Journal of Diabetes and Its Complications - Articles in Press

The effect of ubiquinone in diabetic polyneuropathy: A randomized double-blind placebo-controlled study - Corrected Proof

2012-05-18

Abstract: Introduction: Diabetic polyneuropathy aetiology is based on oxidative stress generation due to production of reactive oxygen species. Ubiquinone is reduced to ubiquinol and redistributed into lipoproteins, possibly to protect them from oxidation.Aims: To evaluate the impact of oral ubiquinone in diabetic polyneuropathy, and the role of lipid peroxidation (LPO) and nerve growth factor (NGF-β).Methods: We conducted a double-blind, placebo-controlled clinical trial, patients were randomized to ubiquinone (400mg) or placebo daily for 12weeks. Main outcomes were clinical scores, nerve conduction studies, LPO, NGF-β and safety.Results: Twenty four patients on experimental group and twenty five on control group met the inclusion criteria (mean age 56years, 22% male and 78% female, mean evolution of type 2 diabetes mellitus 10.7years). Significant improvement on experimental vs control group was found in neuropathy symptoms score (from 2.5±0.7 to 1±0.8, p<0.001), neuropathy impairment score (5.5±4 to 3.1±2.6, p<0.001), sural sensory nerve amplitude (13.0±6.1 to 15.8±5.1μV, p=0.049), peroneal motor nerve conduction velocity (39.7±5.0 to 47.8±4.9m/s, p=0.047), and ulnar motor nerve conduction velocity (48.8±6.8 to 54.5±6.1m/s, p=0.046). There was a significant reduction of LPO in subjects treated with ubiquinone vs placebo (16.7±8.6 and 23.2±15.8nmol/mL, respectively) with p<0.05, and NGF-β did not change (control 66.5±26.7 vs. experimental 66.8±28.4pg/mL, p=0.856). No drug-related adverse reactions were reported.Conclusions: Twelve weeks treatment with ubiquinone improves clinical outcomes and nerve conduction parameters of diabetic polyneuropathy; furthermore, it reduces oxidative stress without significant adverse events.

Hypertension strengthens δ-ALA-D activity inhibition and increases it reactivation index in type 2 diabetic patients - Corrected Proof

2012-05-14

Abstract: Aims: To assess the effect of hypertension on δ-aminolevulinate dehydratase (δ-ALA-D) activity of type 2 diabetic patients (T2DM).Methods: δ-ALA-D activity and reactivation index, as well as markers of oxidative stress, biochemical and anthropometrics parameters were determined in T2DM (n=23), type 2 diabetic patients with hypertension (T2DM/HT) (n=30) and controls (n=30).Results: T2DM/HT presented a greater inhibition of δ-ALA-D activity, a higher reactivation index (p<0.05) and a greater depletion of plasma protein thiol groups (P-SH) when compared to T2DM. Moreover, δ-ALA-D activity was positively associated with SH groups and negatively associated with serum protein carbonyl (PC) while its reactivation index was negatively associated with SH groups and positively associated with PC.Conclusions: These results point out that there is a possible interference of hypertension on the mechanism of the δ-ALA-D activity suggesting that this condition aggravated the oxidative stress of diabetes mellitus.

Antidiabetic effect of S-allylcysteine: Effect on Thyroid hormone and circulatory antioxidant system in experimental diabetic rats - Corrected Proof

Ganapathy Saravanan, Ponnusamy Ponmurugan — 2012-04-30

Abstract: Objective: It is considered that diabetes mellitus and thyroid disease are the two common endocrine disorders and also suggested that insulin and thyroid hormones influence each other actions. The present study was designed to investigate the effect of the administration of S-allylcysteine (SAC), a sulfur containing amino acid derived from garlic on blood glucose, insulin, HbA1C, total protein, albumin, Thyroid hormone (T3, T4), TSH, TBARS and circulatory antioxidant levels (SOD, CAT, GSH and GPx) in STZ-induced diabetic rats.Methods: SAC was administered orally for 45days to control and STZ induced diabetic rats. The effects of SAC on glucose, plasma insulin, HbA1C, total protein, albumin, Thyroid hormone, TSH and circulatory antioxidant levels were studied.Results: The levels of glucose, TBARS, hydroperoxide and HbA1C were increased significantly whereas the levels of plasma insulin, reduced glutathione, superoxide dismutase, catalase, GSH, GPx, total protein, albumin, Thyroid hormone and TSH were decreased in STZ induced diabetic rats. Administration of SAC to diabetic rats showed a decrease in plasma glucose, TBARS, hydroperoxide and HbA1C. In addition, the levels of plasma insulin, SOD, CAT, GPx, GSH, total protein, albumin, Thyroid hormone and TSH were increased in SAC treated diabetic rats. The effect of SAC was compared with gliclazide, a well-known antioxidant and antihyperglycemic drug.Conclusion: From these findings, it is indicated that SAC might be acting through activation in the synthesis and/or secretion of circulating thyroid hormones which in turn stimulate the synthesis of insulin.

