Reduced plasma total homocysteine concentrations in Type 1 diabetes mellitus is determined by increased renal clearance.

INTRODUCTION: Elevated plasma levels of total homocysteine are related to the development of vascular complications. Patients with diabetes mellitus are particularly at risk for the development of these complications. Several factors determine plasma total homocysteine including renal function. AIMS: As early Type 1 diabetes is characterized by a relative glomerular hyperfiltration, increased renal clearance could contribute to decreased levels of homocysteine as observed in Type 1 diabetes mellitus. Therefore we investigated the relationship between plasma total homocysteine and the glomerular filtration rate (GFR). METHODS: In 92 Type 1 diabetes patients and 44 control subjects, we measured GFR and effective renal plasma flow (ERPF) by means of continuous infusion of inulin and p-aminohippurate. Fasting plasma total homocysteine was measured using high performance liquid chromatography. RESULTS: GFR (121 +/- 21 resp. 104 +/- 14 ml/min; P < 0.001) and ERPF (563 +/- 127 resp. 516 +/- 121 ml/min; P = 0.05) were significantly higher in Type 1 diabetes patients as compared with control subjects. Plasma total homocysteine was reduced in Type 1 diabetes patients as compared with control subjects (11.0 +/- 4.5 resp. 13.4 +/- 7 micromol/l; P = 0.01). Plasma total homocysteine was strongly correlated with GFR (Type 1 diabetes patients: r = -0.43, P < 0.001; control subjects: r = -0.39, P = 0.01). CONCLUSION: GFR is a major determinant of plasma total homocysteine levels in Type 1 diabetes patients as well as control subjects. The reduced plasma total homocysteine levels in diabetes patients can be explained by an increased GFR.     

Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia

In an ambulatory population of diabetic subjects (Type 1 and Type 2), the urine excretion of the renal osmolyte, glycine betaine, was compared to known markers of glycemic control, renal dysfunction and to the excretion of related betaines, including trigonelline, proline betaine, carnitine and acetyl-carnitine. Of the 85 subjects, 20 patients had urine glycine betaine concentrations above the reference range for normal subjects. Plasma glycine betaine concentrations were within reference ranges for normal subjects. Patients with elevated glycine betaine excretion tended to have lower plasma glycine betaine concentrations, but this did not reach statistical significance. One way analysis of variance found excretion is independent of treatment, duration of diagnosed diabetes, blood pressure and body mass index (BMI). An association between glycine betaine excretion and glycemic control was observed with statistically significant correlations occurring with both plasma glucose (r = 0.43, P < 0.001) and glycated haemoglobin (HbA1c) (r = 0.35, P < 0.005). The excretion of carnitine, acetyl-carnitine and proline betaine were related to glycine betaine excretion (r = 0.49, P < 0.001; r = 0.40, P < 0.001; r = 0.27, P < 0.05, respectively). Urine carnitine and acetyl-carnitine concentrations were also related to plasma glucose concentrations (r = 0.30, P < 0.01). Increased urine retinol binding protein concentrations (RBP), a marker of proximal tubular dysfunction, correlated with elevated urine glycine betaine excretion and plasma HbA1c (r = 0.28, P < 0.01). These results suggest poor glycemic control is associated with the increase in urine glycine betaine, carnitine, acetyl-carnitine and RBP excretion in diabetic patients. However, < 50% of the observed increase in glycine betaine excretion has been accounted for by the variables measured, suggesting other unidentified processes may also be involved.     

Left ventricular dysfunction in hypertensive patients with Type 2 diabetes mellitus.

