Relationship between blood levels of N-carboxymethyl-lysine and pentosidine and the severity of microangiopathy in type 2 diabetes

The relationship between blood levels of N-carboxymethyl-lysine (CML) or pentosidine and the severity of microangiopathy was investigated in patients with type 2 diabetes. Blood CML and pentosidine levels were measured by ELISA in 97 type 2 diabetics (46 men and 51 women). CML and pentosidine levels were significantly higher in patients with chronic renal failure than in those with normoalbuminuria, microalbuminuria, or macroalbuminuria (all p < 0.05). Among the diabetics without nephropathy (n = 49), blood CML levels were significantly higher in the patients who had proliferative diabetic retinopathy than in those without retinopathy or those who had background retinopathy (both p < 0.01). In contrast, blood pentosidine levels showed no significant differences among the three retinopathy groups. These findings suggest that the blood level of CML is related to the severity of both nephropathy and retinopathy, while the pentosidine level is only related to the severity of nephropathy.     

Apolipoprotein C-III protein concentrations and gene polymorphisms in Type 1 diabetes: associations with microvascular disease complications in the DCCT/EDIC cohort

AIM: We investigated the associations of apolipoprotein C-III (apoCIII) protein and apoCIII gene variation with microvascular disease complications in Type 1 diabetes. METHODS: The serum apoCIII concentration, and both a T(-455)-->C and a SacI gene polymorphisms were determined in 409 patients in the DCCT/EDIC cohort of patients with Type 1 diabetes. Correlations with albumin excretion rate (AER) and the severity of retinopathy were investigated. RESULTS: Higher apoCIII concentrations were associated (P<.0001) with increased triglycerides (r=.78), total (r=.61) and LDL (r=.40) cholesterol, apoAI (r=.26), and apoB (r=.50), AER (r=.08), and the severity of retinopathy (ETDRS score, r=.11), and these relationships persisted after controlling for age, gender, body mass index (BMI), and HbA1c level. The apoCIII concentration was significantly higher in the group of patients with macroalbuminuria (AERs 300 mg/24 h) compared to the groups with microalbuminuria (AER 40-299 mg/24 h; P<.0001) or normoalbuminuria (AER <40 mg/24 h) (P<.0001). The apoCIII concentration also was significantly higher in the group of patients with severe retinopathy (ETDRS 10-23) compared to those with moderate (ETDRS 4-9; P<.02) or mild retinopathy (ETDRS 1-3; P<.0001). Neither the T(-455)-->C polymorphism nor a SacI polymorphism in the 3' UTR were associated with circulating apoCIII concentrations, nor the severity of nephropathy or retinopathy. CONCLUSIONS: Elevated apoCIII levels have been associated with increased macrovascular disease risk. In the DCCT/EDIC cohort of patients, there was an independent positive association of apoCIII level with microvascular complications of Type 1 diabetes.     

Improvement in quality of diabetes control and concentrations of AGE-products in patients with type 1 and insulin-treated type 2 diabetes mellitus studied over a period of 10 years (JEVIN)

