes of obesity, treatment of diabetes, and use of insulin. Denial of obesity was commonly observed. Linking obesity with tubal ligation in female patients not only is appalling but may possibly be a hindrance to family planning program. Level of education had no bearing on these misconceptions.

Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review - Corrected Proof

Kate E. Schemmel, Rosalyn S. Padiyara, Jennifer J. D'Souza — 2009-09-14

Abstract: Purpose: The purpose of this article was to examine how aldose reductase (AR) inhibitors are used in the prevention and treatment of peripheral neuropathy in diabetes, specifically focusing on efficacy.Methods: Medline searches were used to identify clinical trials investigating AR inhibitors and their proposed mechanism of action, efficacy, and adverse effects. Additionally, the references of the articles returned by the Medline search were examined for pertinent publications.Results: Three AR inhibitors were selected for review. Modest improvements in the preservation and restoration of nerve conduction velocities were reported in the studies. Additionally, patients reported improvements in the subjective symptoms associated with diabetic peripheral neuropathy. Adverse effects for the studied agents were minimal or not reported.Conclusions: Given the mechanism by which diabetic peripheral neuropathy can result, targeting the polyol pathway as a method of treatment appears promising, yet the efficacy of newer AR inhibitors is still to be proven. Currently, these agents are not marketed in the United States. As newer studies emerge, diabetes educators will learn more about their efficacy and safety in preventing and treating diabetic peripheral neuropathy.

Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of Nɛ-carboxymethyl lysine - Corrected Proof

2009-08-28

Abstract: Objective: We investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes.Methods: A total of 38 type 2 diabetic patients (22 men and 16 women; mean±S.E.M. age 63.3±1.0 years; duration of diabetes 9.6±0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum Nɛ-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean±S.E.M. duration of diabetes 8.2±0.7 years) as control (C group).Results: The EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (−0.18±0.13 mU/ml in the EP group vs. +0.22±0.09 mU/ml in the C group, P<.05) after 1 year.Conclusions: Epalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.

Impact of comorbid conditions and race/ethnicity on glycemic control among the US population with type 2 diabetes, 1988–1994 to 1999–2004 - Corrected Proof

Dong-Churl Suh, In-Sun Choi, Craig Plauschinat, Jinweon Kwon, Michelle Baron — 2009-08-28

Abstract: Objective: To measure trends in glycemic control in type 2 diabetes in the United States from 1988–1994 to 1999–2004 and to identify factors influencing glycemic control, including the presence of comorbid conditions and race/ethnicity.Methods: Participants in the National Health and Nutrition Examination Surveys (1988–1994 and 1999–2004) aged ≥30 years with diagnosed type 2 diabetes were identified. Outcome measures included glycemic control [glycosylated hemoglobin (A1C) <7%] and pharmacologic treatment rate. Comorbid conditions assessed included obesity, hyperlipidemia, and hypertension.Results: Prevalence of type 2 diabetes increased from 5.8% in 1988–1994 to 7.1% in 1999–2004. Rates of treatment for type 2 diabetes improved, from 72.3% to 82.2%. The proportion of patients who achieved A1C <7% did not change significantly (44.4% to 50.1%, P=.06); however, blood pressure and cholesterol level both improved. During 1999–2004, only 14% of persons treated for type 2 diabetes did not have an additional comorbid condition; 21% had all three comorbid conditions. During 1999–2004, among treated patients, non-Hispanic blacks were 0.43 times as likely (95% CI 0.29–0.63), and Mexican Americans were 0.47 times as likely (95% CI 0.32–0.68), to have A1C <7% compared to non-Hispanic whites.Conclusions: Despite improved treatment rates, one in two individuals with type 2 diabetes has A1C of ≥7%. Most type 2 diabetic subjects also suffer from hypertension, hyperlipidemia, and/or obesity, and glycemic control rates were lowest for those with all three conditions. Non-Hispanic blacks and Mexican Americans are less likely to achieve glycemic control as compared to non-Hispanic whites.

Metformin reverses the deleterious effects of high glucose on osteoblast function - Corrected Proof

Donghu Zhen, Yirong Chen, Xulei Tang — 2009-07-23

Abstract: An association has been previously established between uncompensated diabetes mellitus and the loss of bone mineral density and/or quality. In the present study, we examined the effects of different concentrations of glucose (5.5, 11, 22, and 44 mmol/L) with or without metformin (10–640 μmol/L) on rat primary osteoblasts cultured in an osteogenic medium. With 11 mmol/L glucose, cellular proliferation, alkaline phosphatase (ALP) activity, the number of nodules formed, and calcium deposition in mineralized nodules were increased significantly; intracellular reactive oxygen species (ROS) and apoptosis were slightly reduced, although these reductions were not statistically significant. At higher concentrations of glucose (22 and 44 mmol/L), cellular proliferation, ALP activity, the number of nodules formed, and calcium deposition were greatly reduced; ROS and apoptosis were significantly increased in a dose-dependent manner. Metformin markedly increased cellular proliferation, ALP activity, calcium deposition, and the number of nodules formed and inhibited ROS and apoptosis in all glucose groups. Moreover, we assessed the gene expression levels of Runx2, IGF-1, and IGF-1R. Eleven micromole per liter glucose stimulated Runx2 and IGF-1 expression; 44 mmol/L glucose inhibited Runx2, IGF-1, and IGF-1R expression. Metformin stimulated the expression of Runx2 and IGF-1 in three glucose groups, but it did not affect IGF-1R. In conclusion, our findings suggest that the dual effects of glucose on cell proliferation and development are dose dependent. Metformin not only significantly decreased intracellular ROS and apoptosis, but also had a direct osteogenic effect on osteoblasts at all glucose concentrations, which could be partially mediated via promotion of Runx2 and IGF-1 expression.