Effects on post-prandial glucose and AGE precursors from two initial insulin strategies in patients with Type 2 diabetes uncontrolled by oral agents - Corrected Proof

2012-04-30

Abstract: Objective: Progressive β-cell dysfunction in Type 2 diabetes results in the need for insulin therapy in many patients. Yet the best regimen to prescribe to patients transitioning from oral anti-hyperglycemic drugs (OADs) is not clear. We sought to compare the effects of two standard initial insulin strategies (basal insulin alone versus premixed insulin) on post-prandial glucose metabolism and precursors of advanced glycation end-products in patients with type 2 diabetes suboptimally controlled on OADs.Research Design and Methods: This was a 6-month, open-label, single-center study using a cross-over design. 14 subjects were randomized to one of two protocols: once daily insulin glargine or twice-daily 75%/25% neutral protamine lispro/lispro mix. At 12 weeks, the subjects were crossed-over to the opposite protocol. During each period, insulin doses were titrated to target fasting blood glucose of 90–110mg/dL. At baseline and after the two 12-week treatment periods, subjects were studied in the Clinical Research Center; they consumed three liquid mixed isocaloric meals at 4-h intervals, and glucose, free fatty acids (FFA), lipids, and α-dicarbonyls (3-deoxyglucosone [3-DG] and methylglyoxal [MG]) were measured before and after each meal. Patient data were analyzed in the context of their assigned insulin strategy groups.Result: Both insulin regimens led to a significant improvement in glycemic profiles, including fasting glucose and HbA1c, compared to baseline. However, mean post-prandial glucose was lower with lispro mix than with glargine (153±36 vs. 199±49 mg/dL, respectively; P=0.001). Likewise, there was a reduction in both fasting (48±13 vs. 57±19, P=0.047) and post-prandial (53±19 vs. 63±23; P=0.007) 3DG levels with lispro mix as compared to glargine. No differences were noted in MG concentrations.Conclusion: In type 2 diabetes patients failing OAD therapy, an initial insulin regimen of twice daily premixed insulin results in significantly improved post-prandial glucose levels as well as a reduction in a precursor of AGEs. The effect of these two initial insulin regimens on long-term diabetic complications requires further study.

Urine α-Glutathione S-Transferase, systemic inflammation and arterial function in juvenile type 1 diabetes - Corrected Proof

Peter Holmquist, Petru Liuba — 2012-04-26

Abstract: Background: Despite marked improvement in therapy and monitoring of patients with insulin-dependent (type 1) diabetes, diabetic nephropathy remains a serious complication, with subsequent end-stage renal disease in about 20% of cases.Objective: To investigate in young patients with type 1 diabetes whether urine α-Glutathione S-transferase to creatinine ratio (α-GST:crea) relates to markers of systemic inflammation and subclinical vasculopathy.Design: Children and adolescents (median age and diabetes duration 14 and 6years, respectively) with type 1 diabetes screened in a previous study for proximal tubular (urine α-GST:crea ratio) and renal (plasma creatinine, cystatin C glomerular filtration rate (GFR), and timed urine albumin excretion rate (AER)) function were, within the same timeframe, also investigated for vascular (blood pressure, carotid artery intima–media thickness (IMT) and compliance (CAC), brachial artery flow-mediated dilatation (FMD) and plasma cyclic guanosine monophosphate (cGMP) and inflammatory (C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α)) profiles. Exposure to environmental tobacco smoke (ETS) was assessed through questionnaire (n=67 respondents).Results: None of the patients (n=69) had overt renal insufficiency. AER correlated with age (p=0.01, r=0.3), diabetes duration (p=0.02, r=0.3), FMD (p=0.04, r=−0.3, n=52), CAC (p=0.03, r=−0.3, n=62) and cGMP (p=0.01, r=−0.3, n=59). α-GST:crea was lower (p=0.03) in patients than in controls. α-GST:crea appeared to be particularly lower in older patients (p=0.004, r=−0.34 vs age), in those with worse diabetic control (p=0.03, r=−0.26 vs HbA1c), and in those with lower carotid artery elasticity (p=0.017, r=0.3 vs CAC). Although ETS had no direct significant impact on α-GST:crea, α-GST:crea correlated with FMD only in patients with ETS (r=0.5, p=0.009, n=13). α-GST:crea showed positive association with TNF-α (p=0.01, r=0.3).Conclusion: In children and adolescents with type 1 diabetes, lower levels of urine excretion of α-GST:crea appear to be associated with decreasing elasticity and endothelial vasomotor function of peripheral arteries, especially in patients with ETS. In contrast, higher levels of α-GST:crea are more common in patients with elevated markers of systemic inflammation. Large scale prospective studies are needed to clarify the meaning and mechanisms of this association.

Cardiovascular autonomic function and vibration perception threshold in type 2 diabetes mellitus - Corrected Proof

2012-04-26

Abstract: Objective: The aim of this study was to compare cardiovascular autonomic function tests (AFT) and vibration perception threshold (VPT) of patients with type 2 diabetes mellitus (T2DM) with controls.Research Design/Methods: The study was conducted on 60 diabetic patients comparing with 30 controls. The cardiovascular AFT and VPT were assessed in both groups.Results: Among cardiovascular AFT, E:I ratio [1.24 (1.2–1.32) vs 1.3 (1.24–1.4), p=0.001], and Valsalva ratio [1.28 (1.22–1.4) vs 1.6 (1.5–1.73), p=0.001], the indicators of parasympathetic reactivity were reduced in T2DM. Rise in DBP during handgrip, an indicator of sympathetic reactivity was lower in T2DM [12 (10–14) vs 16 (14–18) mmHg, p=0.001] whereas, fall in SBP during head up tilt [4 (4–8) vs 5 (4–8) mmHg] was comparable. VPT (somatic sensation) was comparable between T2DM and control.Conclusion: Autonomic involvement is more marked than somatic, and parasympathetic involvement is more marked than the sympathetic, possibly reflecting severity and chronological pattern of their involvement.