Advanced glycation end (AGE)-products, a complex and heterogeneous group of compounds, have been implicated in diabetes-related long-term complications. Up to the present, only few data exist about serum levels of the AGE-proteins N- epsilon -carboxymethyllysine (CML) and pentosidine in selection-free populations of patients with type 1 and insulin-treated type 2 diabetes mellitus. In the present 10-year, population-based trial of patients with insulin-treated diabetes mellitus, serum CML and pentosidine levels were examined in correlation to the patients' quality of diabetes control and the prevalence of diabetes-related long-term complications. Jena's St. Vincent Trial (JEVIN) was started in 1989/1990. At this time, a centralised diabetes care system existed. After the baseline examination of 190 patients (83% of the target population) with insulin-treated diabetes mellitus, follow-up examinations were performed in 1994/1995 and 1999/2000. In 1994/1995, the CML concentration in patients with type 1/type 2 diabetes mellitus was 1096.47+/-405.50/1136.43+/-405.24 ng/ml. In 1999/2000, it was significantly lower (727.49+/-342.91 ng/ml, P=.033/743.76+/-312.47 ng/ml, P<.0001). The same tendency showed the AGE-protein pentosidine (type 1: 1994/1995 203.18+/-118.88 vs. 1999/2000 156.59+/-104.84 pmol/ml [P=.029], type 2: 1994/1995 189.72+/-67.66 vs. 1999/2000 151.54+/-127.73 pmol/ml [P=.020]). Parallel to the decrease in the mean concentration of the AGE-products CML and pentosidine mean HbA1c improved and the prevalence of diabetic long-term complications (retino-, neuro-, and nephropathy) remained comparable 1999/2000-1989/1990. Comparing the data of 1999/2000 with those from 1994/1995, there was not only a substantial improvement in patients' quality of diabetes control but also a decrease in the concentration of AGE-products. In patients with diabetes mellitus, the AGE-products seem to be mainly influenced by the quality of diabetes control. However, the most important parameter reflecting the risk for development and progression of diabetes-related long-term complications seems not to be the AGE-products, but patients' HbA1c.     

Serum concentrations of advanced glycation endproducts are associated with the development of atherosclerosis as well as diabetic microangiopathy in patients with type 2 diabetes

We measured serum concentrations of advanced glycation endproducts (AGEs) in patients with type 2 diabetes, to elucidate the mechanisms underlying the elevated serum concentrations of AGEs and to clarify the relationship between serum AGE concentrations and the development of microangiography and macroangiopathy. Serum AGEs were significantly higher in diabetic patients than in age-matched control subjects (p < 0.0001). In diabetic patients, serum AGEs were positively correlated with HbA1c (r = 0.47, p < 0.0001), urinary albumin excretion (UAE) (r = 0.42, p < 0.0001), diabetes duration (r = 0.31, p = 0.0030), and fasting plasma glucose (r = 0.34, p = 0.0010). Multiple regression analysis disclosed that only the HbA1c and UAE levels independently correlated with serum AGE levels. Serum AGEs in diabetic patients with progressive retinopathy and overt nephropathy were significantly higher than in those with less severe retinopathy and nephropathy. Serum AGEs were significantly higher in the diabetic patients with coronary heart disease (CHD) than in those without CHD. These results suggest that the HbA1c and UAE levels are independent risk factors for increased serum AGE concentrations in type 2 diabetic patients, and that higher serum AGE concentrations are associated with increased severity of diabetic retinopathy and nephropathy. Serum AGE concentrations may be a useful marker not only for the severity of diabetic microangiopathy but also for the development of CHD in patients with type 2 diabetes mellitus. Received: 8 May 2000 / Accepted in revised form: 5 September 2000     

N(carboxymethyl)lysine as a biomarker for microvascular complications in type 2 diabetic patients

AIMS: Hyperglycemia is linked to vascular dysfunction in patients with diabetes mellitus, either directly or through advanced glycation end product (AGE) formation. Experimental evidence has indicated the possible involvement of AGEs in the genesis of vascular complications. We investigated whether serum levels of AGEs and of the glycoxidation compound carboxymethyl-lysine (CML) were increased and correlated with vascular complications in type II diabetes mellitus. METHODS: Serum levels of AGEs and CML-human serum protein (CML-HSP) were measured by a specific immunoassay in 51 men and 26 women aged 58 +/- 6.1 years (mean +/- SD) who had been treated for type II diabetes mellitus for 11 +/- 8 years, and in a non-diabetic control group consisting of 39 men and 21 women aged 55.5 +/- 7.5 years. Patients with macroalbuminuria or abnormal creatinine clearance were excluded from the study. RESULTS: The serum levels of AGEs were significantly increased in patients with type II diabetes compared to controls (P<0.001). Blood levels of CML-HSP were significantly increased in diabetic patients compared to normal subjects [35.3 +/- 27.4 and 9.3 +/- 7.2 (mean +/- SD) pmol/mg of protein, respectively; P<0.0001]. In diabetic patients with retinopathy or microalbuminuria (urinary albumin excretion: UAE > 30 mg/24 h), CML-HSP levels were significantly higher (P<0.02), and even more elevated in patients with both complications. CONCLUSION: In patients with type II diabetes, CML-HSP levels that are at variance with the HbA(1c) index for blood glucose may be a biomarker of glycoxidation, and related to the development of microvascular complications.     

