Atrial fibrillation is associated with increased mean platelet volume in patients with type 2 diabetes mellitus

Platelet abnormalities in diabetes mellitus (DM) and atrial fibrillation (AF) may underline the etiology of a prothrombotic state in these conditions. Increased mean platelet volume (MPV) is a marker of abnormal platelet function and activation. We aimed to investigate the possible association of chronic AF with MPV in patients who have type 2 DM. Patients who had type 2 DM with either chronic (≥6 months) AF or normal sinus rhythm (NSR) were included in the study. A total of 162 patients (aged 38–89 years) were divided into 2 groups according to the presence of either AF or NSR. Group 1 consisted of 81 diabetic patients with AF, and group 2 consisted of 81 diabetic patients with NSR. The two groups were not significantly different in terms of age, and gender, as well as in hypertension, smoking, history of coronary artery disease, previous cerebrovascular accidents, microalbuminuria, retinopathy, duration of DM, body mass index, hemoglobin A_1c, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride (p?>?0.05 for all variables). Although no significant difference was present between groups concerning platelet count; for patients with AF, MPV was higher compared with patients with NSR (9.0?±?0.2?fl vs. 8.4?±?0.2?fl; p?=?0.001). Furthermore, no significant difference was noted between groups regarding routine medications received by patients. In multivariate logistic regression analysis, MPV was the only variable independently related to AF (OR?=?2.659; 95% CI, 1.286–5.498; p?=?0.008). Consequently, it is concluded that AF is associated with increased MPV in patients with type 2 DM, suggesting the presence of tentatively related processes leading to reciprocal interaction.     

Poor glycemic control and decreased renal function are associated with increased intrarenal RAS activity in Type 2 diabetes mellitus

Aims

The renin–angiotensin system (RAS) plays an important role in the pathogenesis of diabetic nephropathy. The aim of the present study was to investigate intrarenal RAS activity in patients with type 2 diabetes (T2DM).

Methods

We measured urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, in 14 controls without T2DM, 25 T2DM patients without nephropathy, 11 chronic kidney disease (CKD) patients without T2DM and 46 CKD patients with T2DM. Associations between urinary angiotensinogen and clinical parameters were examined.

Results

Compared with the controls, urinary [angiotensinogen:creatinine] were significantly higher in T2DM patients without nephropathy (4.70 ± 2.22 vs. 8.31 ± 5.27 μg/g, p = 0.037). Age, hemoglobin A1c (HbA1c) and fasting plasma glucose correlated significantly and positively with the log{urinary [angiotensinogen:creatinine]} (r = 0.632, p = 0.007; r = 0.405, p = 0.027; r = 0.583, p = 0.003, respectively) in T2DM patients without nephropathy. In contrast, the urinary [angiotensinogen:creatinine] were not significantly different between CKD patients with and without T2DM (22.7 ± 27.8 vs. 33.5 ± 40.8 μg/g, p = 0.740); although they were significantly higher when compared with non-CKD patients. In the CKD patients with T2DM systolic blood pressure, serum creatinine, estimated glomerular filtration rate and urinary [albumin:creatinine] correlated significantly with the log{urinary [angiotensinogen:creatinine]} (r = 0.412, p = 0.004; r = 0.308, p = 0.037; r = −0.382, p = 0.001; r = 0.648, p < 0.001, p < 0.001, respectively).

Conclusions

Our findings indicate that poor glycemic control is significantly associated with intrarenal RAS activity in T2DM patients without nephropathy, and that decreased renal function is significantly associated with intrarenal RAS activity in CKD patients with T2DM.     

Segmental Tubular Sodium Reabsorption in Type 1 Diabetes

Segmental tubular sodium reabsorption in Type 1 (insulin-dependent) diabetes was measured in 36 patients in a cross-sectional study including one group (n = 13) without significant albuminuria (UalbV < 30 mg 24 h^?1), one group (n = 16) with albuminuria in the range from 30 to 300 mg 24 h^?1, and a group (n = 7) with nephropathy (UalbV > 300 mg 24 h^?1). Lithium clearance was used to measure end proximal delivery. From end proximal delivery, ⁵¹Cr-EDTA clearance (GFR) and sodium clearance, segmental tubular reabsorption was calculated. For all patients, GFR was directly correlated with end proximal delivery (r = 0.62, p<0.0005), while end proximal delivery was inversely correlated to fractional proximal reabsorption (r = ?0.71, p<0.0005). In the subgroup with UalbV less than 30 mg 24 h^?1, the direct correlation between GFR and end proximal delivery was also significant (r = 0.77, p<0.05). In the group with nephropathy (UalbV > 300 mg 24 h^?1), mean GFR and end proximal delivery were decreased and fractional proximal reabsorption was increased, but there was still a positive correlation between GFR and end proximal delivery (r = 0.75, p<0.05) and an inverse correlation between end proximal delivery and fractional proximal reabsorption (r = ?0.85, p<0.05). It is concluded that in these groups of diabetic patients the end proximal delivery is increased while GFR is increased. This finding is an argument against a recent hypothesis explaining intraglomerular hypertension, as well as increased glomerular filtration rate in some patients, as secondary to decreased end proximal delivery and reduced tubuloglomerular feedback activity. Nevertheless, the tubuloglomerular feedback activity may be reduced in Type 1 diabetes due to constant extracellular volume expansion.     