Knowledge and awareness about diabetes and periodontal health among Jordanians - Corrected Proof

Rola Al Habashneh, Yousef Khader, Mohammed M. Hammad, Mohammed Almuradi — 2009-07-23

Abstract: The aim of this study is to evaluate the awareness, perception, sources of information, and knowledge of diabetes mellitus and periodontal health among Jordanians, to examine the factors related to their knowledge, and organize effective education programs. A random sample of 500 diabetic patients was recruited from three hospitals and three comprehensive health centers that represent both urban and rural populations in Jordan between September 25, 2006, and February 20, 2007. Completed questionnaires with the answers were returned by 405 participants (response rate was 81%). Only 28% indicated that they followed up gum diseases with the dentist; 48% were aware that diabetic patients are more prone to gum diseases and oral health complications. About a third (38%) recognized that their periodontal health might affect their glycaemic level. Television and Internet were the main source of knowledge for dentists with the rate of 50%. Knowledge about diabetes and periodontal health among diabetic patients is low, and majority of patients were unaware of the oral health complications of their disease and the need for proper preventive care. Issues on education need to be addressed. Therefore, appropriate educational programs should be planned according to community needs, and the target of these programs should be patients with irregular visits to the dentist and physicians. The clinical implication of our findings is that dentists, physicians, and other health providers should inspect diabetic patients for gum diseases each time they come for care and recommend that diabetic patient see a dentist regularly.

Self-care behaviors of Filipino-American adults with type 2 diabetes mellitus - Corrected Proof

Deovina N. Jordan, James L. Jordan — 2009-07-17

Abstract: Aim: To examine the diabetes self-care behaviors of Filipino-American (FA) adults with type 2 diabetes mellitus (DM).Method: The Summary of Diabetes Self Care Activities–Revised and Expanded measure was administered to 192 (74 males and 118 females) FA adult immigrants with type 2 DM.Results: Older FAs (≥65 years), females, those who were older when they immigrated, and participants diagnosed with type 2 DM longer were more likely to follow recommended medication regimens. Younger FAs (<65 years) and participants diagnosed with type 2 DM for shorter duration of time were less likely to perform blood glucose testing. Most FAs reported following their eating plans; however, those who lived in the United States (US) longer followed healthful eating plans. Likewise, females reported eating five or more servings of fruits and/or vegetables daily. Moreover, older FAs reported evenly spacing carbohydrate intake everyday. Furthermore, older participants, those with less education, participants who were older when they immigrated, and those older when diagnosed with type 2 DM ate fewer foods high in fats. As to physical activity, FA males and participants with higher education exercised more frequently.Conclusion: Younger FAs were less likely to perform optimum type 2 DM self-care behaviors pertaining to diet, medication taking, and blood glucose testing compared to their older counterparts. This finding suggests an increased risk for type 2 DM comorbidities and/or complications in younger FAs, which may require more intensive treatments in later years.

Prevalence of impaired fasting glucose and analysis of risk factors in Han adolescents - Corrected Proof

2009-07-06

Abstract: Objective: To evaluate the prevalence of impaired fasting glucose (IFG) and its relationship with cardiovascular risk factors in Han adolescents aged 13 to 18 years.Methods: Step 1: A cross-sectional study was conducted on 3937 Han adolescents. IFG was defined as a fasting glucose of 5.6 to 7.0 mmol/l. Measurements included anthropometric measurements, fasting plasma glucose (FPG), and serum lipids. Step 2: We identified 60 adolescents with IFG from the IFG group using a random number table, and 60 adolescents with normal fasting glucose (NFG) were matched for age and gender with the random IFG sample. Serum true insulin (TI) was further measured.Results: (1) The prevalence of IFG was 3.5% and was similar in boys and girls (3.9% vs. 3.1%, P=.177). The prevalence of IFG in adolescents with a family history of type 2 diabetes (FHD) was higher than in adolescents without FHD (6.3% vs. 2.5%, P=.000). (2) In logistic regression, the clustering of cardiovascular risk factors among adolescents with IFG was 1.889 (95% CI: 1.125–3.171, P=.016) times compared with adolescents with NFG adjusted by age and gender. (3) Multiple linear regression analysis using FPG as the dependent variable showed that waist circumference (β=0.003, P=.000) was a significant independent predictor. (4) In Step 2, the IFG group showed significantly higher levels of lnTI and lnHOMA-IR than the NFG group (P<.01). FPG was a significant independent predictor for lnTI (β=0.478, P=.000) and lnHOMA-IR (β=0.671, P=.000).Conclusion: We found a high prevalence of IFG in Han adolescents. Genetic susceptibility and abdominal obesity were the main factors causing adolescent IFG. Adolescents with IFG increased the clustering of cardiovascular risk factors.

Risk factors for mortality and ischemic heart disease in patients with long-term type 1 diabetes - Corrected Proof

2009-07-06

Abstract: Aims: The purpose of this study is to evaluate the effect of glycemic regulation, dyslipidemia, and renal dysfunction on mortality (all-cause and cardiovascular) and ischemic heart disease (IHD) in a long-term follow-up of a population-based cohort of Danish type 1 diabetic patients with at least 20 years of diabetes.Methods: A population-based cohort of type 1 diabetic patients was identified as of July 1, 1973 (n=727). In 1993 to 1996, the cohort was reassessed and baseline data were collected from blood and urine samples in 389 patients. Mean (glycemic regulation and lipids) and highest values (creatinine and albuminuria) of the baseline period were used to predict mortality and IHD between baseline and 2006. Data of mortality and morbidity were provided by the Danish Civil Registration System, the Danish Causes of Death Registry, and the Danish National Patient Registry.Results: At the follow-up in 2006, 256 patients (65.8%) were still alive. In a statistical model adjusted for age, sex and duration of diabetes, the following parameters were related to all-cause mortality and cardiovascular mortality: glycemic regulation, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (inversely), total cholesterol, creatinine, and macroalbuminuria. Furthermore, all markers except macroalbuminuria were associated with IHD. Microalbuminuria at baseline was not related to any of the endpoints.Conclusions: Glycemic regulation, dyslipidemia, and renal dysfunction were all related to mortality and IHD in a 13-year follow-up of long-term Danish type 1 diabetic patients. These results underscore the better outcome for tightly regulated type 1 diabetic patients, even in long-term survivors.