Serum levels of carboxy-terminal propeptide of human type I procollagen are an indicator for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus

The finding that glomerular mesangial cells produce human type I collagen suggests that the serum levels of carboxy-terminal propeptide of human type I procollagen (P1CP) may reflect the severity of diabetic nephropathy. We therefore investigated the relationship between serum P1CP levels and the extent of diabetic complications in 100 patients (46 males and 54 females) with Type 2 diabetes and in 64 healthy subjects. Serum P1CP was determined by radioimmunoassay. In diabetes, we defined P1CP levels less than 142 ng/ml as a normal P1CP group (group A), whereas we defined them as equal to or greater than 142 ng/ml as a high P1CP group (group B). The diabetic patients had significantly elevated serum P1CP levels compared with the controls. The prevalence of hypertension, proliferative diabetic retinopathy or macroalbuminuria was significantly higher in group B than in group A. Serum P1CP levels showed a significant positive correlation with urinary albumin excretion, but not with fasting blood glucose, glycosylated hemoglobin A(1c) or serum osteocalcin. Macroalbuminuric patients showed significantly higher P1CP levels than the normoalbuminuric patients. In patients in the absence of diabetic nephropathy, no significant differences of P1CP levels were found among the severity of diabetic retinopathy. The present results suggest that serum P1CP levels reflect the progression of diabetic nephropathy in patients with Type 2 diabetes.     

Increased urinary levels of CXCL5, CXCL8 and CXCL9 in patients with Type 2 diabetic nephropathy

CXC chemokines are particularly significant for leukocyte infiltration in inflammatory diseases. Recent reports have shown that inflammation is one of potential pathogenic mechanisms for diabetic nephropathy. However, information on inflammation related with CXC chemokines in human Type 2 diabetic nephropathy still remains scarce. We measured urinary and serum levels of three CXC chemokines, CXCL5, CXCL8 and CXCL9, in 45 Type 2 diabetic patients (DM), 42 primary renal disease (PRD) patients and 22 healthy controls by enzyme-linked immunosorbent assay. Urinary levels of CXCL5, CXCL8 and CXCL9 in DM were significantly elevated compared to those in controls (P<.0001, P<.01, P<.001; respectively). They increased consistent with urinary albumin excretion rate (UAER) and correlated with UAER in partial correlation analyses (r=0.41, P<.01; r=0.40, P<.01; r=0.45, P<.01; respectively). Urinary levels of CXCL5 in DM were significantly interrelated to HbA(1c) (r=0.42, P<.01). On the other hand, PRD showed significant increased levels of urinary CXCL8 and CXCL9 compared to controls (P<.001, P<.01; respectively), and so did PRD as UAER increased. However, there were no significant elevations of urinary levels of CXCL5 in PRD in spite of the increased UAER. We found significant associations of UAER in DM with diabetes duration, 1/serum creatinine, urinary CXCL5 (adjusted R(2)=0.67, P<.0001) or CXCL9 (adjusted R(2)=0.69, P<.0001) in a stepwise multiple regression analysis. These results suggest that these three CXC chemokines may be involved in the progression of human Type 2 diabetic nephropathy and that CXCL5 may be of use for telling diabetic nephropathy from primary renal diseases.     