Hyperglycemia and oxidative stress in cultured endothelial cells – a comparison of primary endothelial cells with an immortalized endothelial cell line - Corrected Proof

2012-04-23

Abstract: Diabetes mellitus is a major risk factor for the development of cardiovascular disease and oxidative stress plays an important role in this process. Therefore, we investigated the effects of hyperglycemia on the formation of reactive oxygen species (ROS) and nitric oxide/cGMP signaling in two different endothelial cell cultures. Human umbilical vein endothelial cells (HUVEC) and EA.hy 926 cells showed increased oxidative stress and impaired NO-cGMP signaling in response to hyperglycemia. The major difference between the two different cell types was the dramatic decrease in viability in HUVEC whereas EA.hy cells showed rather increased growth under hyperglycemic conditions. Starvation led to an additional substantial decrease in viability and increased superoxide formation in HUVEC. Both endothelial cell types, HUVEC and EA.hy 926, may be used as models for vascular hyperglycemia. However, high growth medium should be used to avoid starvation-induced oxidative stress and cell death.

Frequent insulin dosage adjustments based on glucose readings alone are sufficient for a safe and effective therapy - Corrected Proof

Eran Bashan, Israel Hodish — 2012-04-23

Abstract: Problem: Frequent dosage adjustments are necessary to achieve effective insulin therapy. However, a controversy surrounds the pertinent clinical parameters required to make effective and safe insulin titrations. We hypothesize that glucose readings are sufficient to adjust insulin dosage provided that it is done on a weekly basis.Methods: In a prospective pilot study, we recruited 14 subjects with suboptimally controlled insulin-treated Type-2 and Type-1 diabetes. Subjects were treated with basal-bolus insulin therapy that was titrated weekly for 12 weeks. Dosage adjustments were made by the study Endocrinologist by reviewing subjects' glucose readings, exclusively based on logsheets and contingent upon the approval of the on-site study team. To corroborate that the glucose readings were sufficient for making dosage adjustments, we used software to process only glucose readings and recommend insulin dosage adjustments. The recommendations made by the software were retrospectively compared to the ones made by the study Endocrinologist.Results: All N=568 recommendations were approved by the study team and in 99.3% of the cases the recommendations were clinically similar to the ones made by the software. No hazardous disagreements were found. The mean A1C improved from 9.8% (±2.0) to 7.9% (±1.3) (p=0.001) in 12 weeks and the weekly mean glucose progressively improved from 220.3 mg/dl (±51.9) to 151.5 mg/dl (±19.2) (p<0.0001). The frequency of minor hypoglycemia was 22.7 per patient-year in subjects with Type-2 diabetes and 42.7 in the subjects with Type-1 diabetes. No severe hypoglycemic events occurred.Conclusions: Glucose readings are sufficient to adjust insulin therapy in a safe and effective manner, when adjustments are made on a weekly basis. Thus, dedicated software may help adjust insulin dosage between clinic visits.

The multi-faceted outcomes of conjunct diabetes and cardiovascular familial history in type 2 diabetes - Corrected Proof

Michel P. Hermans, Sylvie A. Ahn, Michel F. Rousseau — 2012-04-23

Abstract: Background: Familial history of early-onset CHD (EOCHD) is a major risk factor for CHD. Familial diabetes history (FDH) impacts β-cell function. Some transmissible, accretional gradient of CHD risk may exist when diabetes and EOCHD familial histories combine. We investigated whether the impact of such combination is neutral, additive, or potentiating in T2DM descendants, as regards cardiometabolic phenotype, glucose homeostasis and micro-/macroangiopathies.Methods: Cross-sectional retrospective cohort study of 796 T2DM divided according to presence (Diab[+]) or absence (Diab[−]) of 1st-degree diabetes familial history and/or EOCHD (CVD(+) and (−)). Four subgroups: (i) [Diab(−)CVD(−)] (n=355); (ii) [Diab(+)CVD(−)] (n=338); (iii) [Diab(−)CVD(+)] (n=47); and (iv) [Diab(+)CVD(+)] (n=56).Results: No interaction on subgroup distribution between presence of both familial histories, the combination of which translated into additive detrimental outcomes and higher rates of fat mass, sarcopenia, hsCRP and retinopathy. FDH(+) had lower insulinemia, insulin secretion, hyperbolic product, and accelerated hyperbolic product loss. An EOCHD family history affected neither insulin secretion nor sensitivity. There were significant differences regarding macroangiopathy/CAD, more prevalent in [Diab(−)CVD(+)] and [Diab(+)CVD(+)]. Among CVD(+), the highest macroangiopathy prevalence was observed in [Diab(−)CVD(+)], who had 66% macroangiopathy, and 57% CAD, rates higher (absolute-relative) by 23%–53% (overall) and 21%–58% (CAD) than [Diab(+)CVD(+)], who inherited the direst cardiometabolic familial history (p 0.0288 and 0.0310).Conclusions: A parental history for diabetes markedly affects residual insulin secretion and secretory loss rate in T2DM offspring without worsening insulin resistance. It paradoxically translated into lower macroangiopathy with concurrent familial EOCHD. Conjunct diabetes and CV familial histories generate multi-faceted vascular outcomes in offspring, including lesser macroangiopathy/CAD.