Pioglitazone, but not metformin, reduces liver fat in Type-2 diabetes mellitus independent of weight changes - Corrected Proof

2009-07-06

Abstract: Background: Pioglitazone (Pio) treatment induces weight gain in Type 2 diabetes mellitus (T2DM), which could worsen hepatic lipid accumulation, and alter adiponectin and high-sensitivity C-reactive protein (hs-CRP).Objective: To compare changes in hepatic lipid, serum adiponectin and hs-CRP in diabetics treated with Pio (with and without weight gain) against metformin (Met) treatment, which produces weight loss.Design: Fifty-one men and women with T2DM, naive to thiazolidinediones, entered a 16-week, open-label, parallel arm study, where participants were randomized to one of three groups: (1) Pio plus the American Diabetes Association diet (Pio+ADA); (2) Pio plus a portion control weight loss diet (Pio+PC), or (3) metformin plus ADA diet (Met+ADA).Methods: Hepatic lipid was assessed with abdominal computed tomography (CT) and the serum adiponectin and hs-CRP by enzyme-linked immunosorbent assay at baseline and study end.Results: Forty-eight subjects completed the study. The Pio+ADA group gained (mean±S.E.M.) 2.15±1.09 kg, while Pio+PC and Met+ADA group lost −2.59±1.25 and −3.21±0.7 kg, respectively. Pio-treated groups (Pio+ADA and Pio+PC) significantly decreased hepatic fat as indicated by increased liver density on CT scan [10.1±2.4: 11.4±1.0 Hounsfield units (HU)], compared with Met+ADA group (−2.4±3.1 HU). The Pio groups demonstrated significantly increased serum adiponectin, (8.6±1.5; 7.4±1.6 μg/ml) independent of weight change, compared to Met+ADA (−0.14±0.6 μgm/ml) group which lost weight. Serum hs-CRP decreased in groups showing weight loss (Pio+PC, −3.1±1.7 mg/l; Met+ADA, −1.5±1.2 mg/l) compared to Pio+ADA (1.8±3.0 mg/l) group that gained weight.Conclusions: Pio treatment in T2DM significantly reduced hepatic lipid and increased adiponectin independent of weight change, while decreasing hs-CRP with weight loss.

Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy - Corrected Proof

2009-06-24

Abstract: The aim of this study was to investigate the modulating effect of atorvastatin on serum paraoxonase 1 enzyme (PON1) activity in type 2 diabetic Egyptian patients with or without nephropathy. The present study was carried out on the following groups: control group, which consisted of 30 healthy persons; Group I, which consisted of 20 type 2 diabetic patients without nephropathy; and Group II, which consisted of 20 type 2 diabetic patients with nephropathy. All the patients selected were under an antidiabetic regimen of insulin, and patients receiving antihypertensive agents were excluded from the follow-up study to avoid drug interaction fallacies. Twenty-two patients (15 without nephropathy and seven with nephropathy) received atorvastatin in individually adjusted oral dosage (range 10–20 mg) once per day for 12 weeks. All cases were subjected to thorough clinical examination and history taking and measurement of serum levels of PON1 activity, malondialdehyde (MDA), glutathione reductase activity, fasting glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), urea, and creatinine. Urine samples were collected for determination of proteinuria. The obtained results showed that PON1 activity and HDL significantly decreased and fasting glucose significantly increased in Group I and Group II when compared to the control group, with significant difference in their levels between Group II and Group I. MDA, total cholesterol, and LDL levels significantly increased and glutathione reductase activity significantly decreased in Group I and Group II when compared to the control group. Urea, creatinine, and proteinuria levels showed significant increase in Group II when compared to the control group and Group I, with nonsignificant difference between control group and Group I. Atorvastatin therapy caused a significant increase in PON1 activity, and serum levels of MDA and glutathione reductase activity were significantly decreased and increased, respectively. Also, total cholesterol, triglyceride and LDL-cholesterol levels were significantly reduced with a significant increase in HDL-cholesterol levels. There was a significant modest reduction in serum urea and creatinine levels as well as in proteinuria level. Fasting glucose level was significantly reduced under the antidiabetic regimen of insulin through the follow-up period. PON1 activity showed a significant negative correlation with glucose and LDL, and a significant positive correlation with HDL in all the studied groups. It could be concluded that atorvastatin with its pleiotropic effects could provide optimal therapeutic intervention to control not only dyslipidemia, but also oxidative stress status with consequent improvement in the course of type 2 diabetes and diabetic nephropathy. More specifically, restoration of PON1 activity by atorvastatin opens a window to investigate other drugs that could provide a new adjuvant therapeutic line for better control of diabetes and diabetic nephropathy. Further research is also recommended to study the distribution of PON1 genetic polymorphism among the Egyptian population to explain the variability in its activity and its relationship with other factors that associate diabetes and its complications.