The clinical characteristics of latent autoimmune diabetes in adults and its relation with chronic complications in metabolically poor controlled Turkish patients with Type 2 diabetes mellitus

It has been reported that some patients with Type 2 diabetes mellitus (DM) have latent autoimmune diabetes in adults (LADA) and may show different clinical characteristics than those with Type 2 DM. We aimed to determine the ratio and clinical features of LADA in patients with diagnosed initially as Type 2 DM. We measured glutamic acid decarboxylase antibodies (GADA) in 54 patients, diagnosed clinically with Type 2 DM. Of 54 patients, 17 (31%) were GADA positive. GADA-positive patients had significantly earlier diabetes onset age (P<.001), lower BMI (P<.05), and lower serum C-peptide value (P<.001) than did those who were GADA negative. A higher proportion of the GADA-positive patients were receiving insulin therapy (P<.01). With respect to the duration of DM, familial history of DM, and the levels of blood pressures, fasting plasma glucose, and HbA1c, there was no difference between the two groups. Nephropathy and retinopathy were more frequent in GADA-positive than in GADA-negative patients. The prevalence of neuropathy was comparable between the two groups. GADA was negatively associated with BMI, C-peptide levels, and diabetes-onset age, but positively related to retinopathy, nephropathy, and insulin treatment. This study indicated that the important portion of the patients who were initially diagnosed as Type 2 DM may have LADA. In Type 2 diabetic patients who have lower BMI and diagnosis of diabetes in relatively younger age, the possibility of LADA should be taken into consideration. The higher prevalence of nephropathy and retinopathy in GADA-positive patients also suggests the importance of early diagnosis and strict metabolic control in these patients.     

Elevated serum levels of<Emphasis Type="Italic"> N</Emphasis><Superscript>ε</Superscript>-carboxymethyl-lysine,an advanced glycation end product,are associated with proliferative diabetic retinopathy and macular oedema

Aims/hypothesis Diabetic retinopathy is a frequent microvascular complication. In search of novel risk markers, we analysed the association between serum levels of the major advanced glycation end product N-carboxymethyl-lysine (CML) and prevalence of advanced stages of retinopathy in Type 2 diabetic patients without nephropathy.Methods We carried out a case-control study of Type 2 diabetic patients with and without advanced stages of diabetic retinopathy. Retinopathy and macular oedema were defined according to standard criteria. Serum levels of CML were estimated by means of a novel competition-based ELISA assay.Results Serum levels of CML were significantly different between age-matched controls (n=792; mean value ± SD: 521±134 ng/ml), Type 2 diabetic patients without severe retinopathy (821±141 ng/ml; p<0.0001) and Type 2 diabetic patients with proliferative retinopathy (1182±346 ng/ml; p<0.0001). Levels of CML greater than 1000 ng/ml represented a 25-fold increase in risk of proliferative retinopathy. Receiver operating characteristics analysis revealed a CML threshold of 1087 ng/ml (100% sensitivity, 93% specificity) for clinically significant macular oedema.Conclusions/interpretation High serum levels of CML were associated with advanced stages of retinopathy. Serum levels were shown to be a progressive risk marker, whereby a level of more than 1000 ng/ml induced a 25-fold increase in risk of proliferative retinopathy and clinically significant macular oedema. Our data suggest that serum levels of CML provide a novel risk marker for advanced stages of diabetic retinopathy in Type 2 diabetic patients.Abbreviations CML N-carboxymethyl-lysine - ETDRS Early Treatment Diabetic Retinopathy Study - RAGE receptor for advanced glycation end products - ROC receiver operating characteristics     

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Aims/hypothesis Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes.Methods Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg^–1·day^–1), AVE7688 (45 mg·kg^–1·day^–1) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively.Results ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone-imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone-imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML.Conclusions/interpretation Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes.     