Does treatment affect the levels of serum Interleukin-6, Interleukin-8 and procalcitonin in diabetic foot infection? A pilot study - Corrected Proof

2012-04-23

Abstract: Aims: To investigate about serum PCT, IL-6 and IL-8 levels and how they are affected by the treatment in diabetic foot patients.Methods: Fifty patients’ blood samples were taken to study ESR and CRP, IL-6, IL-8 and PCT before and at the 14th day of the treatment.Results: The pretreatment results of the 50 patients showed positive correlations between PCT and either ESH (r=0.49, p<0.001), or CRP (r=0.56, p<0.001). Similarly, there was a positive correlation between IL-6 and ESH (r=0.46, p=0.001), just like as it was between IL-6 and CRP (r=0.54, p<0.001). At the 14th day, the levels of ESR (70±30.2 and 58.4±26.2, p=0.02), CRP (63.8±73.1 and 18.1±19.7, p<0.001) and PCT (0.6±2.1 and 0.05±0.02, p=0.007) were significantly decreased while IL-6 was decreased at a close range to statistical significancy at healing patients (97.5±147.2 and 47.1±77.6; p=0.05), but they did not at nonhealing patients. IL-8 levels were not changed anyhow.Conclusions: PCT was significantly decreased such as ESR and CRP were in the early phase of healing; IL-6 and IL-8 levels were also decreased by the treatment, but not statistically significantly. IL-6 and PCT were affected in correlation with the other inflammatory parameters in the beginning, but IL-8 was not. PCT and IL-6 may be useful like CRP and ESR in the diagnosis and follow up of diabetic foot infection, but IL-8 is not. Further investigation is needed.

Relationship between DDAH gene variants and serum ADMA level in individuals with type 1 diabetes - Corrected Proof

2012-04-23

Abstract: Asymmetric dimethylarginine (ADMA) levels are elevated in diabetes and likely contribute to diabetic complications such as retinopathy and nephropathy. The DDAH enzymes are primarily responsible for ADMA metabolism. Polymorphisms in the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes have been previously associated with serum ADMA levels in type 2 diabetes (T2DM). We sought to determine whether they are also associated with ADMA levels in individuals with type 1 diabetes (T1DM). Serum ADMA concentrations were measured in 196 individuals with T1DM. Twenty-six tag SNPs in the DDAH1 gene and 10 in the DDAH2 gene were genotyped. One SNP in the DDAH1 gene (rs3738111) and one in the DDAH2 gene (rs805293) showed a correlation with serum ADMA levels; however, neither survived correction for multiple testing. We found limited evidence that genetic polymorphisms in DDAH genes influence serum ADMA levels in individuals with T1DM. This differs to findings in T2DM and may be due to underlying differences in the cohorts or to fundamental differences in the pathogenesis of the two types of diabetes.

Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes - Corrected Proof

2012-04-23

Abstract: Aims: PAX4 R192H polymorphism was reported to be associated with maturity onset diabetes of the young (MODY) and early onset-age of type 2 diabetes (T2D). This study aimed to evaluate transcriptional repression activity of PAX4 R192H polymorphism on its target promoters comparing with wild-type PAX4.Methods: Wild-type PAX4 and PAX4 R192H proteins were expressed in vitro and the cell compartmentalization of each protein was examined after transfection of the plasmid constructs into βTC3 cells followed by Western-blot analysis. The plasmid containing wild-type PAX4 or PAX4 R192H was co-transfected into βTC3 and αTC-1.9 cells with insulin or glucagon promoter-reporter construct. Transcriptional repression activities were then determined by dual-luciferase reporter assay.Results: Wild-type PAX4 and PAX4 R192H, which were found to be equally expressed in vitro and transfection systems, were present in the nuclear compartment. Transcriptional repressor activities of PAX4 R192H on human insulin and glucagon promoters were reduced when they were compared with those of wild-type PAX4.Conclusions: These results suggested that PAX4 R192H polymorphism generated a protein with defect in transcriptional repressor activities on its target genes, which may lead to β-cell dysfunction associated with MODY and early onset-age of T2D as reported in our previous study.