Association of a functional polymorphism (C59038T) in GTP cyclohydrolase 1 gene and Type 2 diabetic macrovascular disease in the Chinese population - Corrected Proof

Yun-fei Liao, Tian-shu Zeng, Lu-Lu Chen, Yu-ming Li, Fan Yu, Li-jun Hu, Ling Yue — 2009-06-10

Abstract: Nitric oxide (NO) unavailability plays an important role in the progression of macrovascular diseases in Type 2 diabetes (T2DM). C59038T polymorphism in GTP cyclohydrolase 1 (GCH1) gene is a functional mutation involved in NO metabolism and cardiovascular risk in a multiethnic population. To clarify the relationship between C59038T polymorphism and macrovascular disease in T2DM, an association study was performed among 611 unrelated T2DM patients. C59038T polymorphism was detected by polymerase chain reaction (PCR) restriction fragment length polymorphism. The PCR products after digestion displayed three genotypes, including CC, CT, and TT. The prevalence of cardiovascular disease, cerebrovascular disease, and peripheral vascular disease was significantly higher in T2DM patients with TT genotype than those with CC or CT genotype (P<.001). Compared with CC or CC+CT genotype, T2DM patients with TT genotype had a significantly increased risk of macrovascular disease (P<.001, P=.001), with odds ratio for 4.717 [95% confidnce interval: 3.056–7.370] and 4.082 (2.716–5.868), respectively. Subjects with TT genotype showed lower levels of plasma NOx (nitrite and nitrate), flow-mediated artery dilatation and activities of superoxide dismutase but higher levels of plasma malonaldehyde and intima-media thickness of carotid artery than those with CC or CT genotype (P<.05). This study demonstrated that in Chinese T2DM population, C59038T polymorphism was associated with an increased risk of macrovascular disease, which was likely due to its effects on NO metabolism, oxidative stress, and subsequently vascular dysfunction.

Lifetime prevalence of comorbid mood disorders in a representative sample of Canadians with type 1 diabetes - Corrected Proof

Esme Fuller-Thomson, Jami-Leigh Milinovich, Joseph R. Merighi — 2009-06-01

Abstract: Aims: To compare the lifetime prevalence of mood disorders among those with and without type 1 diabetes.Methods: Data from a nationally representative sample were obtained. Individuals were classified as having type 1 diabetes if a health professional diagnosed them with diabetes before age 30 and they began insulin within 1 month of their diagnosis (N=314).Results: The prevalence of mood disorders in persons with type 1 diabetes was 7.9% (95% CI 3.1–12.7) compared to 5.6% (95% CI 5.4–5.8) for those without type 1 diabetes (age- and sex-adjusted OR=1.56, 95% CI 1.04–2.34).Conclusions: Future research would benefit from the use of community-based representative samples.

Relationship between glycemic control and depression among American Indians in the Strong Heart Study - Corrected Proof

2009-05-20

Abstract: Objectives: To examine the relationship between depression and glycemic control in the Strong Heart Study (SHS), a longitudinal study of cardiovascular disease in American Indians.Methods: This cross-sectional analysis focused on the relationship between depression, diabetes and glycemic control among 2832 individuals aged ≥15 years. Depression was measured by the Center for Epidemiologic Studies of Depression Scale and diabetes by American Diabetes Association criteria. An ordered logit regression model was used to assess whether diabetes was related to level of depression (none, mild, moderate, severe). Multiple logistic regression was used to explore the relationship between A1c and severe depression in participants with diabetes.Results: Rates of depression were higher in men and women with diabetes when compared to those without diabetes, respectively (P<.05). For every 1-U increase in A1c, the odds of severe depression increased by 22% (OR 1.22, 95% CI: 1.05–1.42). Female sex (OR 2.97, 95% CI: 1.32–6.69) and body mass index (BMI) (OR 1.04, 95% CI: 1.00–1.08) also were significantly associated with increased risk for severe depression. Although BMI appears to be significantly associated with increased risk for severe depression, the magnitude of this effect was small.Conclusions: Individuals with diabetes have higher rates of depression than those without diabetes, consistent with other populations. There is a positive relationship between severity of depression and A1c levels; men and women with severe depression have higher A1c levels than those with moderate-to-no depression.

The effects of heavy long-term exercise on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin-induced diabetic rat - Corrected Proof

2009-04-24

Abstract: Objective: This study investigated whether exercise training, initiated at the onset of diabetes, could preserve the contractile properties of ventricular myocytes.Research Design and Methods: The effects of a heavy exercise training program on shortening and intracellular Ca2+ in unloaded ventricular myocytes from streptozotocin (STZ)-induced diabetic rats were examined. Animals were divided into four groups: control sedentary (CS), diabetic sedentary (DS), control heavy exercise (CHE), and diabetic heavy exercise (DHE). Exercise protocol: 5×60 min/week, 18 m/min, 5% gradient. Exercise training began 1 week after STZ treatment and continued for 12–23 (mean 17.5) weeks.Results: Diabetes induced prolongation of time-to-peak (TPK) shortening (124±2 ms in DS compared to 97±2 ms in CS rats), which was further increased by exercise (133±3 ms in DHE and 112±2 ms in CHE myocytes). Diabetes had no significant effects on time-to-half (THALF) relaxation of shortening (61±2 ms in DS compared to 56±2 ms in CS myocytes). Exercise induced significant prolongation of THALF in control (66±3 ms) but not in diabetic (69±3 ms) myocytes. Diabetes, though not exercise, significantly prolonged TPK (76±3 ms in DS compared to 64±2 ms in CS) and THALF recovery (160±5 ms in DS compared to 118±4 ms in CS) of the Ca2+ transient. Neither diabetes nor exercise had significant effects on the amplitude of myocyte shortening and the Ca2+ transient.Conclusions: Heavy long-term exercise alters the dynamics but not the amplitude of unloaded myocyte contraction in the STZ-induced diabetic rat.