The relation between plasma endothelin-1 levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy in patients with Type 2 diabetes mellitus

We evaluated the possible relation between plasma endothelin-1 (ET-1) levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy, including nephropathy, neuropathy, and retinopathy in patients with Type 2 diabetes and healthy control group. Sixty-eight (39 females and 29 males) patients with Type 2 diabetes and 14 (6 females and 8 males) healthy subjects were included in the study. Plasma ET-1 levels were found to be 10.46+/-1.24 pmol/l in the diabetic group, whereas 7.97+/-0.41 pmol/l in the control group, which was statistically significant (P<.01). We also found elevated plasma ET-1 levels in patients with the least one microvascular complication when compared with the uncomplicated diabetes group (P=.02). Moreover, plasma ET-1 levels of the uncomplicated group was higher than the control group (P<.05). Plasma ET-1 levels were significantly elevated in hypertensive diabetics than normotensive diabetics (t=2.58, P=.012). It was also found to be elevated in diabetic patients with diabetes duration of more than 10 years when compared with patients less than 10 years (P=.02). These findings can be interpreted as the increased damage of microvascular complications in the disease process that may lead to elevated ET-1 levels. Mean plasma ET-1 levels in diabetic patients with a family history of diabetes was found to be higher than patients with no family history of diabetes. Genetical and environmental factors may have an effect on ET-1 level. We also studied the correlations of plasma ET-1 levels on age, sex, fasting blood glucose levels, treatment modalities HbA1c, hyperlipidemia, C-peptide, Body Mass Index, and smoking, but did not find any statistically significant difference. In conclusion, plasma ET-1 levels are well correlated with microangiopathy, hypertension, increased disease duration, and family history of diabetes, but poorly correlated with metabolic control, treatment modalities, age, sex, hyperlipidemia, obesity, and smoking.     

糖代谢终产物与糖尿病肾病尿毒症的相关研究

目的　研究糖代谢终产物 (AGE)水平与糖尿病肾病 (DN)尿毒症的关系 ,探讨 AGE对 DN的影响及其作用机制。方法　将 6 2例糖尿病 (DM)患者分为 DM无肾病组、DN组 (尿毒症透析组和非透析组 ) ,并设 30例体检正常者做对照组 ,采用 EL ISA法进行血清 AGE检测。结果　 DM无肾病组与对照组比较 AGE明显增高(P<0 .0 5 ) ,与血糖呈正相关 ;DN组 AGE明显增高 (P<0 .0 5 ) ,与血糖及血肌酐呈正相关。尿素症透析组与非透析组 AGE无显著性差异 (P>0 .0 5 )。结论　高血糖状态是引起 DM慢性并发症的主要原因 ;且血糖增高程度与并发症发生率直接相关 ;肾功能衰竭时 AGE明显升高 ,对全身器官造成损害。     

Association between serum C-peptide levels and chronic microvascular complications in Korean type 2 diabetic patients

This study evaluated the association between serum C-peptide levels and chronic vascular complications in Korean patients with type 2 diabetes. Data for 1,410 patients with type 2 diabetes were evaluated cross-sectionally. Fasting and postprandial 2-hour serum C-peptide levels were analyzed with respect to diabetic micro- and macrovascular complications. In the group of patients with lower fasting serum C-peptide quartile, the prevalences of diabetic retinopathy and neuropathy were significantly higher (P = 0.035, P < 0.001, respectively). In the group of patients with lower delta C-peptide (postprandial − fasting C-peptide) quartile, the prevalences of diabetic retinopathy, nephropathy, and neuropathy were significantly higher (P < 0.001 for all). Low delta C-peptide quartile was also associated with increased severity of retinopathy and nephropathy. The age- and sex-adjusted odds ratios (ORs) for retinopathy, neuropathy, and nephropathy in the lowest versus the highest delta C-peptide quartile were 6.45 (95% confidence interval 3.41–12.22), 3.01 (2.16–4.19), and 2.65 (1.71–4.12), respectively. After further adjustment for the duration of diabetes, type of antidiabetic therapy, mean hemoglobin A1c, body mass index, and blood pressure, the ORs were reduced to 2.83 (1.32–6.08), 1.68 (1.12–2.53), and 1.61 (1.05–2.47), respectively, but remained significant. No significant difference was observed in the prevalence of macrovascular complications with respect to fasting or delta C-peptide quartiles. These results suggest that low C-peptide level is associated with diabetic microvascular, but not macrovascular complications in patients with type 2 diabetes mellitus.     