AIMS: To characterize left ventricular function in hypertensive patients with Type 2 diabetes and normal ejection fraction, and to relate these findings to pathogenic factors and clinical risk markers. METHODS: We examined 70 hypertensive patients with Type 2 diabetes mellitus with ejection fraction > 0.55 and fractional shortening > 0.25, all without any cardiac symptoms. Thirty-five non-diabetic subjects served as control subjects. Left ventricular longitudinal function was examined by tissue Doppler derived myocardial strain rate and peak systolic velocities. RESULTS: Hypertensive patients with diabetes had a significantly higher systolic strain rate (-1.1 +/- 0.3 s(-1) vs. -1.6 +/- 0.3 s(-1), P < 0.001) and lower systolic peak velocities (3.3 +/- 1.0 vs. 5.6 +/- 1.0 cm/s, P < 0.001) compared with control subjects. Myocardial systolic strain rate correlated significantly to left ventricular mass (r = 0.40, P < 0.01) and to both HbA1c (r = 0.43, P < 0.01), and fructosamine (r = 0.40, P < 0.01), but was not related to serum levels of carboxymethyllysine, albuminuria, blood pressure (dipping/non-dipping), or oral hypoglycaemic therapy. Patients with diastolic dysfunction had significantly higher levels of urine albumin [21.0 (5-2500) mg/l, vs. 9.5 (1-360), P < 0.01], heart rate (78 +/- 13 vs. 67 +/- 10 b.p.m., P < 0.005), and seated diastolic blood pressure (85 +/- 6 vs. 81 +/- 7 mmHg, P < 0.05) and non-dipping diastolic blood pressure was more frequent. CONCLUSIONS: Long axis left ventricular systolic function was significantly decreased in hypertensive patients with Type 2 diabetes mellitus, and is associated with hyperglycaemia and left ventricular hypertrophy. Diastolic dysfunction was closely related to increased diastolic blood pressure, non-dipping and increased urinary albumin excretion.     

The relationship between glycated hemoglobin and polymorphonuclear leukocyte leukotriene B4 release in people with diabetes mellitus

In order to evaluate polymorphonuclear leukocyte (PMN) activity in diabetes mellitus, leukotriene B4 (LTB4) levels were measured in sixty patients, 31 affected with Type 1 diabetes mellitus and 29 affected with Type 2 diabetes mellitus. The LTB4 levels (12.1+/-0.2 pg/100 microl) in diabetic patients were higher compared to those of the control group (7.9+/-0.1 pg/100 microl) (P < 0.001), and remained significantly higher (P < 0.001) (12.8+/-0.2 pg/100 microl) than in the control group (11.0+/-0.2 pg/100 microl) after stimulation with calcium ionophore. A significant and positive correlation between glycated hemoglobin and LTB4 was demonstrated (P < 0.001, r = 0.80). This study demonstrates that in diabetic patients there is a PMN activation and that this activation is correlated to glycated hemoglobin level.     

Peripheral blood level alterations of TIMP-1, MMP-2 and MMP-9 in patients with type 1 diabetes.

AIM: To determine the plasma levels of enzymes and inhibitors involved in extracellular matrix turnover in patients with Type 1 diabetes with normal renal function. METHODS: Plasma levels of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in 43 Type 1 diabetic subjects and age- and sex-matched controls. RESULTS: No significant difference in plasma MMP-2 between diabetic patients and controls was observed. MMP-9 was detected in the plasma of 15 diabetic patients (35%), but undetectable in all control subjects (P < 0.015). Plasma TIMP-1 concentrations were significantly elevated (P < 0.001) in diabetic patients compared to controls. There was no correlation observed between MMP-2, MMP-9 and TIMP-1 and similarly between MMP-2, MMP-9 and TIMP-1 and age, duration of diabetes, blood pressure and glycated haemoglobin (HbA1c). CONCLUSIONS: This study has demonstrated alterations in several plasma extracellular matrix modulators in the absence of significant vascular disease.     

Determinants of development of microalbuminuria in normotensive patients with type 1 and type 2 diabetes.

The purpose of this study was to identify the risk factors responsible for the development of microalbuminuria in diabetes. Two cohorts of 340 Type 1 and 258 Type 2 normotensive diabetic subjects were followed up for 24 months to evaluate progression to nephropathy. Sixteen Type 1 (4.7%) and 20 Type 2 (7.7%) patients developed persistent micro- or macroalbuminuria. Retinopathy, levels of glycated haemoglobin and the urinary albumin excretion rate (UAER) were indicative of progression in both cohorts. Cardiovascular disease in Type 1 and systolic blood pressure in Type 2 diabetes were the other risk factors. Logistic regression analysis showed that glycated haemoglobin levels [odds ratio (95% confidence interval) 2.08 (1.34, 3.21), p = 0.0007 in Type 1 and 1.77 (1.27, 2.45), p = 0.0005 in Type 2] and retinopathy [1.95 (1.09, 3.41), p = 0.02 in Type 1 and 2.87 (1.45, 5.69), p = 0.002 in Type 2] were risk factors in both cohorts. Male sex [2.06 (1.05, 4.03), p = 0.03] and the UAER [1.06 (1.001, 1.13), p = 0.04] in Type 1 patients, and systolic blood pressure [1.66 (1.05, 2.52), p = 0.02] in Type 2, were the other predictors. It is concluded that in normotensive Type 1 and Type 2 diabetic subjects glycemic control and retinopathy are the most important contributors to the development of incipient nephropathy.     