Toe Amputation: A predictor of future limb loss? - Corrected Proof

2012-04-20

Abstract: Background: Digital toe amputation is a relatively minor surgical procedure but there is a historical view that it is the “first stage in a predictable clinical course” leading to eventual limb loss. There is a paucity of contemporaneous data on the long-term outcomes of patients undergoing toe amputation. We aim to study the experience from our institution, focussing on the risk factors for progression to future limb loss, by conducting a retrospective review of our practice.Methods: Sixty-three patients undergoing toe amputation within our institution were identified and the clinical notes retrospectively reviewed. A database of vascular risk factors and co-morbidity was constructed and correlation with future limb loss was analysed with Chi-squared testing and a logistic regression model.Results: Sixty-three patients with a mean age of 69 (IQR 62–76.5) years were identified. Thirty-five (55.6%) of these patients went on to have a further surgical amputation; 22 major amputations (16 below-knee and 6 above-knee amputations) and 23 minor amputations were performed in total. Forty three (68.3%) patients had diabetes and 31 (49.2%) patients had one or more revascularisation procedures undertaken. There was a significant correlation between patients who did not have diabetes and future limb loss (Chi-squared=4.31, p=0.038), however no other identified risk factor predicted the need for major amputation.Conclusion: Toe amputation is a significant predictor of future limb loss. Our study identified that patients with diabetes are significantly less likely to progress to further limb loss than those with the disease. We hypothesise that this difference is due to the more intensive, multi-disciplinary foot care follow-up that diabetic patients receive. These results highlight the significance of toe amputation and contribute to the evidence for a more intensive out-patient service for these high risk patients.

Factors associated with poor glycemic control in older Mexican American diabetics aged 75 years and older - Corrected Proof

2012-04-20

Abstract: Objective: This study examines the prevalence and correlates of poor glycemic control in Mexican Americans aged 75 years and older with diabetes.Methods: Data are from the 5th wave (2004-05) of the Hispanic Established Population for the Epidemiological Study of the Elderly (H-EPESE). A total of 2,069 Mexican Americans aged 75 and over were interviewed. Six hundred eighty nine subjects (33.5%) reported having been diagnosed with diabetes and 209 (30.3%) subjects agreed to a blood test of their HbA1c level.Results: Of the 209 diabetic subjects with an HbA1c test, 73 (34.9%) had good glycemic control (HbA1c <7%) and 136 (65.1%) had poor glycemic control (HbA1c >7%). Bivariate analysis revealed that subjects with poor control had longer disease duration, had lower education, used the glucometer more frequently, and had more diabetes-complications when compared to those in the good glycemic control group. Multivariable logistic regression analysis found the following factors associated with poor glycemic control: <8 years of education, foreign-born, smoking, obesity, longer disease duration, daily glucometer use, and having macro-complications.Discussion: Prevalence of poor glycemic control is very high in this population with very high and rising prevalence of diabetes. Further studies are needed to explore the effect of these and other characteristics on glycemic control among older Mexican Americans and to develop appropriate interventions to improve diabetes outcomes and increase life-expectancy.

How reliable are cultures of specimens from superficial swabs compared with those of deep tissue in patients with diabetic foot ulcers? - Corrected Proof

2012-04-20

Abstract: Purpose: To assess the reliability of cultures of superficial swabs (SS) by comparing them with cultures of concomitantly obtained deep tissue (DT) specimens in patients with diabetic foot ulcers.Methods: We reviewed clinical and microbiological data from patients with diabetes who presented during a two-year period to our hyperbaric medicine center with a foot ulcer. We identified patients who had at least one concomitantly collected SS and DT pair of specimens sent for culture.Results: A total of 89 culture pairs were available from 54 eligible patients, 33 (61.1%) of whom were hospitalized. Wounds were infected in 47 (87.0%) of the patients and 28 (51.9%) patients had received antibiotic therapy within the previous month. Overall, 65 (73%) of the SS and DT pairs had identical culture results, but in 11 (16.9%) cases the cultures were sterile; thus, only 54 (69.2%) of the 78 culture-positive pairs had identical results. Compared with DT, SS cultures yielded ≥1 extra organism in 10 (11.2%) cases, missed at least one organism in 8 (9.0%), and were completely different in 6 (6.7%). When compared to DT culture results, SS cultures had a positive predictive value of 84.4%, negative predictive value of 44.0%, and overall accuracy of 73.0%.Conclusions: In patients with diabetic foot ulcers, results of specimens for culture taken by SS did not correlate well with those obtained by DT. This suggests that SS specimens may be less reliable for guiding antimicrobial therapy than DT specimens.

Retrospective comparative analysis of metabolic control and early complications in familial and sporadic type 1 diabetes patients - Corrected Proof

2012-04-20

Abstract: Background: Genetic susceptibility and lifestyle are associated with glycemic control and diabetic complications in type 1 diabetes (T1D).Objectives: To investigate metabolic control and occurrence of acute and microvascular complications among familial and sporadic T1D patients.Patients and Methods: Retrieved from our institutional registry of new T1D cases for the years 1979–2008 were 226 familial patients belonging to 121 families (58 parent–offspring, 63 sib-pairs) and 226 sporadic cases matched for age, gender, and year of diagnosis. Extracted from medical files were clinical course and therapeutic regimen.Results: Mean age at diagnosis of diabetes of the cohort was 10.8±5.7 years. Throughout follow-up (11.1±8.7 years) mean HbA1c values were significantly higher in familial than in sporadic cases (8.18%±1.15% vs. 7.85%±1.15%, p=0.005). Diabetic ketoacidosis (DKA) rates were higher in familial than sporadic cases (2.8 vs. 1.9 events per 100 patient-years; incidence rate ratio (IRR)=1.5, 95% CI [1.03, 2.22, p=0.03]). Severe hypoglycemia events per 100 patient-years were comparable in familial and sporadic groups (3.7 vs. 4.0 events); sib-pairs had higher rates than parent–offspring (4.8 vs. 2.4 events; (IRR)=2, 95% CI [1.03, 3.25, p=0.03]). The percentage of patients with microvascular complications was similar in the familial (21.7%) and sporadic (26.7%) groups. In both familial and sporadic cases the most significant predictor for metabolic control and microvascular complications was diabetes duration; a higher mean HbA1c level was the predictor for DKA events.Conclusions: The worse metabolic control and increased rate of DKA in familial T1D patients as compared to those in the sporadic T1D patients warrant intensified surveillance in this population.