Association of plasma fibrinogen level and blood pressure with diabetic retinopathy, and renal complications associated with proliferative diabetic retinopathy, in Type 2 diabetes mellitus.

AIM: To clarify the association of several clinical parameters, including plasma fibrinogen level, with diabetic retinopathy in patients with Type 2 diabetes mellitus (DM). METHODS: A total of 294 Japanese patients with Type 2DM were studied; 53 patients with no diabetic retinopathy (NDR), 90 with background diabetic retinopathy (BDR), and 151 with proliferative diabetic retinopathy (PDR). Multiple logistic regression analysis was performed to assess variables independently associated with diabetic retinopathy in two settings: presence of retinopathy of any severity and presence of advanced retinopathy. RESULTS: The following parameters were identified as independent factors associated with the presence of diabetic retinopathy (NDR vs. BDR + PDR): type of therapy (P<0.0005), log-transformed plasma fibrinogen level (P < 0.05), mean blood pressure (P < 0.05), and duration of diabetes (P < 0.05). The independent variables associated with advanced retinopathy were type of therapy (P<0.00005), age (P<0.0005) and nephropathy (P<0.05). Body mass index, smoking and hypertensive status, HbA1c and total cholesterol levels were not independently associated. CONCLUSIONS: These data suggest that in patients with Type 2 DM, an increased blood viscosity due to high fibrinogen level as well as an elevated intravessel pressure play a role in the development of diabetic retinopathy, and that the progression to PDR is influenced or accompanied by the deterioration of renal status.     

Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with Type 1 diabetes mellitus: relation to glycaemic control and microvascular complications.

AIMS: To evaluate serum levels of vascular endothelial growth factor (VEGF) in a large group of children, adolescents and young adults with Type 1 diabetes mellitus to investigate whether increased VEGF concentrations are associated with long-term glycaemic control and microvascular complications. METHODS: The study involved 196 patients with Type 1 diabetes mellitus (age range 2-24 years, onset of diabetes before the age of 12 years, duration of disease longer than 2 years), without clinical and laboratory signs of microvascular complications; they were divided into three groups (group 1 - n = 37, age < 6 years; group 2 - n = 71, age 6-12 years; group 3 - n = 88, age > 12 years). Fifty-three adolescents and young adults (age 16.1-29.7) with different grades of diabetic retinopathy and microalbuminuria were also selected (group 4). A total of 223 healthy controls were matched for age and sex with each group of patients with diabetes mellitus. RESULTS: VEGF serum levels were significantly increased in pre-school and pre-pubertal children with diabetes as well as in pubertal patients compared to controls. VEGF concentrations were markedly increased in adolescents and young adults with microvascular complications compared with both healthy controls and diabetic patients without retinopathy or nephropathy. Multivariate analysis showed that elevation of VEGF in serum was an independent correlate of complications. One-year mean HbA1c values were significantly correlated with VEGF concentrations (r = 0.372; P < 0.01). Children with HbA1c levels greater than 10% had significantly higher VEGF concentrations when compared with matched patients whose HbA1c levels were lower than 10%. In poorly controlled diabetic children (HbA1c > 10%), long-term (2 years) improvement of glycaemic control (aiming at HbA1c < 7%) resulted in a significant reduction of VEGF levels. CONCLUSIONS: VEGF serum concentrations are increased in prepubertal and pubertal children with diabetes. Glycaemic control influences VEGF serum levels. Severity of microvascular complications is associated with marked increase of VEGF concentrations in the serum of these patients.     

