Biochemical markers of types I and III collagen and limited joint mobility in type 1 diabetic patients

Abstract. Limited joint mobility (LJM), a long-term complication of diabetes, has been shown to be associated with microvascular complications of diabetes. Connective tissue alterations may contribute to the development of LJM and other diabetic complications. We tested whether biochemical markers of types I and III collagen metabolism are associated with LJM in type 1 diabetes. We studied 28 male patients of mean age 43.4 years (SD=9.5) and with a duration of diabetes of 25.2 years (SD=9.7) years. LJM assessment included goniometric measurements of the joints and classification by Rosenblooms method. We measured serum concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal crosslinked telopeptide of type I collagen (ICTP); urinary excretion of crosslinked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) was also measured. Although average serum PIIINP tended to be higher in subjects with moderatesevere LJM (3.1±1.3 µg/l) than in subjects with mild LJM (2.5±0.7 µg/l) or without LJM (2.6±0.4 µg/l), no significant association was found (p<0.27). Concentrations of the other collagen markers were not different in subjects with or without LJM. We conclude that synthesis and degradation of types I and III collagen in diabetic subjects with LJM did not differ from those without LJM to reflect changes in the biochemical markers of these proteins.     

Serum markers for type IV collagen and type III procollagen in the myelofibrosis-osteomyelosclerosis syndrome and other chronic myeloproliferative disorders

Myelofibrosis is characterized by excessive deposition of interstitial and basement membrane collagens in the bone marrow. In this study, specific radioimmunoassays for the aminoterminal propeptide of type III procollagen and for the 7S collagen domain of type IV (basement membrane) collagen were used to determine how this accumulation is reflected in serum. Of the 41 patients with chronic myeloproliferative disorders studied, the highest levels of both parameters were found in idiopathic myelofibrosis and in chronic myelogenous leukaemia associated with bone marrow fibrosis. Increasing degrees of bone marrow fibrosis were accompanied by increasing serum concentrations of both markers, except for osteomyelosclerosis, where notably low values were seen. Pathologically high values of one or both parameters were also found in a few patients with polycythaemia vera or a transitional myeloproliferative disorder. The antigens related to type III procollagen and type IV collagen correlated significantly with each other and with the leucocyte count. These parameters should provide noninvasive means for following the accumulation of interstitial and basement membrane collagens in the bone marrow.     

Pancreatic polypeptide secretion after insulin infusion and protein meal in juvenile type 1 diabetic subjects

Summary An impaired pancreatic polypeptide response (PP) after hypoglycemia has been described in type I diabetic patients with overt autonomic neuropathy. Some authors have suggested that PP release might be useful as sensitive indicator of autonomic neuropathy. The meal test is safer and simpler than the insulin infusion test as PP stimulus. The aim of this study was to compare PP response to insulin infusion and protein meal test and to correlate these responses to the presence of measurable neuropathic disturbances. We thus studied 13 IDDM children and adolescents and 6 normal children. In diabetics the PP response to both tests was not different from that of the control subjects, but PP response to insulin infusion was inversely correlated to the duration of illness and was significantly lower in subjects with pathological heart rate response when compared to the control group. PP responses to the two stimuli were not correlated. We suggest that reduced PP response to hypoglycemia is an early sign of autonomic neuropathy as well as impairment of beat-to-beat variation when impaired PP response to meal test is still not evident. This study was supported in part by CNR grant CT87.01555.     

Serum type IV collagen in various liver diseases in comparison with serum 7S collagen,laminin, and type III procollagen peptide

The clinical significance of the immunoreactive triple helical domain of type IV collagen in serum was evaluated in 73 healthy controls and 161 patients with various biopsy-proven liver diseases. Although serum levels of type III procollagen peptide were increased in all liver diseases, those of type IV collagen, 7S collagen, and laminin were principally increased in chronic liver diseases associated with hepatic fibrogenesis/fibrosis. In both non-alcoholic and alcoholic liver diseases, 7S collagen was increased in serum, while type IV collagen and laminin in serum were particularly increased in alcoholic liver diseases and in hepatocellular carcinoma, in which latter the sensitivity was greater for type IV collagen than for laminin. Gel filtration analysis in Sephacryl S-400 revealed type IV collagen in serum to be a single molecular form with a molecular weight that correspond to type IV collagen, whereas 7S collagen was recognized as several heterogeneous macromolecules. These findings indicate that serum type IV collagen is derived from the type IV protocollagen pool, and is a sensitive marker for the fibrogenetic process in hepatic basement membranes.     