Increased serum pigment epithelium derived factor levels in Type 2 diabetes patients

Serum PEDF levels (mean (S.D.)) were increased in 96 Type 2 diabetic vs. 54 non-diabetic subjects; 5.3 (2.8) vs. 3.2 (2.0)mug/ml, p<0.001. In diabetes, PEDF correlated with BMI, serum creatinine and LDL-cholesterol, but not with other lipids, HbA1c or CRP. PEDF did not differ by drugs, complications, or gender.     

Interactive effect of retinopathy and macroalbuminuria on all-cause mortality, cardiovascular and renal end points in Chinese patients with Type 2 diabetes mellitus.

AIMS: To examine the effect of albuminuria and retinopathy on the risk of cardiovascular and renal events, and all-cause mortality in patients with Type 2 diabetes. METHODS: A post-hoc analysis of 4416 Chinese patients without macrovascular complications at baseline (age 57.6 +/- 13.3 years). Glomerular filtration rate (eGFR) was estimated by the abbreviated Modification of Diet in Renal Disease Study Group Formula, further adjusted for Chinese ethnicity. Clinical end points were all-cause mortality, cardiovascular events (heart failure or angina, myocardial infarction, lower limb amputation, re-vascularization procedures and stroke) and renal end points (reduction in eGFR by more than 50% or eGFR < 15 ml/min/1.73 m2 or death as a result of renal causes or need for dialysis). RESULTS: Compared with individuals without complications, subjects with retinopathy and macroalbuminuria had higher rates of cardiovascular events (14.1 vs. 2.4%), renal events (40.0 vs. 0.8%) and death (9.3 vs. 1.7%, P < 0.001). For composite event of death, cardiovascular and renal events, the presence of retinopathy, microalbuminuria alone, macroalbuminuria alone, retinopathy with microalbuminuria or retinopathy with macroalbuminuria increased the risk [hazard ratio (95% CI)] by 1.61 (1.05 to 2.47; P = 0.04), 1.93 (1.38 to 2.69; P < 0.001), 4.34 (3.02 to 6.22; P < 0.001), 2.59 [1.76 to 3.81; P < 0.001) and 6.83 (4.89 to 9.55; P < 0.001) fold, respectively. The relative excess risk as a result of interaction between retinopathy and macroalbuminuria was 15.31, implying biological interaction in the development of renal events. CONCLUSIONS: In Chinese patients with Type 2 diabetes, retinopathy interacts with macroalbuminuria to increase the risk of composite cardio-renal events.     

Cross-sectional associations of C-reactive protein with vascular risk factors and vascular complications in the DCCT/EDIC cohort

