Journal of Diabetes and Its Complications - Articles in Press

Diabetic keto-acidosis as a presentation of cystic fibrosis-related diabetes: a case report - Corrected Proof

2010-07-26

Abstract: Cystic fibrosis (CF) is one of the most common genetically inherited diseases and often complicated by diabetes mellitus. With increasing longevity, the incidence and prevalence of cystic fibrosis-related diabetes (CFRD) rise and microvascular complications develop. CFRD is an entity on its own with characteristics seen in both type 1 and type 2 diabetes. Keto-acidosis, a potentially life-threatening complication of diabetes, is an extremely rare presentation of CFRD.Here we present the history of a 21-year-old CF patient with no prior diagnosis of CFRD who developed keto-acidosis after an episode of pulmonary infection.Based on this case report we would like to emphasize the importance of screening for and early treatment of CFRD. We also discuss the management policy of CFRD and when and whether to initiate insulin therapy.

Substantially increased risk of cancer in patients with diabetes mellitus: A systematic review and meta-analysis of epidemiologic evidence in Japan - Corrected Proof

Hiroshi Noto, Keiichiro Osame, Takehiko Sasazuki, Mitsuhiko Noda — 2010-07-26

Abstract: Aims: Several meta-analyses have shown that diabetes mellitus affects the risk of certain site-specific cancers. However, a meta-analysis on the overall risk of cancer has not yet been performed.Methods: We performed a search of MEDLINE and the Cochrane Library for pertinent articles (including their references) that had been published as of June 10, 2010. English-language, original observational cohort studies and case-control studies conducted in Japan were included for a qualitative review and a meta-analysis.Results: A total of 22,485 cancer cases were reported in four cohort studies and one case-control study (with a total of 250,479 subjects). With these five reports, a meta-analysis of the all-cancer risk in both men and women showed an increased risk in subjects with diabetes, compared with nondiabetic subjects (OR 1.70, 95% CI 1.38–2.10). The increase in the risk ratio adjusted for possible confounders was significant in men and borderline in women (adjusted RR 1.25, 95% CI 1.06–1.46 in men; adjusted RR 1.23, 95% CI 0.97–1.56 in women). An analysis of site-specific cancers revealed increased risks for incident hepatocellular cancer (OR 3.64, 95% CI 2.61–5.07) and endometrial cancer (OR 3.43, 95% CI 1.53–7.72).Conclusions: As is the case in Western countries, Asian people with diabetes have a higher risk of incident cancer than those without diabetes. Cancer prevention and early detection should be important components of diabetes management in light of the exponentially increasing prevalence of diabetes, which has substantial implications in public health and clinical practices.

Stroke in the diabetic and non-diabetic population in Germany: relative and attributable risks, 2005–2007 - Corrected Proof

Andrea Icks, Marsel Scheer, Jutta Genz, Guido Giani, Gerd Glaeske, Falk Hoffmann — 2010-07-12

Abstract: Background: Reduction of cardiovascular events has been declared to be a main objective in diabetes care. Little is known about incidences of stroke in the diabetic compared to the non-diabetic population and its trend. We evaluated nationwide incidence of stroke in the diabetic compared to the non-diabetic populations as well as relative and attributable stroke risks due to diabetes in Germany.Methods: Using data of a statutory health insurance (1.6 million members in Germany), we assessed all first strokes in 2005–2007. We estimated sex/age-specific and standardised incidence of strokes in the diabetic and non-diabetic populations and relative and attributable risks due to diabetes.Results: A total of 6160 subjects had a first stroke [66.6% male, mean age (S.D.)=67.0 (13.9) years]; 31.4% had diabetes. Incidence per 100,000 person years (standard: 2004 German population) in the diabetic and non-diabetic populations, respectively, is as follows: men: 476 [95% confidence interval (CI)=438–514] and 255 (95% CI=243–266); women: 342 (95% CI=305–378) and 173 (95% CI=163–182).Age-standardised relative risks are as follows: 1.9 (95% CI=1.7–2.0) in men and 2.0 (95% CI=1.8–2.2) in women. The following are attributable risks among exposed: 0.46 (95% CI=0.41–0.51) in men and 0.49 (95% CI=0.43–0.55) in women; population attributable risks are as follows: 0.14 (95% CI=0.11–0.16) in men and 0.14 (95% CI=0.11–0.17) in women.Conclusions: In this nationwide study, we found the stroke risk in the diabetic population to be still significantly increased compared to the non-diabetic population. The risk increase seems to be as high as earlier observations in other countries, despite large efforts to improve diabetes care.