Toll-like receptor 4 and inducible nitric oxide synthase gene polymorphisms are associated with Type 2 diabetes - Corrected Proof

Renata A. Bagarolli, Mario José A. Saad, Sara Teresinha O. Saad — 2009-04-24

Abstract: Background: The toll-like receptor 4 (TLR4) and inducible nitric oxide synthase are proteins from the innate immune system that, when activated, can induce insulin resistance. Polymorphisms in these genes, TLR4 and NOS2, respectively, could affect the immune response, as well as the prevalence of Type 2 diabetes (T2DM).Objective: The aim of the present study was to investigate the contribution of four polymorphisms (two from TLR4 and two from NOS2) to susceptibility to T2DM in a southeast Brazilian population.Design: A total of 211 patients with T2DM and 200 unrelated controls were genotyped for the Asp299Gly and Thr399Ile polymorphisms of the TLR4 gene and for the insertion (I)/deletion (D) AAAT and (CCTTT)n polymorphisms of the NOS2 promoter gene.Results: With regard to the NOS2 promoter region, the data showed that the I allele of the I/D AAAT polymorphism was more prevalent in the T2DM group and that the L/L genotype of the (CCTTT)n polymorphism was also more frequent in the same group. In contrast, the 299Gly allele and the 399Ile allele from the Asp299Gly and Thr399Ile TLR4 gene polymorphisms, respectively, were associated with protection of T2DM. It is believed that the persistence of these genetic variations in human populations may be indicative of a selective advantage in the face of different environmental pressures.Conclusions: Genetic variations in the NOS2 gene promoter and TLR4 coding sequence may lead to deleterious and protective effects, respectively, arising from altered function of the innate immune system in patients with T2DM.

Cellular basis of diabetic nephropathy: V. Endoglin expression levels and diabetic nephropathy risk in patients with Type 1 diabetes - Corrected Proof

2009-04-24

Abstract: Endoglin is an accessory receptor molecule that, in association with transforming growth factor β (TGF-β) family receptors Types I and II, binds TGF-β1, TGF-β3, activin A, bone morphogenetic protein (BMP)-2 and BMP-7, regulating TGF-β dependent cellular responses. Relevant to diabetic nephropathy, endoglin, expressed in vascular endothelial and smooth muscle cells, fibroblasts, and mesangial cells, negatively regulates extracellular matrix (ECM). The aim of this study was to evaluate endoglin expression in cultured skin fibroblasts from patients with Type 1 diabetes with and without diabetic nephropathy. Kidney and skin biopsies were performed in 125 Type 1 diabetic patients. The 20 with the fastest rate of mesangial expansion (estimated by electron microscopy) and proteinuria (“fast-track”) and the 20 with the slowest rate and normoalbuminuria (“slow-track”), along with 20 controls were studied. Endoglin mRNA expression was assessed by microarray and quantitative real-time polymerase chain reaction (QRT-PCR) and protein expression by Western blot. Age and sex distribution were similar among groups. Diabetes duration was similar (20±8 vs. 24±7 years), hemoglobin A1c lower (8.4±1.2% vs. 9.4±1.5%), and glomerular filtration rate higher (115±13 vs. 72±20 ml/min per 1.73 m2) in slow-track vs. fast-track patients. Microarray endoglin mRNA expression levels were higher in slow-track (1516.0±349.9) than fast-track (1211.0±274.9; P=.008) patients or controls (1223.1±422.9; P=.018). This was confirmed by QRT-PCR. Endoglin protein expression levels correlated with microarray (r=0.59; P=.044) and QRT-PCR (r=0.61; P=.034) endoglin mRNA expression. These studies are compatible with the hypothesis that slow-track Type 1 diabetic patients, strongly protected from diabetic nephropathy, have distinct cellular behaviors that may be associated with reduced ECM production.

Effects of rosiglitazone and aspirin on experimental model of induced type 2 diabetes in rats: focus on insulin resistance and inflammatory markers - Corrected Proof

Amany A. Abdin, Amal A. Baalash, Hala E. Hamooda — 2009-03-31

Abstract: Both insulin resistance and decreased insulin secretion are major features of the pathophysiology of type 2 diabetes. Inflammatory pathways are found to be critical in mechanisms underlying insulin resistance, which is a major determinant of increased risk of cardiovascular complications in type 2 diabetes, and so, it is a potential therapeutic target. Thiazolidinediones (e.g., rosiglitazone) act primarily as insulin sensitizers and were discovered to have anti-inflammatory effects leading to reevaluation of their potential use in treatment of diabetes. Acetyl salicylic acid (aspirin), which is currently recommended for cardiovascular disease (CVD) or even CVD risk factors, is shown to ameliorate diabetic process. This work aimed to study correlation between homeostasis model assessment estimate of insulin resistance (HOMA-IR) with serum levels of inflammatory markers tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), C-reactive protein (CRP), and free fatty acids (FFAs) in experimental model of induced type 2 diabetes in rats, with evaluation of effects of rosiglitazone and aspirin (low or high dose), alone or in combination. There is significant elevation of insulin resistance and serum levels of fasting glucose, insulin, TNF-α, IL-6, CRP, and FFAs in the diabetic group when compared to the normal group, with positive significant correlation between levels of each of TNF-α, IL-6, CRP, and FFAs with insulin resistance (HOMA-IR). Administration of rosiglitazone, low-dose aspirin, or high-dose aspirin to diabetic rats caused nonsignificant lowering in insulin level with significant reduction of levels of other parameters when compared to the diabetic group. Also, there is no significant difference in the measured parameters between diabetic rats administered a combination of rosiglitazone with high-dose aspirin and those administered a combination of rosiglitazone with low-dose aspirin. It was concluded that aspirin and rosiglitazone offer unique approaches for treatment of type 2 diabetes due to their insulin-sensitizing and anti-inflammatory properties, and their combination was found to provide augmented beneficial effects. Also, in view of the potential dose-dependent adverse effects of aspirin, with no achievement of further benefit by high dose in this study, it is strongly recommended to use low-dose aspirin as a safe and effective medication for diabetes.

