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Association of non-alcoholic fatty liver disease with microvascular complications of type 2 diabetes.
Afarideh, M, Aryan, Z, Ghajar, A, Ganji, M, Ghaemi, F, Saadat, M, Heidari, B, Mechanick, JI, Esteghamati, A
Primary care diabetes. 2019;(6):505-514
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects risks of type 2 diabetes (T2D), diabetes-related complications, and cardiovascular disease in a complex manner. This study is designed to clarify associations of sonographically-detected NAFLD and serum liver enzymes with diabetes-related microvascular complications. METHODS A matched case-contorl study was designed for 440 patients with T2D and at least one of the chronic diabetes-related microvascular complications and 495 age- and gender-matched control patients with T2D. RESULTS Considering pre-existing and newly developed chronic microvascular complications, diabetic peripheral neuropathy was found in 347 out of 935 (37.1%) study patients, diabetic retinopathy in 141/935 (15.1%), and diabetic nephropathy in 103/935 (11.0%). Diagnosis of diabetic retinopathy and diabetic nephropathy were inversely associated with the presence of NAFLD in the crude logistic regressions (OR [95% CI] = 0.18 [0.05-0.63], p value = 0.007; OR [95% CI] = 0.17 [0.04-0.59], p value = 0.011, respectively). The subgroup of NAFLD with elevated liver enzymes had lower odds of having diabetic peripheral neuropathy in the fully adjusted model (OR [95% CI] = 0.34 [0.12-0.98], p value = 0.048). CONCLUSION Diagnosis of NAFLD with or without elevated serum liver enzymes was inversely correlated with certain chronic diabetes microvascular complications. Possible explanations for this counter-intuitive and unexpected finding are discussed and center on reverse-causality, wherein sicker patients may develop beneficial compensatory physiological and behavioral adaptations. Diversity of studied patients, in particular with regards to the ethnic and racial differences among the Western and Asian populations may also partly account for contrasting findings of the relationship between NAFLD and microvascular complications of diabetes.
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Diabetic polyneuropathy is a risk factor for decline of lower extremity strength in patients with type 2 diabetes.
Nomura, T, Ishiguro, T, Ohira, M, Ikeda, Y
Journal of diabetes investigation. 2018;(1):186-192
Abstract
AIMS/INTRODUCTION The present study elucidated the effect of diabetic polyneuropathy (DPN) on lower extremity strength in a wide age range of type 2 diabetes patients. MATERIALS AND METHODS Participants (n = 1,442) were divided into three age groups (30-49 years, 50-69 years and 70-87 years), and comparisons were made separately for each sex. Lower extremity strength was measured in terms of knee extension force (KEF) with a hand-held dynamometer. KEF was compared according to the presence or absence of DPN. Furthermore, the effect of DPN on KEF with other diabetic complications (diabetic retinopathy and diabetic nephropathy), diabetes status (diabetes duration and glycated hemoglobin) and habitual behavior (regular exercise, smoking and drinking behaviors) as explanatory variables was analyzed using multiple regression analysis in several models. RESULTS The frequency of DPN differed among age groups, ranging from 14.3 to 49.6%, and increasing with age. There was no significant difference in KEF between patients aged 30-49 years with and without DPN. However, among both men and women aged 50-69 years and 70-87 years, patients with DPN showed significantly diminished KEF (11.0-12.9% and 11.9-16.6%, respectively) compared with those without DPN (P < 0.01-0.001). In women aged 50-69 years and 70-87 years, and in men aged 50-69 years, DPN was a significant explanatory variable for KEF in all multiple regression analysis models. CONCLUSION DPN might reinforce a KEF decline in middle-aged and elderly type 2 diabetes patients.
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Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy.