OBJECTIVE: To determine the relationships between C-reactive protein (CRP) levels and features of Type 1 diabetes. RESEARCH DESIGN AND METHODS: Serum CRP was measured by nephelometry in a cross-sectional study of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort (n=983) and nondiabetic subjects (n=71). RESULTS: CRP levels [geometric mean (95% CI)] were higher in diabetic than in control subjects, 1.6 (1.5-1.7) vs. 1.2 (1.1-1.5) mg/l, P=.019. CRP was higher in diabetic women (n=438) than in men (n=545) [2.0 (1.8-2.3) vs. 1.3 (1.2-1.5), P<.001]. Diabetic subjects formerly in the DCCT intensive treatment group had higher CRP levels than those who were randomized to the conventional treatment group [1.8 (1.6-1.9), n=479 vs. 1.5 (1.3-1.6), n=456, P=.010], attributable to greater BMI in the prior intensive group. In diabetes, CRP correlated with HbA(1c) (r=0.13, P<.0001) and with insulin resistance traits: BMI (r=0.34, P<.0001), waist-to-hip ratio (WHR; males: r=0.35, P<.0001; females: r=0.22, P<.0001), diastolic blood pressure (r=0.07, P=.025), triglycerides (r=0.19, P<.0001), apoB (r=0.22, P<.0001), LDL particle concentration (r=0.26, P<.0001), and LDL particle size (r=-0.22, P<.0001). CRP was not associated with complications. Significant independent predictors of CRP in diabetes were gender, BMI, WHR, concurrent HbA(1c), and oral contraceptive pill use. CONCLUSIONS: CRP was elevated relative to nondiabetic subjects, and in diabetes was higher in females. Elevated CRP in Type 1 diabetes was associated with poor glycemic control, larger body habitus, and other factors that comprise the insulin resistance syndrome. Nevertheless, CRP levels were not associated with complications. Longitudinal studies are warranted.     

Endothelial dysfunction, ambulatory pulse pressure and albuminuria are associated in Type 2 diabetic subjects.

AIM: Elevated pulse pressure (PP) is associated with microvascular complications in Type 2 diabetic patients. In non-diabetic subjects, elevated PP has been associated with endothelial dysfunction. The relation between endothelial dysfunction and PP in diabetic subjects has not previously been examined. We examined the relation between PP, markers of endothelial activation and albuminuria in Type 2 diabetic patients. METHODS: In 46 Type 2 diabetic patients and 19 non-diabetic subjects, we performed 24-h ambulatory blood pressure (AMBP) monitoring. Urinary albumin excretion rate was measured as three urinary albumin/creatinine ratios. Von Willebrand factor (vWF), fibrinogen, E-selectin and soluble intercellular adhesion molecule 1 (ICAM-1) were measured in plasma. RESULTS: Thirty-four patients had normoalbuminuria (group N) and 12 had micro- or macroalbuminuria (group A). PP levels increased in a stepwise manner from the control group (group C) to group N and group A; night PP 43 +/- 5, 48 +/- 10 and 59 +/- 12 mmHg (groups C, N and A, respectively, P < 0.001). Likewise, plasma levels of vWF, fibrinogen, E-selectin and ICAM-1 increased from group C to group A; e.g. ICAM-1 [median (interquartile range)] 191 (160-217), 213 (189-262) and 316 (260-417) ng/ml, groups C, N and A, respectively, P < 0.001). In diabetic patients, night PP and plasma levels of E-selectin and ICAM-1 correlated (r = 0.38, P < 0.01 and r = 0.37, P = 0.01, night PP with E-selectin and ICAM-1, respectively). CONCLUSION: Increased PP is associated with endothelial activation and albuminuria in Type 2 diabetic patients. Thus, endothelial dysfunction may represent a pathophysiological link between an elevated PP and microvascular complications in these subjects. Prospective studies are needed to further elucidate these associations.     

Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) gene polymorphisms and their relationship to Type 2 diabetes in Asian Indians.

AIMS: The objective of the present investigation was to examine the relationship of three polymorphisms, Thr394Thr, Gly482Ser and +A2962G, of the peroxisome proliferator activated receptor-gamma co-activator-1 alpha (PGC-1alpha) gene with Type 2 diabetes in Asian Indians. METHODS: The study group comprised 515 Type 2 diabetic and 882 normal glucose tolerant subjects chosen from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in southern India. The three polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Haplotype frequencies were estimated using an expectation-maximization (EM) algorithm. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies. RESULTS: The three polymorphisms studied were not in linkage disequilibrium. With respect to the Thr394Thr polymorphism, 20% of the Type 2 diabetic patients (103/515) had the GA genotype compared with 12% of the normal glucose tolerance (NGT) subjects (108/882) (P = 0.0004). The frequency of the A allele was also higher in Type 2 diabetic subjects (0.11) compared with NGT subjects (0.07) (P = 0.002). Regression analysis revealed the odds ratio for Type 2 diabetes for the susceptible genotype (XA) to be 1.683 (95% confidence intervals: 1.264-2.241, P = 0.0004). Age adjusted glycated haemoglobin (P = 0.003), serum cholesterol (P = 0.001) and low-density lipoprotein (LDL) cholesterol (P = 0.001) levels and systolic blood pressure (P = 0.001) were higher in the NGT subjects with the XA genotype compared with GG genotype. There were no differences in genotype or allelic distribution between the Type 2 diabetic and NGT subjects with respect to the Gly482Ser and +A2962G polymorphisms. CONCLUSIONS: The A allele of Thr394Thr (G --> A) polymorphism of the PGC-1 gene is associated with Type 2 diabetes in Asian Indian subjects and the XA genotype confers 1.6 times higher risk for Type 2 diabetes compared with the GG genotype in this population.     