Mortality after major amputation in diabetic patients with critical limb ischemia who did and did not undergo previous peripheral revascularization: Data of a cohort study of 564 consecutive diabetic patients - Corrected Proof

2009-03-31

Abstract: Background: To evaluate the survival after major lower limb amputation, at a level either below (BKA) or above (AKA) the knee, in diabetic patients admitted to hospital because of critical limb ischemia (CLI).Methods: From January 1999 to December 2003, 564 diabetic patients were consecutively admitted to our Foot Center because of CLI and followed up until December 2005. A revascularization procedure was performed in 537 patients (95.2%): in 420 with peripheral angioplasty, in 117 with peripheral bypass graft. Neither endoluminal nor surgical revascularization was practicable in 27 (4.8%) patients.Results: Major amputation was performed in a total of 55 (9.8%) patients. Among the clinical and demographic variables evaluated, age was significantly lower (67.3±10.1 vs. 76.7±10.4, P<.001), duration of diabetes was higher (17.1±11.1 vs. 13.4±10.0, P=.013), and current smoking was more frequent (38.5% vs. 25.0%, P<.001) in revascularized amputees. The amputation free median time for revascularized patients was 5.11 months, and for nonrevascularized patients, 0.33 months. The log-rank test for equality of survivor function without amputation between amputees with or without revascularization was 31.76 (P<.001).Among the 55 amputees, 11 (28.2%) out of the 39 revascularized patients and 13 (81.2%) out of the 16 nonrevascularized patients died. The log-rank test for equality of survivor function was 6.83 (P=.009).The Cox model performed to evaluate the association between the recorded variables and the mortality showed a significant hazard ratio only with age (hazard ratio for 1 year 1.11, P=.003, confidence interval 1.04–1.19).Conclusions: Our data suggest that the revascularization allows to postpone the major amputation, and that the survival of revascularized amputees is better than that of nonrevascularized amputated patients. All these data offer further encouragement to revascularize all diabetic patients with CLI.

Alpha tocopherol use in the management of diabetic cardiomyopathy: lessons learned from randomized clinical trials - Corrected Proof

Turgay Celik, Cagdas Yuksel, Atila Iyısoy — 2009-03-31

Abstract: Although animal studies suggested that there may be a role for antioxidants (especially alpha-tocopherol) as therapy for heart failure (HF), the results obtained from human trials are disappointing. The variability in the response to antioxidant therapy may be due to genetic polymorphisms in enzymes involved in oxidative stress. We strongly believe that we do not have enough data supporting the use of antioxidant treatment in the management of HF patients, including a diabetic subset.

Prevalence of diabetes, metabolic syndrome, and cardiovascular risk factors in US Asian Indians: results from a national study - Corrected Proof

2009-03-23

Abstract: Background: Although studies of immigrant Asian Indians in other countries show high rates of diabetes (DM), metabolic syndrome (MetS), and cardiovascular disease (CVD), no randomized, population-based studies of this rapidly growing ethnic group exist in the US.Methods: The sample comprised 1038 randomly selected Asian Indian immigrants, aged 18 years and older at seven US sites. Prevalence of diabetes and MetS (age-adjusted and sex-adjusted means) was estimated and ANOVA was used to calculate gender and group differences (normoglycemia/impaired fasting glucose/diabetes) for CVD risk factors.Results: The mean age was 48.2 years. The majority of respondents were male, married, educated, and with some form of health insurance. Prevalence of diabetes was 17.4%, and 33% of the respondents had prediabetes. Cardiovascular risk factors, especially high levels of triglycerides, total cholesterol, LDL cholesterol, homocysteine, and C-reactive protein, and low levels of HDL cholesterol, were also prevalent; elevated lipoprotein(a) was not observed. The age-adjusted prevalence of MetS was 26.9% by the original NCEP/ATP III criteria, 32.7% by the modified NCEP/ATP III criteria, and 38.2% by the IDF criteria. The MetS rates for women, but not for men, increased with age using all three criteria. There was a progressive worsening of all metabolic parameters as individuals progressed from normal to IFG to diabetes.Conclusion: The prevalence rates of diabetes and MetS among US Asian Indians are higher than reported in earlier, nonrandomized, smaller surveys. These data provide a firm basis for future mechanistic and interventional studies.

Gestational diabetic patients with adequate management have normal cardiovascular autonomic regulation during the third trimester of pregnancy and 3 months after delivery - Corrected Proof

2009-03-13

Abstract: Objective: The aim of the present study was to evaluate the influence of gestational diabetes mellitus (GDM) on hemodynamics and cardiovascular autonomic regulation at rest and their responses to head-up tilt (HUT).Research Design and Methods: We prospectively studied 79 pregnant women (51 with GDM, 28 without GDM) during the third trimester of pregnancy and after parturition. The maternal electrocardiogram and arterial blood pressure were noninvasively measured. Heart rate and blood pressure were measured in the supine position and in the upright position. Stroke volume was assessed from noninvasive blood pressure signals, heart rate variability (HRV) was analyzed in frequency domain, and baroreflex sensitivity by the cross-spectral and sequence methods.Results: Between the GDM group and control pregnant women there were no significant differences in hemodynamics and cardiovascular autonomic regulation throughout the protocol. Increased normalized low-frequency component and low-frequency to high-frequency ratio suggested a change in sympathovagal balance towards sympathetic predominance during pregnancy in both groups. The response to head-up tilt (HUT) was similar in both GDM and control pregnant women. The pregnancy modulated the response to HUT in systolic and diastolic blood pressure, stroke volume, cardiac index, peripheral resistance, total power of HRV, and its low- and high-frequency components.Conclusions: Our results suggest that pregnancy modulates cardiovascular autonomic regulation and hemodynamics equally in subjects with GDM and without GDM, suggesting that metabolic disorder during pregnancy does not result in cardiovascular dysfunction when GDM is in good balance.