McDonnell, A, Collins, S, Ali, Z, Iavarone, L, Surujbally, R, Kirby, S, Butt, RP
Pain. 2018;(8):1465-1476
Abstract
The effect of PF-05089771, a selective, peripherally restricted Nav1.7 sodium channel blocker on pain due to diabetic peripheral neuropathy was investigated in a randomised, placebo and active-controlled parallel group clinical trial (NCT02215252). A 1-week placebo-run in the period was followed by a 4-week treatment period and a 1-week placebo run-out/taper-down period. Single-blind placebo was administered throughout run-in and run-out periods. Subjects were randomised to receive either PF-05089771 150 mg twice daily, pregabalin 150 mg twice daily, or placebo during the 4-week treatment period. One hundred thirty-five subjects were randomised. The primary endpoint was the average pain score derived from subjects' Numerical Rating Scale scores over the past 7 days of week 4 of the double-blind treatment period. Predefined efficacy criteria for the trial were the effect of PF-05089771 being >0.5 units better than placebo at interim analysis after completion of the first part of the study. Although a trend for a reduction in the weekly average pain score in the PF-05089771 treatment group was observed, this was not statistically significant when compared with placebo at week 4, with a mean posterior difference of -0.41 (90% credible interval: -1.00 to 0.17). The effect of PF-05089771 was smaller than that seen with pregabalin, which was statistically significant when compared with placebo at week 4, with a mean posterior difference of -0.53 (90% credible interval: -0.91 to -0.20). As predefined efficacy criteria were not met, the study did not proceed to the second part. PF-05089771 was well tolerated. Possible reasons for the modest efficacy observed with PF-05089771 are discussed.
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Prevalence and correlates of diabetic peripheral neuropathy in a Saudi Arabic population: a cross-sectional study.
Wang, DD, Bakhotmah, BA, Hu, FB, Alzahrani, HA
PloS one. 2014;(9):e106935
Abstract
The purpose of this cross-sectional study was to investigate the prevalence and correlates of diabetic peripheral neuropathy (DPN) in a Saudi population. The study population consisted of 552 diabetic participants with an average age of 53.4 years. Among this population, 62.7% were male and 94.9% had type 2 diabetes. The average body mass index was 31.1 kg/m2. DPN was diagnosed based on a combination of reduced vibration perception measured by neurothesiometer and/or reduced light touch perception evaluated by the 10-g Semmes-Weinstein monofilament, as well as neurological symptoms. Information on socio-demographic variables, smoking status, duration of diabetes, and medications was obtained through interviews by physicians. Body weight, height, waist circumference, blood pressure and clinical markers were assessed following standard procedures. The prevalence of DPN in this population was 19.9% (95% CI, 16.7%-23.5%). In the multivariable analyses, longer duration of diabetes [odds ratio (OR) for every 5-year increase, 2.49, 95% CI, 1.75-3.53], abdominal obesity (OR, 2.53, 95% CI, 1.41-4.55), and higher levels of fasting blood glucose (OR for every 1 mmol/L increase, 1.05, 95% CI, 0.99-1.12), creatinine (OR for every 10 µmol/L increase, 1.07, 95% CI, 0.99-1.14) and white blood cell count (OR for every 106/L increase, 1.08, 95% CI, 1.01-1.16) were associated with higher odds of DPN, while oral hypoglycemic medication use was associated with a lower odds of DPN (OR, 0.47, 95% CI, 0.26-0.85). In this large Saudi population, several correlates for DPN, in addition to glycemic control and diabetes duration, were identified, including abdominal obesity, creatinine and white blood cell count.
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Cardiovascular autonomic neuropathy is associated with macrovascular risk factors in type 2 diabetes: new technology used for routine large-scale screening adds new insight.
Fleischer, J, Yderstraede, K, Gulichsen, E, Jakobsen, PE, Lervang, HH, Eldrup, E, Nygaard, H, Tarnow, L, Ejskjaer, N
Journal of diabetes science and technology. 2014;(4):874-80
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Abstract
The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.