Autoantibodies against adrenal medulla in type 1 and type 2 diabetes mellitus: no evidence for an association with autonomic neuropathy

Objective. To examine the role of autoimmunity in the development of autonomic neuropathy in diabetes mellitus.
Design. Retrospective cross-sectional study.
Setting. The Department of Medicine, University Hospital, Uppsala, and the Department of Endocrinology, University of Lund, Malmö General Hospital, Malmö, Sweden.
Subjects and main outcome measures. We examined 135 patients with type 1 ( n =96) or type 2 ( n =39) diabetes mellitus. Tests for cardiovascular autonomic functions were performed, and patient sera were analysed for the presence of autoantibodies against the adrenal medulla by indirect immunofluorescence, Western blot and immunoprecipitation techniques.
Results. Sera from 13% (12/96) of the type 1 and 20% (8/39) of the type 2 patients showed a positive cytoplasmic immunofluorescence (IF) staining of the adrenal medullary cells, as did 20% (30/151) of sera from healthy controls. Fifty-eight and 64% of type 1 and type 2 patients, respectively, had cardiovascular autonomic neuropathy, but no correlation between autonomic neuropathy and positive IF against the adrenal medulla was observed, with the exception of significant drops in diastolic blood pressure 8 min after tilt ( P <0.005) in type 1 patients. The various IF-positive sera reacted with several different proteins when analysed with Western blot technique using a total homogenate of the bovine adrenal medulla. These did not correspond to any of the proteins involved in the synthesis or storage of catecholamines which were considered as putative autoantigens.
Conclusion. The finding of similar frequencies of immunoglobulins binding to adrenal medulla in both type 1 and 2 diabetic patients as well as in normal controls, argues against a role of anti-adrenomedullary antibodies in the pathogenesis of autonomic diabetic neuropathy.     

Exercise is not associated with better diabetes control in type 1 and type 2 diabetic subjects

In the clinical setting, the impact of educational efforts on the amount of regular exercise and its effects on diabetes control are unclear. Fifty type 1 diabetic, 50 type 2 diabetic and 70 non-diabetic subjects were evaluated using a questionnaire for type, duration and intensity of exercise to assess weekly energy expenditure. Diabetic subjects did not exercise more than controls: 36% of the type 1, 46% of the type 2 and 46% of the control subjects admitted no physical activity, and those exercising regularly had similar energy expenditure: 1808±320, 2722±617, 2523±304 (mean±SEM) kcal/week respectively (P=NS). There was no correlation between the degree of activity and HbA_1c levels, or hypoglycaemic events. HbA_1c levels were less than 6,8% in 31% of non-active active patients versus 21% of active patients (P=NS). A negative correlation was found between physical activity and daily insulin usage (r=0.27,P<0.05), but differences between patients averaged only 4 IU/1000 kcal energy expenditure/day. We conclude that patients' attitude towards exercise was not improved by our educational methods and that physical exercise was not necessarily associated with good blood glucose control.     

2型糖尿病患者尿白蛋白/肌酐比值与糖尿病视网膜病变关系的研究

目的 探讨2型糖尿病患者尿白蛋白/肌酐比值(UACR)与糖尿病视网膜病变(DR)的关系.方法 595例2型糖尿病患者进行UACR和眼底摄片检查,并根据UACR将患者分为3组:正常白蛋白尿组(n =519)、微量白蛋白尿组(n=28)和大量白蛋白尿组(n=48).比较3组患者的年龄、糖尿病病程等基本情况及DR发生率;同时以正常白蛋白尿组为参照,分析另外两组患者DR的相对危险度;最后,运用多元逐步线性回归和二元Logistic回归验证UACR与DR发生率的关系.结果 (1)3组患者的年龄、糖尿病病程、腰臀比、收缩压、舒张压、UACR差异有统计学意义(P＜0.05).(2)3组患者DR发生率依次升高,分别为30.4％、53.6％、54.2％,且差异有统计学意义(P＜0.001).(3)微量白蛋白尿组患DR的相对危险度为2.638 (95％ CI:1.225 ～ 5.682),大量白蛋白尿组患DR的相对危险度为2.702(95％ CI:1.486 ～4.902),且差异均存在统计学意义(P＜0.05).(4)多元逐步线性回归和二元Logistic回归显示,UACR与DR发生率有着显著的联系(P＜0.05).结论 2型糖尿病患者UACR与DR的发生密切相关.     