Improvement in bedtime plasma glucose level serves as a predictor of long-term blood glucose control in patients with Type 2 diabetes: a study with monotherapy of 50/50 premixed insulin analogue three times daily injection - Corrected Proof

Masami Tanaka, Hitoshi Ishii — 2010-06-23

Abstract: Aim: To examine which timing of blood glucose level is more important to achieve adequate blood glucose control with insulin lispro mixture-50 (Mix 50) three times daily (TID) monotherapy.Methods: The study enrolled 35 Type 2 diabetic patients. Blood glucose levels before each meal and at bedtime were measured 2 weeks after the start of the study and were analyzed in relation to improvement in hemoglobin A1c (HbA1c) at 6–8 weeks and 6 months.Results: HbA1c improved significantly (10.1±1.6 % at baseline, 7.8±1.1 % at 6–8 weeks and 6.8±1.1 % at 6 months). Only the blood glucose level measured at bedtime correlated with improvement in HbA1c at 6–8 weeks. For the insulin-naïve patients, only bedtime plasma glucose level also had a significant correlation with improvement in HbA1c at 6 months.Conclusions: Bedtime plasma glucose level can serve as a predictor of the outcome of long-term blood glucose control during Mix 50 TID monotherapy and that bedtime plasma glucose level needs to be reduced sufficiently to achieve adequate blood glucose control.

Clustering of unhealthy lifestyle behaviors is associated with nonadherence to clinical preventive recommendations among adults with diabetes - Corrected Proof

2010-06-16

Abstract: Aim: Analyze clustering of unhealthy lifestyle behavior and its relationship with nonadherence to clinical preventive care services among Spanish diabetic adults.Methods: Cross-sectional study including 2156 diabetic adults from the 2006 Spanish National Health Survey. Subjects were asked about their uptake of BP measurement, lipid profile, influenza vaccination, and dental examination. Lifestyle behaviors included smoking status, physical activity, alcohol consumption, and dieting. Binary logistic regression models were built to assess the association between clustering of unhealthy lifestyle and the uptake of each preventive activity.Results: Almost 16% and 36% of the subjects had not undergone blood pressure (BP) and blood lipids measurements, respectively. Forty percent had not been vaccinated and 72% had not received dental examination. Fourteen percent of the subjects had three to four unhealthy behaviors and this increased the probability of not having BP check-up (OR 2.32, 95% CI 1.38–3.91), blood lipids testing (OR 1.63, 95% CI 1.14–2.33), and not being vaccinated (OR 1.99, 95% CI 1.37–2.89). Number of unhealthy lifestyle behaviors is linearly associated with number of preventive measures unfulfilled.Conclusions: Adherence to recommended clinical preventive services is under desirable levels among Spanish diabetes sufferers. These preventive services are provided neither equitably nor efficiently, since subjects with unhealthier lifestyles are less likely to receive them.