Cost-effectiveness analysis of medical intervention in patients with early detection of diabetic foot in a tertiary care hospital in Bangladesh - Corrected Proof

Samira Humaira Habib, Kazal Boron Biswas, Salima Akter, Soma Saha, Liaquat Ali — 2009-02-24

Abstract: The economic burden resulting from diabetic foot consumes a major portion of resources. The study was undertaken to assess the cost-effectiveness of medical intervention in patients with diabetic foot. At baseline 906 patients were analyzed. Then 200 patients with diabetic foot were purposively selected from a tertiary diabetes care hospital. Of these, 100 were late in detection and poorly managed (late diabetic foot or LDF) and 100 were detected early and properly managed (early diabetic foot or EDF). Among 906 patients, 2.8% (25 patients) were found to develop diabetic foot. Total cost of treatment was US$13,308.16 with an average of US$443.60 per patient. Comparing the cost of patients who underwent amputation with the patients who are not yet amputated, cost difference was US$6657.74. The result showed that cost of amputation was 5.54 times higher than the usual treatment. The average cost of care was US$134 per patient. Among the average annual cost, LDF consumed US$18,918. Fifty percent of the costs were attributable to drugs for both groups of which 77% was for LDF and 29% to hospitalizations. The regression equation showed that medical cost is significantly related to complications. Proper management can substantially reduce the cost of care of patients with diabetic foot.

Astragalus polysaccharides inhibited diabetic cardiomyopathy in hamsters depending on suppression of heart chymase activation - Corrected Proof

Wei Chen, Yi-Ming Li, Mao-Hua Yu — 2009-02-23

Abstract: Diabetic cardiomyopathy is associated with high morbidity and mortality of heart failure. Overactivation of the local chymase–Ang II system plays a dominant role in diabetic cardiomyopathy. Astragalus polysaccharide (APS) is used in traditional Chinese medicine to boost immunity. To study the effect of APS on local system of chymase-Ang II in diabetic cardiomyopathy, we investigated APS/normal saline (NS)-administrated streptozotocin-induced diabetic hamsters. After APS/NS administration at a dose of 1 g/kg per day for 10 weeks, hemodynamic parameters, levels of insulin (INS), C-peptide (C-P), glycosylated serum protein (GSP), lipoproteins, myocardial enzymes, and Ang II (plasma and myocardial) were tested; myocardial collagen (type I and III), myocardial ultrastructure, and activities of matrix metalloproteinase (MMPs) were measured; activities and expression of cardiac chymase and ACE were detected by using quantitative real-time RT-PCR and RIA; protein expression of cardiac phosphoric extracellular signal-regulated kinase 1/2 (p-ERK1/2) was measured by Western blot. AP-administrated diabetic hamsters had lower levels of GSP, lipoproteins, myocardial enzymes, myocardial Ang II, expression of collagen I and I/ III, activities of pro-MMP-2 and MMP-2, activities and expression of chymase, and expression of p-ERK1/2 than NS-administrated diabetic hamsters and could better protect the myocardial ultrastructure. There was no difference in hemodynamic parameters between two groups. These results indicate that APS could inhibit diabetic cardiomyopathy in hamsters depending on the suppression of the local cardiac chymase–Ang II system.

Diabetic ketoacidosis presenting with emphysematous pyelonephritis - Corrected Proof

Yara M. Eid, Mona M. Abdel Salam — 2009-02-23

Abstract: Mr. A.M.A. is 28-year-old Egyptian male patient who presented to the ER with diabetic ketoacidosis (DKA) and left loin pain of 3 weeks duration. The patient had a history of hospital admission 5 months earlier because of urinary tract infection and DKA. Workup of this clinical case revealed emphysematous pyelonephritis.

Exendin-4 treatment of nonobese diabetic mice increases beta-cell proliferation and fractional insulin reactive area - Corrected Proof

2009-02-17

Abstract: Objective: The notion of combining immunomodulatory agents with the incretin exendin-4 (Ex-4) has seen considerable favor as a potential therapy for the reversal of type 1 diabetes in man. While the addition of Ex-4 provides modest improvement to the effectiveness of immunological-based monotherapies in reversing hyperglycemia in the nonobese diabetic (NOD) mouse, the mechanism of action underlying this effect remains controversial and formed the basis for this investigation.Research Design and Methods: Female NOD mice with new onset diabetes received either Ex-4 (0.2 μg) or saline via daily intraperitoneal injection for 30 days. To maintain viability after diagnosis of diabetes, animals also received subcutaneous insulin pellets. When persistent hyperglycemia returned, animals were sacrificed and histological studies performed to assess beta-cell proliferation (BrdU+/insulin+; Ki67+/insulin+) and fractional insulin reactive area.Results: Ex-4-treated animals experienced diabetes reversal rates no better than controls. Despite this, Ex-4-treated mice demonstrated increased fractional insulin area (P=.035) and beta-cell proliferation as evidenced by elevated BrdU (P=.0001) and Ki67 staining (P=.04) with insulin co-localization. Also noteworthy, Ex-4-treated mice had poor weight gain following diagnosis in comparison to saline-treated animals (P=.003).Conclusions: Ex-4 monotherapy (0.2 μg daily–10 μg/kg per day) in NOD mice with new onset diabetes increases beta-cell proliferation and fractional insulin area. Ex-4 remains a promising component of combination therapies for type 1 diabetes. Additional studies are needed to identify a dose that maximizes beta-cell proliferation and minimizes potential side effects.