Connective tissue components in serum in multiple myeloma: Analyses of propeptides of type I and type III procollagens,type I collagen telopeptide,and hyaluronan

The present study was performed to evaluate whether information concerning synthesis and degradation of type I collagen in multiple myeloma (MM) as obtained by serum analyses of C-terminal propeptide of type I procollagen (PICP) and the C-terminal telopeptide of type I collagen (ICTP) may be useful in evaluating the development of osteolytic bone destruction. Serum N-terminal propeptide of type III procollagen (PIIINP) may give information about marrow fibrosis in MM. No data are available about MM and serum hyaluronan, another important component of bone marrow stroma. We examined 15 consecutive patients before treatment and 15 sex- and age-matched controls. We found highly significant elevations in serum ICTP (median 6.2 vs. 2.4 μg/L; P < 0.01), PIIINP (median 5.2 vs. 2.9 μ/L; P < 0.01) and hyaluronan (median 122 vs. 45 μ/L; P < 0.01). ICTP in serum correlated closely to bone morbidity (r = 0.69; P < 0.01). Furthermore, serum ICTP correlated highly significantly to serum PIIINP (P < 0.01) and serum β₂-microglobulin (P < 0.01), whereas there was no correlation between hyaluronan and any of the collagen-derived peptides or β₂-microglobulin. The MM group was followed for 9–25 months and analysis of survival data suggested that serum ICTP may be of predictive value (P < 0.05). We conclude that important changes in connective tissue metabolism occur in MM. ICTP in serum seems to be a noninvasive marker of bone morbidity and may be of prognostic value. Furthermore, elevation of hyaluronan in serum is common in MM, the significance of which is unknown. © 1994 Wiley-Liss, Inc.     

FFA、oxLDL-C与2型糖尿病视网膜病变的相关性研究

目的探讨游离脂肪酸（FFA）、氧化低密度脂蛋白（oxLDL-C）与2型糖尿病视网膜病变（DR）的相关性。方法2型糖尿病（T2DM）组108例,分为单纯糖尿病（DM）组40例和糖尿病视网膜病变（DR）组68例,与42例健康对照（NC）组比较。铜显色法测定血清FFA、酶联免疫吸附法测定ox-LDL-C,对视网膜相关危险因素行logistic回归分析。结果DR组与DM组、NC组比较;血清FFA、oxLDL-C明显升高,（P〈0.05）。T2DM组为整体,有无视网膜病变为因变量,FFA、oxLDL-C及其他危险因素为自变量,进行logistic回归分析。最后LDL-C、FFA-C、oxLDL-C和病程进入回归方程。结论FFA、oxLDL-C是DR的重要危险因素。     

2型糖尿病心脏自主神经病变临床特征和危险因素分析

目的探讨2型糖尿病心脏自主神经病变(diabetic cardiac autonomic neuropathy,DCAN)的临床特征及相关危险因素。方法纳入2012年2月至2013年1月在广东省人民医院内分泌科就诊的2型糖尿病患者47例(按1999年世界卫生组织建议的糖尿病诊断标准),所有2型糖尿病患者进行葡萄糖耐量试验(OGTT)、胰岛素释放试验、血脂等分析,并以Ewing试验作为诊断DCAN的标准,对DCAN的患病情况、临床特征及可能的主要危险因素进行分析。同时,招募糖耐量正常者19例设为正常对照组。结果以Ewing试验为标准诊断心脏自主神经病变(cardiac autonomic neuropathy,CAN),正常对照组CAN的患病率仅为5.3%(1/19),2型糖尿病组为55.3%(26/47),两组比较差异有统计学意义(P=0.001)。2型糖尿病组中病程≤5年患者的DCAN患病率为45.2%(14/31),>5年患者为75.0%(12/16),两者比较差异有统计学意义(P=0.051)。2型糖尿病组中DCAN患者心率、收缩压、空腹胰岛素、胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)、尿酸与正常对照组患者比较,差异有统计学意义(P<0.05)。静息心率>80次/min、收缩压>140 mm Hg(1 mm Hg=0.133 kPa)、空腹胰岛素>100 pmol/L、胰岛素抵抗指数>5.3或胰岛素分泌指数>102.65、尿酸>350μmol/L的患者的DCAN患病率均较正明显增加,均差异有统计学意义(P<0.05)。Logistic回归分析显示,糖化血红蛋白(HbA1c)(OR=11.788)、胰岛素抵抗指数(OR=17.211)、尿酸(OR=5.757)是DCAN的主要独立危险因素。结论 2型糖尿病患者是CAN的高危人群;糖化血红蛋白、胰岛素抵抗指数、尿酸是DCAN的主要独立危险因素。     