Aerobic physical training restores biomechanical properties of Achilles tendon in rats chemically induced to diabetes mellitus - Corrected Proof

2012-04-20

Abstract: The aim of this study is to evaluate if the application of a moderate aerobic exercise protocol reverses the damage caused by diabetes on the mechanical properties of the Achilles tendon.Methods: Forty-four rats were divided randomly into four groups as follows: Sedentary Control Group-SCG, Sedentary Diabetic Group-SDG, Trained Control Group-TCG and Trained Diabetic Group-TDG, the trained groups were submitted to a protocol of moderate physical training on a continuous treadmill. For mechanical testing the tendons were fixed in a conventional mechanical testing machine and pulled to the point of failure of the specimen, the cell load of 500N. The parameters were: Elastic Modulus (MPa), Stress Maximum Strength (MPa), Strain Specific Maximum Force (mm), Energy / Tendon Area (N.mm/mm2) and Cross-sectional Area (mm2).Results: The evaluation of the biomechanical properties of the Achilles tendon of the SDG indicated that the elastic modulus (MPa) is decreased when compared to the TDG and the other groups (p<0.01). However, the specific deformation (%), the deformation at maximum force (mm), and energy / tendon area (N.mm/mm2) of the SDG were significantly higher than in the other groups (p<0.01). Moreover, moderate aerobic training on a treadmill caused the biomechanical property values to move closer to the values shown by the control groups (p>0.01).Conclusion: In summary, our study indicates that moderate-intensity aerobic training restored the normal mechanical properties of tendons in diabetic animals, since the elastic modulus (MPa), the specific deformation (%), the deformation of the maximum force (mm) and energy / tendon area (N.mm/mm2) approached the values shown by the control groups.

Scanning laser edema index: A reliable tool to correlate with diabetic retinopathy and systemic risk factors? - Corrected Proof

2012-04-20

Abstract: To correlate Heidelberg Retina Tomograph (HRT) derived macular edema (DME) index with severity of diabetic retinopathy and systemic factors.A total of 300 diabetic patients were recruited for the study for each of them a value for the macular edema index was obtained using the HRT II. Patients' age, gender, duration and type of diabetes mellitus, latest HbA1c result and presence or absence of co-morbid factors (hypertension, ischemic heart disease, nephropathy) were recorded together with the stage of diabetic retinopathy. These were correlated with DME.Out of 300 patients, HRT defined macula edema was seen in 68 patients (22.6%). There is a wider and higher range (95% percentile) of macula edema index in the severe non proliferative diabetic retinopathy (NPDR) group. Independent samples t test showed significant difference between the severe NPDR group and no DR group (p<0.001), mild NPDR group (p<0.05) and moderate NPDR group (p<0.05). A higher macula edema index was also found to have a low degree of correlation with more advanced stages of retinopathy (r=0.310; p<0.001). Also nephropathy showed a strong and significant correlation with DME. Hypertension had moderately significant correlation with DME. This study found no correlation between ischemic heart disease and DME.HRT derived scanning laser edema index is a reliable objective tool to evaluate diabetic retinopathy and systemic risk factors.

Human C-reactive protein accentuates macrophage activity in biobreeding diabetic rats - Corrected Proof

Ishwarlal Jialal, Harmeet Kaur, Sridevi Devaraj — 2012-04-20

Abstract: Objective: Type 1 diabetes (T1DM) is a pro-inflammatory state characterized by high C-reactive protein (CRP) levels. However, there is a paucity of data examining the role of CRP in promoting the pro-inflammatory state of diabetes. Thus, we examined the pro-inflammatory effects of human CRP using spontaneously diabetic bio-breeding (BB) rats.Methods: Diabetic rats (n=9/group) were injected with Human serum albumin (huSA) or Human CRP (hCRP, 20mg/kg body weight; i.p.) for 3 consecutive days. Blood and peritoneal macrophages (MØ) were obtained following euthanasia. Peritoneal macrophages were used for measuring superoxide anion release, NF-κB DNA binding activity, proinflammatory mediator secretion.Results: hCRP administration resulted in significantly increased superoxide anion production, along with increased release of cytokines/chemokines, and plasminogen activator inhibitor (PAI-1) and Tissue Factor (TF) activity in diabetic rats compared to huSA. hCRP-treated BB rat MØ showed significant induction of protein kinase C (PKC)-alpha, PKC-delta and p47 phox expression and NF-κB compared to huSA.Conclusions: Thus, our data suggest that human CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant and procoagulant states of diabetes predominantly via increased macrophage activity and this could have implications with respect to vascular complications and anti-inflammatory therapies.