Urinary kallikrein excretion in Type 1 (insulin-dependent) diabetes mellitus

Summary Kidney haemodynamics appear to change after the early phases of diabetic nephropathy: increases in glomerular filtration rate and in renal plasma flow have been widely reported, while kidney size is increased. As the renal kallikrein-kinin system has been demonstrated to regulate kidney blood circulation, we have evaluated the excretion of urinary kallikrein in 87 Type 1 (insulin-dependent) diabetic patients with and without hyperfiltration. Urinary kallikrein excretion was measured in 24-h urine collections. The esterolytic activity was determined by fluorimetric assay. The excretion of urinary kallikreins was significantly higher in hyperfiltering patients (472±125 esterase units/24 h) than in normofiltering (168±77 esterase units/24 h) and control subjects (151±39 esterase units/24 h), p<0.001. Furthermore, we observed a positive correlation between urinary kallikrein excretion and glomerular filtration rate (r=0.785). These data suggest that variations of kallikrein and kinin concentrations may play a role in the alteration of renal haemodynamics in Type 1 diabetes. It is possible that the kinin-kallikrein system, the renin-angiotensin system and the prostaglandins may interact to determine the haemodynamic alterations which are present in the diabetic disease.     

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.     

Exercise-induced platelet and leucocyte activation is not enhanced in well-controlled Type 1 diabetes,despite increased activity at rest

Aims/hypothesis Stress can evoke a prothrombotic state with activated platelets and leucocytes, and increased platelet activation at rest has been reported for diabetic subjects. Thus, prothrombotic responses to stress may be enhanced in diabetes mellitus. We therefore evaluated platelet and leucocyte responses to exercise in Type 1 diabetic patients.Methods Type 1 diabetes mellitus patients with good metabolic control and healthy subjects matched for age and body mass index (n=15 for both) performed a maximal exercise test. Platelet and leucocyte activation and their heterotypic aggregation were monitored by whole blood flow cytometry.Results Diabetic platelets did not show higher basal levels of P-selectin expression, but were more reactive to ADP and thrombin stimulation. Diabetic patients had increased lymphocyte and monocyte CD11b expression, and increased circulating platelet–monocyte aggregates. Exercise evoked thrombocytosis, increased circulating platelet P-selectin expression, enhanced platelet sensitivity to ADP and thrombin, and elevated plasma levels of soluble P-selectin to a similar degree in diabetic patients and healthy subjects. Exercise induced marked leucocytosis and elevated plasma elastase, but only slightly increased leucocyte CD11b expression and leucocyte reactivity to stimulation by N-formyl-methionyl-leucyl-phenylalanine. In all of these there was no difference between diabetic patients and healthy subjects. The numbers, but not percentages of circulating platelet–leucocyte aggregates were markedly increased by exercise, but the increase was less prominent among diabetic patients.Conclusions/interpretation Strenuous exercise evokes platelet and leucocyte activation in Type 1 diabetic patients and healthy subjects. Platelet and monocyte hyperactivity were found at rest, but responses to stress were not augmented in metabolically well-controlled Type 1 diabetes mellitus patients.Abbreviations FITC fluorescein isothiocyanate - fMLP N-formyl-methionyl-leucyl-phenylalanine - MAb monoclonal antibody - PLA platelet–leucocyte aggregate - P-Lym platelet–lymphocyte aggregate - P-Mon platelet–monocyte aggregate - P-Neu platelet–neutrophil aggregate - RPE R-phycoerythrin     

A high weight gain early in life is associated with an increased risk of Type 1 (insulin-dependent) diabetes mellitus