LDL-containing immune complexes in the DCCT/EDIC cohort: associations with lipoprotein subclasses - Corrected Proof

2010-06-04

Abstract: Immune complexes containing modified LDL (LDL-IC) and NMR-determined Total LDL particle concentrations are significantly associated with intima-media thickness (IMT). We analyzed the associations between concentrations of NMR-determined lipoprotein subclasses and LDL-IC in the DCCT/EDIC cohort. LDL-IC concentrations in women and men of the DCCT/EDIC cohort did not differ significantly and were positively associated with Total LDL particle concentrations in men and women (r=0.34, r=0.32, respectively; P<.01) and with Small LDL concentration (r=0.22, r=0.13, respectively; P<.01). In women, Large LDL concentrations were also associated with LDL-IC (r=0.20, P<.01) while in men, the association was more modest (r=0.11, P<.05). Thus, both Small and Large LDL are associated with LDL-IC formation. Based on the results from statistical mediation analyses, we concluded that plasma concentrations of LDL-IC may provide a physiological link between the statistically significant association of Total LDL particle concentration with carotid artery IMT in subjects with Type 1 diabetes. Furthermore, after adjusting for conventional risk factors, there was a decrease in LDL-IC concentration even in the presence of high Total LDL particle concentrations in those women with high concentrations of Large HDL, but the association was not evident in men. This suggests that the associations between Large HDL and Total LDL particle concentrations, and their associations with LDL-IC levels, differ by gender and suggest that LDL-IC partially mediate the contribution of Total LDL particle concentration to increased carotid IMT in diabetic men.

The prevalence of peripheral neuropathy in a population-based study of patients with type 2 diabetes in Sweden - Corrected Proof

2010-05-20

Abstract: Aims: To assess peripheral neuropathy following a standardized foot examination protocol in a representative population-based cohort of subjects with type 2 diabetes.Methods: In a geographically defined population, aged 40–70 years with diabetes prevalence of 3.5% according to medical records, we investigated 156 type 2 diabetic subjects, 95% Caucasian, mean age 61.7±7.2 years, duration of diabetes 7.0±5.7 years, and HbA1c 7.3±2.4% (6.4% Mono-S), by questionnaires, clinical examinations, blood sampling, and review of medical records. Foot examination included clinical signs of peripheral neuropathy and tests of sensibility with monofilament, tuning fork, and assessments of the vibration perception thresholds (VPT).Results: Peripheral autonomic neuropathy (PAN) as judged by two or more signs of dysfunction was the most common and affected 43%. The prevalence of peripheral sensory neuropathy (PSN) was 15% by monofilament, 24% by tuning fork, and 28% by VPT expressed as ZscoreVPT ≥2.0 S.D. Twenty-nine percent had a VPT ≥25 V. Signs of peripheral motor neuropathy (PMN) affected 15%.Peripheral neuropathy, at least one variable, affected 67%, whereas 25% were affected by more than one variable of neuropathy, i.e., polyneuropathy. Exclusion of other identified causes for neuropathy than diabetes reduced the prevalence of diabetic polyneuropathy to 23%.Concurrent diabetic complications were 29% for retinopathy, 14% for incipient nephropathy, and 8% for overt nephropathy. The prevalence of macrovascular complications was 62% for CVD, 26% for PVD, and 11% for cerebrovascular lesion (CVL).Conclusion: Peripheral neuropathy was common in this representative type 2 diabetes population. Clinical signs of PAN were the most frequent followed by diminished perception of vibration and touch.

The importance of glycemic control: how low should we go with HbA1c? Start early, go safe, go low - Corrected Proof

Katrien Benhalima, Eberhard Standl, Chantal Mathieu — 2010-05-12

Abstract: Epidemiologic data indicate a continuous relationship between hemoglobin A1c (HbA1c) and risk for microvascular and macrovascular complications of diabetes. Intensive glycemic control reduces risk of microvascular complications in Type 1 and Type 2 diabetes, and long-term treatment and follow-up studies have shown that initial intensive control is associated with reduced cardiovascular risk. Recent intervention trials in older, high-risk patients with Type 2 diabetes have not shown a benefit of intensive control in reducing cardiovascular risk over a rather short-term follow-up period of up to 5 years, with some data indicating that intensive control accompanied by hypoglycemia is detrimental in patients with high cardiovascular risk. Indeed, hypoglycemia with current antidiabetic agents—primarily insulin and sulphonylureas—is the main limiting factor in achieving desirable levels of glycemic control. Still, the goal in treating both Type 1 and Type 2 diabetes should be to safely get HbA1c as close to normal as possible. In Type 2 diabetes, this goal should be tempered for the time being in patients with shorter life expectancy or co-existing cardiovascular disease or other co-morbidities, in whom a target of 7.0–7.5% may be advisable until we can demonstrate that lower targets in such patients can be safely achieved. Newer agents with lower risk of hypoglycemia—e.g., insulin analogues, incretin mimetics and incretin enhancers—may form an integral component of strategies for safely achieving lower HbA1c levels.