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Effect of early multifactorial therapy compared with routine care on microvascular outcomes at 5 years in people with screen-detected diabetes: a randomized controlled trial: the ADDITION-Europe Study.
Sandbæk, A, Griffin, SJ, Sharp, SJ, Simmons, RK, Borch-Johnsen, K, Rutten, GE, van den Donk, M, Wareham, NJ, Lauritzen, T, Davies, MJ, et al
Diabetes care. 2014;(7):2015-23
Abstract
OBJECTIVE To determine the benefit of multifactorial treatment on microvascular complications among people with type 2 diabetes detected by screening. RESEARCH DESIGN AND METHODS This study was a multicenter cluster randomized controlled trial in primary care with randomization at the practice level. In four centers in Denmark; Cambridge, U.K.; the Netherlands; and Leicester, U.K., 343 general practices participated in the trial. Eligible for follow-up were 2,861 of the 3,057 people with diabetes detected by screening included in the original trial. Biomedical data on nephropathy were collected in 2,710 (94.7%) participants, retinal photos in 2,190 (76.6%), and questionnaire data on peripheral neuropathy in 2,312 (80.9%). The prespecified microvascular end points were analyzed by intention to treat. Results from the four centers were pooled using fixed-effects meta-analysis. RESULTS Five years after diagnosis, any kind of albuminuria was present in 22.7% of participants in the intensive treatment (IT) group and in 24.4% in the routine care (RC) group (odds ratio 0.87 [95% CI 0.72-1.07]). Retinopathy was present in 10.2% of the IT group and 12.1% of the RC group (0.84 [0.64-1.10]), and severe retinopathy was present in one patient in the IT group and seven in the RC group. Neuropathy was present in 4.9% and 5.9% (0.95 [0.68-1.34]), respectively. Estimated glomerular filtration rate increased between baseline and follow-up in both groups (4.31 and 6.44 mL/min, respectively). CONCLUSIONS Compared with RC, an intervention to promote target-driven, intensive management of patients with type 2 diabetes detected by screening was not associated with significant reductions in the frequency of microvascular events at 5 years.
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Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial.
Fonseca, VA, Lavery, LA, Thethi, TK, Daoud, Y, DeSouza, C, Ovalle, F, Denham, DS, Bottiglieri, T, Sheehan, P, Rosenstock, J
The American journal of medicine. 2013;(2):141-9
Abstract
PURPOSE To determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy. RESEARCH DESIGN AND METHODS This multicenter, randomized, double-blind, placebo-controlled trial involved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45 volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg or placebo. The primary end point was effect on VPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36), as well as plasma levels of folate, vitamins B(6) and B(12), methylmalonic acid (MMA), and homocysteine. RESULTS There was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistently reported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P=.013 vs placebo) and week 24 (P=.033). Improvement in NTSS scores was related to baseline MMA and inversely related to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by 2.7±3.0 μmol/L with LMF-MC-PLP versus an increase of 0.5±2.4 μmol/L with placebo (P=.0001). Adverse events were infrequent, with no single event occurring in ≥2% of subjects. CONCLUSIONS LMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as the trial duration may have been too short to show an effect on VPT. In addition, further research on the effects in patients with cobalamin deficiency would be useful.
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A prospective multi-centric open clinical trial of homeopathy in diabetic distal symmetric polyneuropathy.