糖尿病视网膜病变合并糖尿病肾病的危险因素及其预测价值

目的探讨糖尿病视网膜病变(DR)合并糖尿病肾病(DN)的危险因素及预测价值。方法回顾性分析2017年5月至2018年5月南京医科大学附属无锡市人民医院内分泌科收治的2型糖尿病(T2DM)患者1 969例,其中糖尿病视网膜病变(DR)合并糖尿病肾病(DN)患者609例,单纯DR患者746例,未并发DN和DR患者614例,比较3组患者的血糖、血压、肝功能和肾功能指标水平,分析DR合并DN的危险因素及预测价值。采用SPSS 18.0统计软件对数据进行分析。组间比较采用单因素方差分析或χ~2检验。多因素logistic回归分析DR合并DN的危险因素。受试者工作特征(ROC)曲线分析因素预测DR合并DN的价值。结果除高密度脂蛋白胆固醇(HDL-C)水平和左侧颈动脉内膜中层厚度(IMT)外,3组患者其余指标差异均具有统计学意义(P0.05)。多因素logistic回归分析结果显示年龄(OR=0.966,95%CI 0.932～1.000; P=0.049)、白蛋白(ALB)(OR=0.872,95%CI 0.837～0.908; P0.001)、服用他汀类药物(OR=0.400,95%CI 0.265～0.606; P0.001)是DR合并DN的保护因素,高血压病程(OR=1.021,95%CI 1.005～1.037; P=0.011)、收缩压(OR=1.018,95%CI 1.007～1.029; P=0.002)、空腹血糖(OR=1.054,95%CI 1.002～1.108; P=0.040)、甘油三酯(OR=1.133,95%CI 1.021～1.256;P=0.019)、低密度脂蛋白胆固醇(OR=1.355,95%CI 1.017～1.805; P=0.038)、血尿酸(OR=1.124,95%CI 1.016～1.244;P=0.023)、胱抑素C(OR=2.466,95%CI 1.495～4.068; P0.001)、眼底评分(OR=1.275,95%CI 1.088～1.494; P=0.003)、左室后壁厚度(OR=1.306,95%CI 1.051～1.622; P=0.016)和颈动脉粥样斑块形成(OR=1.578,95%CI 1.051～2.370;P=0.028)为危险因素。ROC曲线分析结果表明胱抑素C预测DR合并DN价值最高,AUC为0.677。结论 T2DM患者DR合并DN的患病率较高,其发生与多种因素相关,其中,胱抑素C预测DR合并DN价值最高。     

糖尿病视网膜病变与勃起功能障碍的关系

目的探讨糖尿病视网膜病变（DR）与勃起功能障碍（ED）的关系。方法对2型糖尿病（T2DM）合并视网膜病变组（DR组）22例、T2DM无视网膜病变组（非DR组）92例用国际勃起功能指数（IIEF）评分,比较两组间的评分情况。结果DR组的评分明显低于非DR组（P〈0．05）,DR组的ED发生率明显高于非DR组（P〈0．05）。结论糖尿病视网膜病变与ED的发生密切相关。     

The prevalence of retinopathy and associated medical risk factors in type I (insulin-dependent) diabetes mellitus

The prevalence of diabetic retinopathy and the associated medical risk factors, such as age at onset and duration of diabetes, metabolic control, blood pressure, albumin clearance and serum creatinine, were studied in 501 patients with type I diabetes mellitus. The prevalence of retinopathy, characterized as simplex, maculopathy, preproliferative, and proliferative, was 60.5%. Patients with retinopathy were younger at the onset of diabetes, and had a longer duration of disease. In patients with more than 10 years of diabetes, proliferative retinopathy was more frequent if onset was before they were 15 years old, despite the fact that the duration of diabetes did not differ. Patients with severe retinopathy had worse metabolic control, and were more frequently treated for hypertension. In addition, the systolic blood pressure was elevated in all groups of patients with any type of retinopathy, whereas the diastolic blood pressure was elevated only in patients with more severe forms. Patients with severe retinopathy also had higher levels of albumin clearance.     