Diabetes-induced erectile dysfunction: epidemiology, pathophysiology and management - Corrected Proof

2010-05-12

Abstract: Erectile dysfunction (ED) is defined as the inability of the male to attain and maintain erection of penis sufficient to permit satisfactory sexual intercourse. Prevalence of impotence in diabetic men is ≥50%. The pathophysiology of diabetes-induced erectile dysfunction (DIED) is multifactorial and no single etiology is at the forefront. The proposed mechanisms of erectile dysfunction in diabetic patients includes elevated advanced glycation end-products, increased levels of oxygen free radicals, impaired nitric oxide synthesis, increased endothelin B receptor binding sites and up-regulated RhoA/Rho-kinase pathway, neuropathic damage and impaired cyclic guanosine monophosphate (cGMP)-dependent protein kinase-1. The treatment of DIED is multimodal. Treatment of the underlying hyperglycemia and comorbidities is of utmost importance to prevent or halt the progression of disease. Oral medications are considered as the first line therapy for management of DIED. If oral agents cannot be used or have insufficient efficacy despite appropriate dosing and education, second-line treatments should be addressed. When there is lack of efficacy or when there is dissatisfaction with other modalities, penile prostheses are often the best alternative for ED and are considered as the third line therapy for DIED. Future strategies in the evolution of the treatment of DIED are aimed at correcting or treating the underlying mechanisms of DIED.

Apocynin restores endothelial dysfunction in streptozotocin diabetic rats through regulation of nitric oxide synthase and NADPH oxidase expressions - Corrected Proof

Murat Olukman, Cahide Elif Orhan, Fatma Gül Çelenk, Sibel Ülker — 2010-03-12

Abstract: Aim: Increased production of reactive oxygen species (ROS) in the diabetic vasculature results in the impairment of nitric oxide (NO)-mediated relaxations leading to impaired endothelium-dependent vasodilation. An important source of ROS is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and the inhibition of this enzyme is an active area of interest. This study aimed to investigate the effects of apocynin, an NADPH oxidase inhibitor, on endothelial dysfunction and on the expression of NO synthase (NOS) and NADPH oxidase in thoracic aorta of diabetic rats.Method: Streptozotocin (STZ)-diabetic rats received apocynin (16 mg/kg per day) for 4 weeks. Endothelium-dependent and -independent relaxations were determined in thoracic aortic rings. Western blotting and RT-PCR analysis were performed for NOSs and NADPH oxidase in the aortic tissue.Results: Acetylcholine-induced relaxations and l-NAME-induced contractions were decreased in diabetic aorta. The decrease in acetylcholine and l-NAME responses were prevented by apocynin treatment without a significant change in plasma glucose levels. Endothelial NOS (eNOS) protein and mRNA expression exhibited significant decrease in diabetes, while protein and/or mRNA expressions of inducible NOS (iNOS) as well as p22phox and gp91phox subunits of NADPH oxidase were increased, and these alterations were markedly prevented by apocynin treatment.Conclusion: NADPH oxidase expression is increased in diabetic rat aorta. NADPH oxidase-mediated oxidative stress is accompanied by the decreased eNOS and increased iNOS expressions, contributing to endothelial dysfunction. Apocynin effectively prevents the increased NADPH oxidase expression in diabetic aorta and restores the alterations in NOS expression, blocking the vicious cycle leading to diabetes-associated endothelial dysfunction.

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.

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.

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.

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.

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.