Cerebral haemodynamics, cognition and brain volumes in patients with type 2 diabetes - Corrected Proof

2012-04-20

Abstract: Background: Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and brain abnormalities on MRI. The underlying mechanisms are unclear. We examined the relationship between cerebral haemodynamics (cerebral blood flow (CBF) and cerebrovascular reactivity (CVR)) and cognitive performance and brain volumes in patients with T2DM, at baseline and after four years.Methods: 114 patients with T2DM, aged 56–80 years, underwent a detailed cognitive assessment and MRI scan. In 68 patients the evaluation was repeated after four years. CBF (two-dimensional flow-encoded phase-contrast MRI) and CVR (carbogen breathing response middle cerebral artery; transcranial Doppler) were measured at baseline. Cognitive performance was expressed as composite z-score and regression based index score. Brain volumes were measured on MRI by automated segmentation. The relationship of haemodynamics with cognition and brain volumes was examined with linear regression analyses adjusted for age, sex and IQ.Results: Mean CVR was 51.8%±18.0% and mean rCBF 53.3±11.3 ml/min/100 ml brain tissue. CBF was associated with baseline cognitive performance (standardized regression coefficient β (95% CI): 0.17 (0.00; 0.32) and total brain volume (0.23 (0.05; 0.41)). No correlation was found between CVR and baseline cognitive performance. Neither CBF nor CVR predicted change in cognition (CBF 0.11 (−0.21; 0.44); CVR 0.07 (−0.21; 0.36)) or total brain volume (CBF 0.09 (−0.22; 0.39); CVR 0.13 (−0.13; 0.40)) over four years.Conclusions: CBF was associated with impaired cognition and total brain volume in cross-sectional analyses, but did not predict changes in cognition or brain volumes over time. Apparently, alterations in cerebral haemodynamics play no major etiological role in cognitive decline or change in brain volumes in non-demented individuals with T2DM.

Simple function tests for autonomic neuropathy have a higher predictive value on all-cause mortality in diabetes compared to 24-h heart rate variability - Corrected Proof

Ole May, Hanne Arildsen — 2012-04-18

Abstract: Aim: To compare the long-term predictive power of heart rate variability (HRV) based on 24 h ECG recordings with a battery of simple autonomic function tests with regard to all-cause mortality in diabetic individuals.Methods: 240 diabetic persons were randomly selected from the diabetic population. A 24-h ECG was obtained and analysed on the Pathfinder 700. In the RR Tools Program time domain and frequency domain parameters were computed. Five function tests were conducted: Valsalva ratio, heart rate response to standing (30:15 ratio), expiration/inspiration ratio (E/I ratio), orthostatic blood pressure response (Ortho BP), and increase in diastolic blood pressure during sustained handgrip.Results: 178 patients agreed to participate and 136 patients who completed all 5 function tests and had an acceptable ECG recording were included in the analyses. 64 individuals (47%) died during the 15½ year follow-up. Using Cox proportional hazard analyses correcting for age and gender we found that among the HRV parameters only the power in the low frequency band (LF) had an independent predictive value on all-cause mortality (p=0.0002). Multivariate analysis of the five function tests showed that Valsalva (p=0.002), 30:15 ratio (p=0.037), and handgrip (p=0.037) were independent predictors of death. When finally the independent predictors among the function tests and the HRV parameters were assessed in the same model, no significant value could be shown for LF power (p=0.44).Conclusion: The study indicates that simple autonomic function tests are superior to HRV based on 24-h ECG recordings in predicting all-cause mortality in the diabetic population.

Evaluation of metabolite changes in visual cortex in diabetic retinopathy by MR-Spectroscopy - Corrected Proof

Ercan Ozsoy, Selim Doganay, Metin Dogan, Alpay Alkan, Penpe Gul Firat — 2012-04-18

Abstract: Purpose: To evaluate metabolite changes in the visual cortex of diabetic patients with nonproliferative or proliferative diabetic retinopathy by Magnetic Resonance Spectroscopy (MRS).Materials and Methods: 15 normal subjects (group 1), 15 patients with diabetes who did not have diabetic retinopathy (group 2), 15 patients with nonproliferative diabetic retinopathy (NPDR) (group 3), and 15 patients with proliferative diabetic retinopathy (PDR) (group 4) were included in the study. Furthermore, diabetic patients were divided into two groups according to HbA1c levels (Group A: 20 patients, HbA1c <8%; Group B: 20 patients, HbA1c >8%). In all cases' left visual cortex, amounts of N-acetyl-aspartate (NAA), choline (Cho), and creatine (Cr) were measured by MRS. NAA/Cr, Cho/Cr, and NAA/Cho ratios were calculated. Furthermore, all cases' complete blood count (CBC) and biochemical parameters were evaluated.Results: There was no statistically significant difference for NAA/Cr, Cho/Cr, and NAA/Cho ratios between groups 1, 2, 3, and 4 (P>0.05). However there was a statistically significant difference for NAA/Cr and NAA/Cho ratios between groups A and B (P<0.05). There was no statistically significant difference for Cho/Cr ratio between groups A and B (P>0.05).Conclusion: Although NAA/Cr and NAA/Cho ratios decrease in the visual cortex while diabetic retinopathy progresses, these decreases are not statistically significant. While HbA1c levels increase, the NAA concentration decreases in the visual cortex which indicates neuronal loss. The metabolite changes in the visual cortex are associated with acute events rather than chronic.