The diabetic hand: a forgotten complication? - Corrected Proof

Nikolaos Papanas, Efstratios Maltezos — 2009-02-17

Abstract: The manifestations of diabetes in the hand were much discussed in the 1970s and 1980s. The present review aims to revisit the diabetic hand and to discuss the pathology of the hand that may be clinically important in diabetic patients. In the strict sense of the term, the “diabetic hand” encompasses the three most widely studied conditions which have traditionally been associated with diabetes, namely limited joint mobility, Dupuytren's contracture and trigger finger. There is evidence that these entities are significantly more frequent in patients with diabetes and also that they may be associated with diabetes duration, poor metabolic control and presence of microvascular complications. In a more general sense, though, there are other conditions affecting the hands, which also occur more frequently in diabetes. From a practical point of view, increased alertness both for neuropathic hand ulcers in patients with profound neuropathy and for diabetic hand infections is absolutely necessary. Recently, reduced hand strength is beginning to be recognized as a further complication of diabetes. Thus, the hand may reveal substantial pathology in diabetes, and ideally, clinical examination should not ignore it.

Correlation of electroretinography b-wave absolute latency, plasma levels of human basic fibroblast growth factor, vascular endothelial growth factor, soluble fatty acid synthase, and adrenomedullin in diabetic retinopathy - Corrected Proof

2009-02-13

Abstract: Background: We investigated the b-wave latency of electroretinogram (ERG), human basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), soluble fatty acid synthase (s-Fas), and adrenomedullin (ADM) in diabetic retinopathy.Patients and Methods: Thirty control and 60 type II diabetic women (mean age 45±3.9 years, duration of diabetes 10.1±2.1 years) were investigated. Diabetics without complications (Group II) and with retinopathy (Group III) were diagnosed depending on clinical findings, abnormal fundus examination, and ERG. Plasma levels of b-FGF, VEGF, s-Fas, and ADM were measured.Results: ERG showed a significant increase of b-wave absolute latency, plasma b-FGF, VEGF, s-Fas, and ADM in diabetic retinopathy (P<.05). A positive correlation was found between b-wave latency and VEGF and s-Fas, and a negative correlation with b-FGF and ADM.Conclusion: This study elucidates the causative role of VEGF and s-Fas in diabetic retinopathy. VEGF may potently promote growth of endothelial cells and formation of new vessels implicated in proliferative retinopathy. s-Fas could be involved in advancement of apoptotic changes in retinopathy and high levels of b-FGF, and ADM may be compensatorily neuroprotective and vasculoprotective. The results showed that diabetic retinopathy is the result of multiple factors, so it is optimistic to believe that reversing VEGF or s-Fas will halt retinopathy, targeting multiple mechanisms simultaneously by administering combination treatments of VEGF antagonists; antiapoptotic drugs together with b-FGF and/or ADM may be prospective.

Gabapentin therapy improves heart rate variability in diabetic patients with peripheral neuropathy - Corrected Proof

2009-02-06

Abstract: Purpose: Diabetic cardiac neuropathy, which is characterized by reduced heart rate variability (HRV), frequently coexists with peripheral neuropathy. Gabapentin has been used for the treatment of diabetic neuropathy. We aimed to evaluate the possible effect of gabapentin treatment on autonomic function in patients with type 2 diabetes via HRV.Methods: Thirty patients with type 2 diabetes mellitus and peripheral neuropathy and 28 age- and sex-matched healthy controls were consecutively registered. Each patient underwent HRV measurements, and diabetic patients were administered gabapentin. After 3 months of gabapentin therapy, HRV parameters were measured again.Results: Baseline HRV parameters were blunted in patients with diabetes mellitus according to the controls [standard deviation of all NN intervals (SDNN, ms): 106.3±29.9 vs. 148.8±36.5, P=.001; power spectrum of the high-frequency band (HF, ms2): 133.6±98.3 to 231.4±197.6, P=.02; power spectrum of the low-frequency band (LF, ms2): 341.8±247.8 to 511.5±409.4, P=.048; LF/HF ratio: 3.3±2.4 to 2.6±1.5, P=.33]. After 3 months of treatment with gabapentin, some HRV parameters showed some improvement. SDNN (106.2±29.8 to 119.4 ± 25, P=.016) and HF (133.6±98.3 to 167.6±118.3, P=.021) increased significantly. LF/HF ratio decreased (from 3.3±2.4 to 2.3±1.9, P=.039) and LF remained unchanged (341.8±247.8 to 352.3±228.9, P=.88).Conclusions: Therapeutic doses of gabapentin not only alleviate neuropathic symptoms but also improve cardiac autonomic function in diabetic patients with peripheral neuropathy.

Detection of VDR gene ApaI and TaqI polymorphisms in patients with type 2 diabetes mellitus using PCR-RFLP method in a Turkish population - Corrected Proof

Fuat Dilmec, Elmas Uzer, Feridun Akkafa, Elif Kose, André B.P. van Kuilenburg — 2009-02-02

Abstract: Type 2 diabetes mellitus (T2DM) is by far the most common type of diabetes and is characterized by insulin resistance and altered insulin secretion. Some genes, such as the vitamin D receptor gene (VDR, NM_001017535; GI: 7421), involved in its metabolic pathway have been regarded as good candidates for T2DM. In this study, we investigated whether there was an association of VDR: g.59979G>T or c.1025-49G>T (ApaIG>T) and g.60058T>C or c.1056T>C (TaqIT>C) polymorphisms in the 3′ untranslated region of VDR with T2DM in a Turkish population. We collected blood samples from 241 individuals (72 patients with T2DM and 169 healthy individuals), and their DNA was isolated. Polymorphisms of the VDR were analyzed by DNA amplification with polymerase chain reaction and endonuclease digestion with ApaI and TaqI. Body mass index was higher in T2DM patients than in control individuals. However, the frequency of g.59979TT genotype in T2DM patients was not significantly increased compared to healthy subjects (37.5% vs. 36.1%, respectively). Although the VDR g.60058CC genotype in T2DM patients (19.4%) was higher than that in healthy individuals (11.2%), there was no significant difference. In the same way, there was no difference between the groups in allele frequencies. In conclusion, our study did not provide evidence for the association of two examined VDR polymorphisms with T2DM in a Turkish population.