Increased plasma glycated low-density lipoprotein concentrations in diabetes: a marker of atherogenic risk

Nonenzymatic glycation of apolipoprotein B in the low-density lipoprotein (LDL) complex has been considered a proatherogenic modification contributory to the increased susceptibility of patients with diabetes to atherosclerosis. We postulated that glycated LDL concentrations might be associated with other markers of cardiovascular disease. To explore this hypothesis, we measured glycated LDL concentrations by a monospecific immunoassay in 50 patients with type 1 and 100 patients with type 2 diabetes and examined relationships with the amount of albumin excretion and the serum cholesterol and triglyercide concentrations. Plasma glycated LDL showed a significant positive correlation (r = 0.325; P < 0.001) with urinary albumin excretion that was higher in type 1 (r = 0.463) than in type 2 (r = 0.245) patients. The mean glycated LDL concentration progressively increased with increasing albumin excretion when patients were subcategorized into groups of normoalbuminuria, low (相似文献   

Leukocyte count and vascular function in Type 2 diabetic subjects with treated hypertension

BACKGROUND: Traditional cardiovascular risk factors may only partially explain abnormal vascular function in Type 2 diabetic patients. This study examined the associations between vascular function and markers of inflammation in Type 2 diabetic subjects with treated hypertension. METHODS: Flow-mediated dilatation (FMD) and glyceryl-trinitrate mediated dilatation (GTNMD) of the brachial artery were used to assess endothelium-dependent and -independent function, respectively, in 29 hypertensive Type 2 diabetic subjects (HbA1c <9%), and 17 healthy control subjects. Plasma C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and leukocyte count were used as markers of inflammation. Soluble L-selectin, P-selectin, and von Willebrand factor (vWf) were measured to assess leukocyte, platelet and endothelial cell activation, respectively. RESULTS: Compared with controls, diabetic subjects had impaired FMD (3.9+/-3.0 vs. 5.5+/-2.4%, P=0.07) and GTNMD (11.4+/-4.8% vs. 15.4+/-7.1%, P=0.04). They also had higher levels of CRP (2.7+/-2.6 vs. 1.4+/-1.1 mg/l, P=0.03), fibrinogen (3.4+/-0.7 vs. 2.7+/-0.3 g/l, P<0.001) and TNF-alpha (20.9+/-13.4 vs. 2.5+/-1.7 pg/l, P<0.001). In diabetic subjects, after adjustment for age and gender, leukocyte count was an independent predictor of FMD (P=0.02), accounting for 17% of total variance. Similarly, leukocyte count (P<0.001) accounted for 23% and IL-6 (P=0.03) for 12% of the variance in GTNMD. vWf was correlated with leukocyte count (r=0.38, P=0.04), FMD (r=-0.35, P=0.06) and GTNMD (r=-0.47, P=0.009), whilst P-selectin correlated with fibrinogen (r=0.58, P=0.001). CONCLUSION: These cross-sectional observations are consistent with the hypothesis that reduced FMD and GTNMD in Type 2 diabetes is at least in part secondary to increased inflammation, with associated endothelial and platelet activation.     

Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy

CONTEXT: Pigment epithelium-derived factor (PEDF) is a strong inhibitor of angiogenesis. Eyes with diabetic retinopathy have low levels of ocular PEDF; however, the PEDF levels in the blood of diabetics have still not been determined. OBJECTIVES: Our objective was to determine the plasma levels of PEDF in diabetic patients and to determine the relationship with the stage of the diabetic retinopathy. DESIGN AND SETTING: This study was designed as a cross-sectional, institutional study. PATIENTS OR OTHER PARTICIPANTS: A total of 145 Japanese were studied; 112 had type 2 diabetes mellitus, and 33 were healthy controls. INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: The plasma level of PEDF was measured by ELISA, and the stage of diabetic retinopathy was determined by ophthalmic examinations. Clinical systemic status of diabetic patients was also examined. RESULTS: The plasma PEDF level in diabetic patients (6.68 +/- 0.54 microg/ml; mean +/- sem) was significantly higher than that in controls (4.38 +/- 0.59 microg/ml, P = 0.03), and the level was especially high in patients with proliferative diabetic retinopathy (7.78 +/- 0.98 microg/ml; n = 45; P = 0.005). The gender (P = 0.03), blood urea nitrogen (P = 0.005), and triglycerides (P = 0.04) were significant and independent determinants of plasma PEDF levels in diabetic patients. CONCLUSIONS: The PEDF level in the plasma was significantly elevated in diabetic patients, especially those with proliferative diabetic retinopathy. High levels of PEDF in the plasma may be related to the progression of diabetic retinopathy.     

NT-proBNP in normoalbuminuric patients with Type 2 diabetes mellitus.

OBJECTIVE: To examine levels of NT-proBNP and its relation to hypertension, as well as diastolic function in normoalbuminuric patients with Type 2 diabetes. RESEARCH DESIGN AND METHODS: The study comprised 60 Type 2 diabetic patients without albuminuria. Thirty patients were normotensive and 30 had hypertension. Exclusion criteria were cardiac symptoms and an ejection fraction < 55%. Thirty age- and sex-matched normal subjects served as controls. Diastolic dysfunction was assessed with echocardiography, by means of mitral inflow and colour M-Mode flow propagation recordings. RESULTS: Overall NT-proBNP was significantly elevated in the Type 2 diabetes group, compared with the controls [54.5 pg/ml (5-162) vs. 32.7 pg/ml (5-74.3) P = 0.02]. NT-proBNP was significantly higher among hypertensive patients compared with both normotensive patients and controls but no difference was found between the normotensive patients and the controls [58.0 pg/ml (8.5-162), P < 0.05 vs. 50.8 pg/ml (5-131) P = 0.4]. Patients with concentric and eccentric hypertrophy had significantly higher NT-proBNP levels compared with the control group [81.0 pg/ml (5-147), P < 0.001 and 66.8 pg/ml (42-128), P < 0.001], whereas patients with left ventricular remodelling (enlarged relative wall diameter but normal left ventricular mass) were comparable with the control group [42.3 pg/ml (8.3-142) P = 0.55]. Patients with left atrial enlargement also had incremental NT-proBNP values. NT-proBNP was only moderately correlated to age (r = 0.33, P < 0.05) and left ventricular diastolic diameter (r = 0.41, P < 0.05), but unrelated to diastolic function. CONCLUSIONS: NT-proBNP is significantly increased in hypertensive, normoalbuminuric patients with Type 2 diabetes. These findings were related to left ventricular hypertrophy and increased left atrial and ventricular diameters.     

A novel advanced glycation index and its association with diabetes and microangiopathy

Formation of advanced glycation end products (AGEs) is an important mechanism by which chronic exposure to high glucose levels leads to vascular complications. Measurement of AGEs is hence of great importance for clinicians and researchers concerned with the management and prevention of diabetic vascular disease. The aim of this study was to evaluate a simple methodology to detect AGEs in the serum and to correlate their levels with diabetes and microangiopathy, specifically retinopathy and nephropathy. We studied 157 subjects, which included nondiabetic control subjects (n = 38), type 2 diabetic patients without microangiopathy (n = 65), and type 2 diabetic subjects with retinopathy (n = 29) or both retinopathy and nephropathy (n = 25). All subjects were assessed for their glycemic and lipid status. Serum AGEs were monitored by recording the Maillard-specific fluorescence that resulted from sequential addition of serum into the buffer. The resultant linear regression was modeled to yield the slope values that were termed advanced glycation index (AGI) in arbitrary units. The serum levels of AGI (mean +/- SD) were higher in diabetic subjects without complications (6.0 +/- 1.6 units) compared with nondiabetic subjects (4.6 +/- 1.0 units), still higher among diabetic subjects with retinopathy (7.6 +/- 1.2 units) and highest in diabetic subjects with both retinopathy and nephropathy (8.3 +/- 2.0 units). Among diabetic subjects, AGI had a significant positive correlation with duration of diabetes (r = 0.25, P = .006), glycated hemoglobin (r = 0.27, P = .004), cholesterol (r = 0.24, P = .009), triglycerides (r = 0.23, P = .014), and serum creatinine (r = 0.30, P = .001), and a significant negative correlation with creatinine clearance (r = -0.27, P = .003). Logistic regression analysis using diabetic microangiopathy as the dependent variable showed an association with AGI even after including age, duration of diabetes, and glycated hemoglobin (P < .001) into the model. Advanced glycation index is a simple method to detect AGEs, and it correlates well with diabetes, particularly with microangiopathy.     