Diabetes mellitus in genetically isolated populations in Jordan: prevalence, awareness, glycemic control, and associated factors - Corrected Proof

2012-04-16

Abstract: Objectives: Diabetes mellitus is one of the most common non-communicable diseases globally. This study seeks to estimate the prevalence of impaired fasting glycemia and type 2 diabetes mellitus in genetically isolated populations in Jordan: the Circassians and Chechans.Research Design and Methods: Data were analyzed from a cross-sectional study that included a random sample of adult Circassians and Chechans. A subject was defined as affected by diabetes mellitus if diagnosis was known to patient or, according to the American Diabetes Association definition. Impaired fasting glucose was defined as a fasting serum glucose level of ≥6.1 mmol/L (100 mg/dl) but <7 mmol/L. HbA1c >7% was defined as ‘unsatisfactory’ metabolic control.Results: The prevalence of impaired fasting glycemia was 18.5% for Circassians and 14.6% for Chechans. Prevalence of diabetes was 9.6% for Circassians and 10.1% for Chechans. The prevalence of impaired fasting glycemia and diabetes were significantly higher in men, older age groups, married, subjects of lower educational level, past smokers, and subjects with obesity. Low high-density lipoprotein cholesterol was the most common abnormality in the two populations.Conclusions: The homogenous, genetically isolated Circassian and Chechan populations sharing the same environmental influences suggest a role for genetic risk factors for diabetes. Thus these two populations are suitable for additional genetics studies that may lead to the identification of novel risk factors for type 2 diabetes. In addition, more than half of patients with diabetes were with unsatisfactory control. Therefore, they are likely to benefit from programs encouraging healthy weight and physical activity.

Comparison of demographic factors and cardiovascular risk factor control among U.S. adults with type 2 diabetes by insulin treatment classification - Corrected Proof

2012-04-13

Abstract: Aims: Data on glucose and cardiovascular disease (CVD) risk factor control among persons with type 2 diabetes mellitus (DM) according to insulin treatment status are lacking. We examined DM control, risk factors, and comorbidities among U.S. persons according to insulin treatment status.Methods: In the U.S. National Health and Nutrition Examination Surveys 2003–2006, we examined in 10,637 adults aged ≥30 with type 2 DM the extent of control of A1c, LDL-C, HDL-C, triglycerides, and blood pressure (BP) and composite goal attainment by insulin use status.Results: 6.6% (n=889, projected to 14.3 million) had type 2 DM; of these, 22.9% were insulin users and 57.2% were treated only by other diabetes medications. Overall, 58.2% had an A1c<7% (53 mmol/mol) (insulin users 33.1%, non-insulin treated 66.1%, and 77.9% of those not on medication, p<0.0001). Overall, 44.2% were at a BP goal of <130/80 mmHg, 43.8% had an LDL-C<100 mg/dl (2.6 mmol/L), and 13.9% a BMI<25 kg/m2. Only 10.2% were simultaneously at A1c, LDL, and BP goals (5.4% of those on insulin).Conclusions: U.S. adults with type 2 DM, especially those treated with insulin remain inadequately controlled for A1c and CVD risk factors and have a high prevalence of comorbidities.

Time-course changes in nerve conduction velocity (NCV) in type 2 diabetes - Corrected Proof

Jiro Morimoto, Yutaka Suzuki, Ai Tada, Megumi Akui, Yuri Ozawa, Taro Maruyama — 2012-04-13

Abstract: Aim: Changes in NCV were surveyed over 10 years in type 2 diabetes patients to clarify the time-course relationships between NCV and retinopathy stage and between NCV and HbA1c. In addition, the natural course of diabetic sensorimotor polyneuropathy (DSPN) was discussed based on the findings.Methods: Using a simple NCV measurement device, NCV (MCV and SCV) was measured once a year over 10 years in 474 patients with type 2 diabetes. These patients were grouped based on the retinopathy stage and HbA1c level in the course to investigate the time-course relationships between the retinopathy stage and NCV and between HbA1c and NCV.Results: The retinopathy stage and NCV reduction were strongly correlated, and NCV decreased as retinopathy progressed. On comparison of time-course NCV among the retinopathy stages, continuity of NCV reduction along with the retinopathy progression was noted. Regarding the relationship between HbA1c and NCV, NCV reduction was moderate in the group maintaining HbA1c at a relatively favorable level, but morbid reduction of NCV could not be prevented even though favorable control was maintained.Conclusion: NCV reduction is strongly correlated with retinopathy progression from more than 10 years before its manifestation through reaching proliferative retinopathy. It was also suggested that NCV reduction can be attenuated by controlling blood glucose, but the reduction cannot be prevented completely. Based on these findings, DSPN is a progressive complication that starts from an early phase after onset of diabetes and steadily aggravates, keeping step with retinopathy aggravation, and it may be difficult to completely prevent the progression.