Renal and retinal microangiopathy after 15 years of follow-up study in a sample of Type 1 diabetes mellitus patients

PURPOSE: In the present study, the objective is to determine the epidemiological risk factors in the appearance of diabetic retinopathy and nephropathy in 112 Type 1 diabetic patients after 15 years. METHODS: A 15-year follow-up study was done in a cohort of 112 consecutive Type 1 (IDDM) diabetes mellitus patients without diabetic retinopathy or nephropathy at enrolment in 1990. We studied the incidence of diabetic retinopathy and/or microalbuminuria. The epidemiological risk factors included in the study were gender, diabetes duration, HbA(1c) levels, arterial hypertension, levels of triglycerides and fractions of cholesterol (HDL-cholesterol and LDL-cholesterol). RESULTS: The incidence of diabetic retinopathy was 55.40% at the end of study; the risk factors associated were duration of diabetes mellitus (P<.001), high levels of HbA(1c) (P=.009), presence of arterial hypertension (P=.007) and high levels of LDL-cholesterol (P=.002). The incidence of microalbuminuria was 41.07% and that of overt nephropathy, 19.60%; the risk factors associated were high levels of HbA(1c) (P<.001) and presence of arterial hypertension (P=.023). At the end of study, four groups of patients were formed: patients without microalbuminuria or retinopathy, patients with microalbuminuria only, patients with retinopathy only and patients with retinopathy and microalbuminuria. From the results of the discriminate analysis, we may assume that for the development of retinal lesions only, in the diabetes mellitus, the duration of the disease, the high levels of HbA(1c) and the arterial hypertension are most important, and for the development of renal and retinal lesion simultaneously, the important factor is poor control of glycemia measured by levels of HbA(1c) and arterial hypertension. CONCLUSIONS: In conclusion, microalbuminuria correlated well with severe forms of diabetic retinopathy, and at the end of the study, two groups of patients had been configured: the first group had developed only diabetic retinopathy, and the second, their patients with diabetic retinopathy together with renal lesion (microalbuminuria). For the first group, the duration of diabetes mellitus was the most important risk factor, and for the second group, the levels of HbA(1c) and blood pressure were the most important.     

Increased cholesterylester transfer activity in complicated Type 1 (insulin-dependent) diabetes mellitus — its relationship with serum lipids

Summary In Type 1 (insulin-dependent) diabetes mellitus, macrovascular complications and the increased risk for cardiovascular disease in patients with microvascular complications may be related to alterations in plasma cholesterylester transfer. The activity of cholesterylester transfer protein, which mediates cholesterylester transfer between lipoproteins and lipoprotein lipid levels, was assessed in 7 normolipidaemic control subjects, 7 Type 1 diabetic control subjects without complications, 11 Type 1 diabetic patients with microvascular complications (retinopathy, incipient nephropathy) and in 7 Type 1 diabetic patients with macrovascular atherosclerotic lesions.The cholesterylester transfer activity was 30% higher in the diabetic groups with macrovascular and microvascular lesions than in the 2 control groups. Very low + low density lipoprotein cholesterol was higher in the 3 diabetic groups than in the non-diabetic control group. High density lipoprotein cholesterol was not different. The cholesterylester transfer activity was correlated positively with HbA1, urinary albumin excretion rate, serum cholesterol, very low + low density lipoprotein cholesterol and apolipoprotein B. The high density lipoprotein over very low + low density lipoprotein cholesterylester molar ratio was lower in the diabetic groups with micro- and macrovascular complications. A role for cholesterylester transfer activity in the lipoprotein abnormalities found in complicated Type 1 diabetes is suggested. A high cholesterylester transfer activity might be indicative of mechanisms which promote atherogenesis.     

Prevalence of diabetic complications in fibrocalculous pancreatic diabetic patients and type 2 diabetic patients: a cross-sectional comparative study