Increased plasma markers of inflammation and endothelial dysfunction and their association with microvascular complications in Type 1 diabetic patients without clinically manifest macroangiopathy.

AIMS: To evaluate whether plasma biomarkers of inflammation and endothelial dysfunction differed in Type 1 diabetic patients as compared with those in non-diabetic subjects, and to examine the association of these biomarkers with early stages of microvascular complications. METHODS: Plasma biomarkers of inflammation [fibrinogen, hs-C-reactive protein (hs-CRP)] and endothelial dysfunction [von Willebrand factor (v-WF), intercellular adhesion molecule-1, plasminogen activator inhibitor-1 (PAI-1) activity] were measured in 88 non-smoking young patients with Type 1 diabetes without clinical macrovascular disease and in 40 healthy controls. RESULTS: Plasma levels of hs-CRP, fibrinogen, v-WF, soluble intracellular adhesion molecule-1 (sICAM-1) and PAI-1 activity were markedly higher (P < 0.01 or less) in Type 1 diabetic patients than in healthy controls; these results were essentially unchanged when healthy controls were compared with patients without complications. After stratification by microvascular complication status, plasma biomarkers of inflammation and endothelial dysfunction were significantly increased in those with more advanced disease compared with those with early complications or without complications, respectively. However, while the significant differences in these biomarkers were little affected by adjustment for sex, age, BMI and blood pressure values, they were totally abolished after additional adjustment for diabetes duration and glycaemic control. CONCLUSIONS: These results indicate that in Type 1 diabetes there is a subclinical, chronic inflammation which is, at least partly, independent of clinically manifest macro- and microvascular complications, smoking or other traditional cardiovascular risk factors; this subclinical inflammation is closely correlated to the magnitude and duration of hyperglycaemia.     

Risk factors for development of impaired renal function in Type 2 diabetes mellitus patients in primary care.

AIMS: To evaluate risk factors for the development of an impaired renal function, defined as a glomerular filtration rate (GFR) by Cockcroft-Gault formula < 50.5 ml/min, in primary care patients with Type 2 diabetes mellitus. METHODS: A case-control study of Type 2 diabetes mellitus patients with impaired renal function and age, sex and practice matched controls with Type 2 diabetes mellitus without impaired renal function in 10 Dutch family practices performing the Nijmegen Monitoring Project. Main outcome measure was the independent risk factors of impaired renal function. RESULTS: Eighty-seven individuals with impaired renal function were identified. The point prevalence of impaired renal function in the sample population on 31 March 2001 was 87/873 (10.0%; 95% confidence interval 7.0-15.1%). Of 87 cases, 23 (26.5%; 17.3-30.9%) were found to have impaired renal function at diagnosis. Conditional multiple logistic regression analysis revealed the following independent risk factors for the development of impaired renal function: duration of diabetes > or = 8 years (adjusted odds ratio 5.6 (2.5-12.5); P < 0.001), glomerular filtration rate by Cockcroft-Gault formula 50.5-80.5 ml/min at diagnosis [3.5 (1.5-8.1); P < 0.01] and existing macrovascular complications at diagnosis [2.6 (1.1-6.3); P < 0.01]. CONCLUSION: Duration of diabetes > or = 8 years, mild renal impairment at the time of diagnosis and existing macrovascular complications at the time of diagnosis are independent risk factors for the development of impaired renal function in white patients with Type 2 diabetes mellitus.     