Nayak, C, Oberai, P, Varanasi, R, Baig, H, Ch, R, Reddy, GR, Devi, P, S, B, Singh, V, Singh, VP, et al
Homeopathy : the journal of the Faculty of Homeopathy. 2013;(2):130-8
Abstract
OBJECTIVES To evaluate homeopathic treatment in the management of diabetic distal symmetric polyneuropathy. METHODS A prospective multi-centric clinical observational study was carried out from October 2005 to September 2009 by Central Council for Research in Homeopathy (CCRH) (India) at its five institutes/units. Patients suffering from diabetes mellitus (DM) and presenting with symptoms of diabetic polyneuropathy (DPN) were screened, investigated and were enrolled in the study after fulfilling the inclusion and exclusion criteria. Patients were evaluated by the diabetic distal symmetric polyneuropathy symptom score (DDSPSS) developed by the Council. A total of 15 homeopathic medicines were identified after repertorizing the nosological symptoms and signs of the disease. The appropriate constitutional medicine was selected and prescribed in 30, 200 and 1 M potency on an individualized basis. Patients were followed up regularly for 12 months. RESULTS Out of 336 patients (167 males and 169 females) enrolled in the study, 247 patients (123 males and 124 females) were analyzed. All patients who attended at least three follow-up appointments and baseline curve conduction studies were included in the analysis.). A statistically significant improvement in DDSPSS total score (p = 0.0001) was found at 12 months from baseline. Most objective measures did not show significant improvement. Lycopodium clavatum (n = 132), Phosphorus (n = 27) and Sulphur (n = 26) were the medicines most frequently prescribed. Adverse event of hypoglycaemia was observed in one patient only. CONCLUSION This study suggests homeopathic medicines may be effective in managing the symptoms of DPN patients. Further studies should be controlled and include the quality of life (QOL) assessment.
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[Efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy].
Gu, XM, Zhang, SS, Wu, JC, Tang, ZY, Lu, ZQ, Li, H, Liu, C, Chen, L, Ning, G
Zhonghua yi xue za zhi. 2010;(35):2473-6
Abstract
OBJECTIVE To evaluate the efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy with regards to sensory symptoms and nerve conduction velocity. METHODS A total of 236 diabetics with symptomatic polyneuropathy were enrolled into this 5-center, randomized, double-blind and placebo-controlled study of α-lipoic acid 1800 mg daily (n = 117) or matching placebo (n = 119) for 12 weeks. The primary outcome was total symptom score (TSS). Secondary end points included nerve conduction velocity, individual symptom score, HbA1c and safety parameters. The above parameters were reviewed and recorded at zero point and after treatment for 2, 4, 8, 12 weeks separately. RESULTS 73.27% patients with symptomatic polyneuropathy improved after treatment with α-lipoic acid for 12 weeks versus 18.27% with placebo. TSS declined by 2.6 ± 2.3 with α-lipoic acid. And it was more than 0.7 ± 1.4 versus placebo (P < 0.05). TSS decreased quickly after treatment with α-lipoic acid for 2 weeks (P < 0.05). And it was better than placebo. Individual symptom scores of pain, extremity numbness, burning sensation or resting abnormal sensations were significantly diminished as compared to those before treatment and placebo group (all P < 0.05). Nerve conduction velocity had no change. HbA1c further decreased at the end of trial after α-lipoic acid treatment (P < 0.05). The incidence rates of adverse effects were 25.4% vs 11.8% in the treatment and control groups. The major manifestation was burning sensation from throat to stomach (12.7%). CONCLUSION Oral treatment with high-dose α-lipoic acid for 12 weeks may improve symptoms in patients with diabetic polyneuropathy. Dose of 600 mg thrice daily for 2 weeks has marked effects with a reasonable safety.
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Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestat.
Hotta, N, Kawamori, R, Atsumi, Y, Baba, M, Kishikawa, H, Nakamura, J, Oikawa, S, Yamada, N, Yasuda, H, Shigeta, Y, et al
Diabetic medicine : a journal of the British Diabetic Association. 2008;(7):818-25
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AIMS: The long-term efficacy of epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to epalrestat treatment. METHODS Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor-Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity > or = 40 m/s and with glycated haemoglobin (HbA(1c)) < or = 9.0%. Longitudinal data on HbA(1c) and subjective symptoms of the patients for 3 years were analysed (epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. RESULTS Stratified subgroup analyses revealed significantly better efficacy of epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA(1c) < or = 7.0%). CONCLUSION Our results suggest that epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.