OBJECTIVE: To determine the prevalence of diabetes-related complications in subjects with fibrocalculous pancreatic diabetes (FCPD) and compare them with subjects with type 2 diabetes mellitus matched for age, sex, and duration of diabetes. METHODS: The study group comprised of 277 FCPD patients and 277 age, sex, and duration of diabetes-matched type 2 diabetic patients. All the study subjects underwent a detailed clinical examination, and fasting blood samples were obtained for biochemical studies. Peripheral Doppler was used for diagnosis of peripheral vascular disease (PVD). Vibratory perception threshold (VPT) was determined using biothesiometry for diagnosis of neuropathy. Diagnosis of coronary artery disease (CAD) was based on medical history and 12-lead resting ECG. Retinal photographs were used for diagnosis of retinopathy using a modified version of Early Treatment Diabetic Retinopathy Study (ETDRS) grading system. RESULTS: FCPD patients had lower body mass index (BMI) (P<.001), systolic blood pressure (P<.0001), diastolic blood pressure (P<.001), serum cholesterol (P<.001), serum triglyceride (P<.001), and serum creatinine (P<.01) but higher glycosylated hemoglobin (P<.001) levels compared to patients with type 2 diabetes. Prevalence of CAD was significantly higher among type 2 diabetic patients (11.9%) compared to FCPD patients (5.1%), P<.003. There was no significant difference in the prevalence of other diabetic complications between the two study groups (type 2 diabetes vs. FCPD: retinopathy-37.2% vs. 30.1%, PVD-4.3% vs. 4.7%, Neuropathy-25.3% vs. 20.9%, Nephropathy-15.0% vs. 10.1%). Multiple logistic regression analysis revealed the following risk factors for diabetes complications among type 2 diabetic subjects-retinopathy: BMI (P=.028), duration of diabetes (P<.001), and glycosylated hemoglobin (P=.026); nephropathy: diastolic blood pressure (P=.016) and glycosylated hemoglobin (P=.040); neuropathy: age (P<.001), duration of diabetes (P=.003), and glycosylated hemoglobin (P=.001). Among subjects with FCPD, systolic blood pressure (P=.013), glycosylated hemoglobin (P=.021), and duration of diabetes (P<.001) were associated with retinopathy; BMI (P=.057), glycosylated hemoglobin (P=.010), and duration of diabetes (P=.024) with nephropathy and age (P=.011) and BMI (P=.010) with neuropathy. Conclusion: The prevalence of retinopathy, nephropathy, neuropathy, and PVD was similar among FCPD patients and type 2 diabetic patients, but the prevalence of CAD was lower among FCPD patients.     

Differential accumulation of advanced glycation end products in the course of diabetic retinopathy

Aims/hypothesis. Glycated proteins, formed by reaction of glucose and protein, react further yielding numerous, mostly undefined advanced glycation end products (AGE). The recently characterized imidazolone-type AGE (AG-1) is non-oxidatively formed involving 3-deoxyglucosone whereas some AGEs, particularly Nɛ-(carboxymethyl)lysine (CML), are formed only in the presence of oxygen. Methods. To study the possible contribution of oxidative and non-oxidative AGE formation in the development of diabetic retinopathy antibodies directed against CML-type and imidazolone-type AGEs were characterized by dot blot analysis and used to localize these well-characterized epitops in the retinas from diabetic rats (early course) and from human Type I (insulin-dependent) diabetes mellitus with laser-treated proliferative diabetic retinopathy (late course). Results. In non-diabetic rats CML was moderately positive in neuroglial and vascular structures of non-diabetic rat retinas and increased strongly in diabetic retinas. Anti-imidiazolone antibody staining was strongly positive only in diabetic capillaries. Advanced human diabetic retinopathy showed strong CML-immunolabelling of the entire retina whereas control samples showed moderate staining of neuroglial structures only with the polyclonal CML-antibody. Anti-imidiazolone antibody staining was faint in the inner retina of control sections but were strong throughout the entire diabetic retina. Immunolabelling for the AGE-receptor was congruent with a marker of Müller cells. Conclusion/interpretation. Our data indicate that the oxidatively formed CML is present in non-diabetic retinas as a regular constituent but increases in diabetes both in neuroglial and vascular components. Imidazolone-type AGE are restricted to microvessels and spread during later stages over the entire retina, co-localizing with the expression of AGE-receptor. [Diabetologia (1999) 42: 728–736] Received: 22 October 1998 and in revised form: 11 January 1999