Clinically apparent atherosclerotic disease in diabetes is associated with an increase in platelet microparticle levels.

BACKGROUND: The commonest cause of mortality in patients with Type 2 diabetes is atherothrombosis, which can be related to abnormalities in the coagulation and fibrinolytic pathways, as well as in platelet function. Platelet microparticles (PMPs) may contribute to the prothrombotic state and may promote the progression of atherosclerosis. We hypothesized that PMPs are elevated in Type 2 diabetes and that patients with Type 2 diabetes and clinically apparent atherosclerosis would have the highest levels. Similarly, we hypothesized that soluble plasma P-selectin (sPsel) and CD40L (both molecules which are released by activated platelets), as well as %CD62P (P-selectin) and %CD63 positivity on platelets quantified by flow cytometry, would be highest in patients with Type 2 diabetes and clinically apparent atherosclerotic disease, and might be correlated to PMP levels. METHODS: Venous blood was obtained from 21 Type 2 diabetic patients without atherosclerotic complications, 18 diabetic patients with clinically apparent atherosclerotic disease and 21 non-diabetic control subjects. PMPs, as well as %CD62P and %CD63 positivity on platelets, were quantified by flow cytometry. sPsel and CD40L were measured using ELISA. RESULTS: Patients with Type 2 diabetes and clinically apparent atherosclerotic disease had the highest PMP (P=0.045) and sPsel (P=0.046) levels, compared with patients without complications (who had intermediate PMP levels) and control subjects. Control subjects had the lowest CD40L levels (P<0.001) when compared with patients with Type 2 diabetes, with no difference in sCD40L levels between the two diabetic subgroups. %CD62P and %CD63 positivity did not differ between the groups. PMP levels correlated with %CD62P positivity (P=0.026) but not to %CD63 positivity (P=0.089), sCD40L (P=0.407) or sP-sel (P=0.163); sCD40L levels did not correlate with any other marker of platelet activation. CONCLUSION: PMPs are elevated in Type 2 diabetes. In addition, patients with clinically apparent atherosclerosis had the highest levels of PMPs and sPsel. Thus, PMPs may be a marker of symptomatic atherosclerotic vascular disease in Type 2 diabetes, and may both represent a useful risk stratification tool as well as a novel therapeutic target for anti-thrombotic drugs.     

Serum adiponectin and leptin levels in patients with lipodystrophies

Lipodystrophies are characterized by selective but variable loss of body fat and metabolic complications of insulin resistance. We hypothesized that reduced synthesis and secretion of adipocyte-specific proteins may be related to the metabolic complications of lipodystrophy. Therefore, we compared fasting serum concentrations of adiponectin and leptin, in 18 patients with congenital generalized lipodystrophy (CGL), 11 with acquired generalized lipodystrophy (AGL), 46 with familial partial lipodystrophy-Dunnigan variety (FPLD) and 18 with acquired partial lipodystrophy (APL) and studied their relationship to metabolic parameters. Patients with CGL and AGL had markedly reduced serum adiponectin levels compared to those with FPLD and APL (median [range]: 1.5 [0.4-7.5], 3.2 [0.6-7.7], 6.9 [1.9-23.2] and 7.9 [3.1-13.3] microg/mL, respectively, p < 0.0001); the same trend was noted for serum leptin levels (0.63 [0.05-3.7], 2.18 [0.05-11.30], 2.86 [0.23-9.00] and 6.24 [1.21-10.4] ng/mL, respectively, p < 0.0001). Serum adiponectin levels correlated negatively with fasting serum triglycerides (r = -0.6, p < 0.001) and insulin levels (r = -0.5, p < 0.0001) and positively with serum high-density lipoprotein cholesterol levels (r = 0.5, p < 0.001). Serum adiponectin levels were lower in patients with diabetes compared to non-diabetic subjects (3.0 vs. 7.1 microg/mL, p < 0.001). Our results indicate that serum adiponectin and leptin levels are extremely low in patients with generalized lipodystrophies and may be related to severe insulin resistance and its metabolic complications in lipodystrophies.