初诊2型糖尿病患者血小板分布宽度与糖尿病周围神经病变的关系

【摘要】目的 探索初诊2型糖尿病（type 2 diabetes mellitus，T2DM）患者血小板分布宽度（platelet distribution width，PDW）水平与糖尿病周围神经病变（diabetic peripheral neuropathy，DPN）风险之间的相关性。方法 按顺序连续纳入2017年1月至2021年12月徐州医科大学附属徐州市立医院内分泌科住院的初诊T2DM患者1001例，采集患者的一般资料、空腹血糖（fasting plasma glucose，FPG）、糖化血红蛋白（glycated hemoglobin，HbA1c） 、甘油三酯（triglyceride，TG）、总胆固醇（total cholesterol，TC）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol，LDL-C）、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol，HDL-C）、血小板（platelet，PLT）、PDW、血小板压积（plateletocrit，PCT）、平均血小板体积（mean platelet volume，MPV）、血小板大细胞比率（platelet large cell ratio，PLCR）、尿微量白蛋白/尿肌酐（microalbumin/creatinine，MALB/CREA，ACR），根据有无DPN分为T2DM伴DPN组（n=481）和T2DM不伴DPN组（n=520），以Logistic回归分析评估PDW水平与DPN风险的相关性。结果T2DM伴DPN组的PDW水平较T2DM不伴DPN组显著增高（14.58 ± 2.26 vs 14.20 ± 2.41 fl，P=0.01）。校正年龄、性别、吸烟、饮酒、阿司匹林使用史、糖尿病病程、体重指数、血压、FPG、HbA1c、TG、TC、LDL-C、HDL-C、PLT、PCT、MPV、PLCR、ACR的多因素Logistic回归分析显示，PDW水平与DPN独立相关，PDW每增加1个单位DPN风险增加11%（OR=1.11，P<0.05），PDW每增加1个标准差DPN风险增加29%（OR=1.29，P<0.05）。与第一分位相比，PDW在第三分位（OR=2.43，P=0.01）和第四分位（OR=2.01，P<0.05）时DPN风险显著增加。将DPN作为定量指标进行多因素线性回归分析显示，PDW水平与神经传导速度显著负相关。结论 初诊T2DM患者中，DPN者的PDW水平较非DPN者显著升高，PDW水平增高是DPN风险的独立危险因素。     

The development and progression of diabetic retinopathy in type I diabetic patients: a cohort study

To describe the course and risk factors for development and progression of retinopathy, we studied a cohort of 333 Israeli Jewish patients with Type 1 (insulin-dependent) diabetes mellitus. The median age at diagnosis was 9.5 (range 0.04–26.2) years and the median duration of follow-up was 14 (range 1.6–30) years. Evaluation of both retinae was performed yearly since referral and HbA₁ values were tested every 3 months since 1978. During a follow-up of 4070 patient-years, 162 patients developed non-proliferative retinopathy. The median retinopathy-free interval was 14.9 years and after 30 years all patients were affected. Pre-pubertal duration of diabetes was relevant. Independent and significant risk factors for early onset of non-proliferative retinopathy were: poor cumulative glycaemic control (median retinopathy-free interval in the 1st vs 4th quartiles of mean HbA₁ values over all years: 18.0 vs 12.5 years, p = 0.0001); onset of diabetes during or after puberty (median retinopathy-free interval in patients with onset of diabetes before, during or after pubescence: 16.3, 13.2 and 14.0 years, respectively, p = 0.0001); and non-Ashkenazi Jewish origin (median retinopathy-free interval 15.8 years in Ashkenazi vs 14.0 in non-Ashkenazi patients, p = 0.0004). Of 162 patients with non-proliferative retinopathy, progression to proliferative retinopathy occurred in 37, during 707 patient-years. The first event of proliferative retinopathy was diagnosed within the 1st year after non-proliferative retinopathy evolved, and at 6.3 years since onset of non-proliferative retinopathy 75 % of the patients were still free of proliferative changes. Risk factors significantly and independently associated with an early progression to the proliferative stage were: poor glycaemic control in the last 3 years prior to the development of proliferative retinopathy and non-Ashkenazi Jewish origin. All patients in the 4th quartile of HbA₁ values were affected by proliferative retinopathy within 11.6 years after onset of non-proliferative retinopathy. © 1997 John Wiley & Sons, Ltd.     

Dupuytren's disease in type I diabetic subjects: investigation of biochemical markers of type III and I collagen

OBJECTIVE: To clarify whether biochemical markers of collagen type III and I metabolism show alterations in type I diabetic subjects with Dupuytren's disease (DD) compared to those without DD. METHODS: DD was assessed in a total of 28 type I diabetic subjects, mean age 43.4 +/- 9.5 (SD) and duration of diabetes 25.2 +/- 9.7 years. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: The prevalence of DD was 32% (9 of 28 diabetic subjects). Average serum ICTP was 2.7 +/- 0.8 micrograms/l in subjects without DD and 3.6 +/- 1.2 micrograms/l with DD (p = 0.0276). No significant association between other collagen markers and DD was found. The reference intervals of PIIINP and ICTP were exceeded only in 1 and 2 subjects, respectively, and they both had DD. CONCLUSION: The degradation of type I collagen might be increased in diabetic subjects with DD. The overall implication was that synthesis or degradation of type III and I collagen in diabetic subjects with DD did not differ enough from those without DD to reflect changes in the biochemical markers of type III and I collagen.