Summary Growth during the first years of life in relation to type of feeding in infancy was retrospectively studied in an unselected population-based group of 297 children who had been diagnosed with Type 1 (insulin-dependent) diabetes mellitus before the age of 15 years (probands) and 792 individually-matched referent subjects. Reliable data were collected from child welfare clinics. Probands weighed slightly less at birth but their weight gain at 6, 9, 18 and 30 months of age was significantly greater (p<0.02) than that of referent children. The weight gain of children who had never been breast-fed was more marked than that of breast-fed children; this was found for both probands and referent children. But also among exclusively breast-fed children (> 2 months), probands gained significantly more in weight from birth up to 18 and 30 months of age than exclusively breast-fed referent children. Early weight gain appears to be a risk factor for development of Type 1 diabetes. The lower weight gain in breast-fed compared to non-breast-fed children may explain the protective effect of breast feeding against Type 1 diabetes observed in several studies.     

Factors associated with clinic non-attendance in adults with Type 1 diabetes mellitus

In order to examine the causes of non-attendance in a diabetic clinic, a 1-year retrospective casenote review of 259 diabetic patients with no evidence of major complications was undertaken. Frequency of clinic attendance, clinic non-attendance, and glycaemic control (HbA_1c) were recorded. In a sub-sample of 82 patients, more detailed demographic data was obtained via questionnaire. During the previous year 39 % of patients had failed to attend the clinic on at least one occasion and 10 % were recurrent non-attenders. Non-attenders had a significantly higher mean HbA_1c compared with those who did attend (8.1 ± 2.2 vs 7.6 ± 1.6 %; p = 0.03). They were also significantly younger (mean age 27 ± 7 vs 29 ± 9 yrs; p = 0.02) and had a significantly shorter duration of diabetes (12 ± 8 vs 15 ± 10 yrs; p = 0.02). Attendance did not differ according to gender or age of onset of diabetes. Sub-sample analysis showed that smokers, those with children at home, and single parents were all more likely to default from their appointments. Non-attendance is a significant problem at our diabetic clinic, however, by addressing the reasons why patients fail to attend clinic we hope to develop strategies to encourage regular attendance. This may be translated into improved glycaemic control and ultimately reduce the risk of late diabetic complications. © 1998 John Wiley & Sons, Ltd.     

Low bone mineral density is associated to poor glycemic control and increased OPG expression in children and adolescents with type 1 diabetes

Aims

To investigate early alterations on bone mineral density (BMD) and RANK, RANKL and OPG mRNA expression in peripheral blood leukocytes (PBL) in children and adolescents with type 1 diabetes (T1D) and the relationship with glycemic control and bone biomarkers.

Methods

This cross-sectional study included 75 children and adolescents with T1D and 100 individuals without diabetes (normoglycemic–NG) aged 6–20 years old. T1D individuals were considered to have good (T1DG) or poor (T1DP) glycemic control according to the values of HbA1c. Phosphorus, magnesium, total and ionized calcium, osteocalcin, alkaline phosphatase and tartaric-resistant acid phosphatase (TRAP) values were determined in blood samples. BMD was measured by DEXA. RANK, RANKL and OPG mRNA expression was measured in PBL by real-time PCR.

Results

Osteocalcin values were decreased in diabetic groups in comparison to NG group (p < 0.05), and a negative correlation with both serum glucose (r = −0.265, p < 0.01) and Hb1Ac (r = −0.252, p < 0.01) in T1D group was found. BMD was lower in diabetic groups in comparison with NG group (p < 0.05) and a negative correlation was observed between BMD and both serum glucose (r = −0.357, p < 0.01) and HbA1c (r = −0.351, p < 0.01) in T1D group. OPG mRNA expression was significantly increased in T1D and T1DP groups in comparison with NG group (p < 0.05). In conclusion, children and adolescents with early onset T1D presented low bone mineral density associated to unsatisfactory glycemic control, increased OPG mRNA expression and low osteocalcin concentration.     

Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation

Aims/hypothesis Platelet activation, endothelial dysfunction and inflammation may be involved in early stages of diabetic microangiopathy. We therefore investigated patients with Type 1 diabetes mellitus, without (n=19) and with (n=20) microangiopathy, matched for glycaemic control and duration of disease, and matched with healthy control subjects (n=27).Methods Platelet activation was measured as platelet P-selectin expression using whole blood flow cytometry and as soluble P-selectin by immunoassay. Von Willebrand factor antigen in plasma, serum soluble E-selectin, CD40 ligand (sCD40L) and C-reactive protein (CRP) served as markers for endothelial function and inflammation.Results Thrombin-induced platelet P-selectin expression was enhanced, and soluble P-selectin and sCD40L concentrations were increased in patients with microangiopathy compared with the control subjects (p<0.01 for both) and with patients without microangiopathy (p<0.05 for P-selectin expression and sP-selectin), whereas all three parameters were similar in patients without microangiopathy and in the control subjects. CRP and soluble E-selectin were increased in patients with microangiopathy, compared with the control subjects (p<0.01 and p<0.05), whereas von Willebrand factor did not differ between the groups.Conclusions/interpretation Microangiopathy in Type 1 diabetes is associated with platelet hyperactivity, endothelial dysfunction and low-grade inflammation, indicating an increased risk for cardiovascular disease.Abbreviations sP-selectin Soluble P-selectin - sCD40L soluble CD40 Ligand - CRP C-reactive protein     

2型糖尿病患者大血管病变与活化血小板的相关性研究

目的探讨2型糖尿病患者活化血小板与大血管病变的关系。方法将江苏省苏北人民医院2002-05~2004-11收治的98例2型糖尿病患者,按有无大血管病变分为大血管病变组50例、单纯糖尿病组48例;另设50名正常人为对照组。采用流式细胞仪检测活化血小板标记物血小板膜糖蛋白(PAC-1、CD62P)的表达以及糖化血红蛋白(HbA1c)、C反应蛋白(CRP)、空腹血糖(FBG)、空腹C肽值(C-P)、甘油三酯(TG)、胆固醇(TC)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)等,做相关性分析。结果单纯2型糖尿病患者活化血小板标志物的阳性表达率比正常对照组明显升高(P<0·05),大血管病变组活化血小板标志物的阳性表达率比单纯2型糖尿病组升高更明显(P<0·01)。相关分析中,活化血小板的阳性表达率与LDL-C呈明显正相关。结论活化血小板标志物的阳性表达率与2型糖尿病大血管病变发生呈明显相关,LDL-C水平的增高是导致动脉粥样硬化的独立危险因素。     

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.     

胰高血糖素与2型糖尿病及其肾病的关系

胰高血糖素是调控糖代谢平衡的重要激素之一,血清胰高血糖素的异常升高与2型糖尿病的起始和进展相关.糖尿病肾病是糖尿病常见的微血管并发症之一,胰高血糖素及其受体信号系统可能在它的发生、发展中发挥重要作用.其可能机制是通过cAMP、一氧化氮和前列腺素等诱导肾小球高滤过,通过增加DNA和蛋白质的合成诱导系膜细胞的增生、肥大,并可与肾素-血管紧张素系统(RAS)相互作用,最终引起肾小球损伤.胰高血糖素及其受体可作为治疗2型糖尿病及其肾脏并发症的靶点.     

Factors Related to the Electric Taste Threshold in Type 1 Diabetic Patients

To specify the factors related to taste function in Type 1 diabetes mellitus, 50 diabetic out-patients and 50 control subjects paired for age and sex were screened for taste disorders. None of them consumed significant amounts of alcohol, smoked, or had disease or took drugs capable of altering taste. Taste was studied with electrogustometry, retinopathy was detected by fluorescein angiography, nephropathy by measurement of albuminuria and microalbuminuria, peripheral neuropathy by electroneurography and electromyography, and autonomic neuropathy by cardiovascular function tests. The electrogustometric threshold was, on average, significantly higher in the diabetic group (133 ± 30 μA) than in the control group (29 ± 9 μA; p < 0.001). Electric hypogeusia (electrogustometric threshold > 100 μA) was found among 54% of the diabetic patients vs 2% of the control subjects (p < 0.001). In the diabetic group, the electrogustometric threshold was associated with complications of diabetes, especially with peripheral neuropathy (210 ± 24 vs 90 ± 22 μA; p < 0.001) and microalbuminuria (185 ± 25 vs 86 ± 21 μA; p < 0.01). It was correlated with age (r = 0.37; p < 0.01) and duration of diabetes (r = 0.52; p < 0.001) but not with HbA_1c (r = ?0.04). Using multivariate analysis, duration of diabetes and peripheral neuropathy had the strongest association with taste impairment. These results support previous findings, suggesting that taste impairment is a degenerative complication of diabetes mellitus.     

ApoE基因多态性与中国人2型糖尿病及其肾病并发症的关系

目的　研究 Apo E基因多态性与中国人 2型糖尿病及其肾病并发症的关系。方法　以载脂蛋白 E(Apo E)基因为候选基因 ,运用聚合酶链反应——限制性片段长度多态性 (PCR- RFL P)方法检测了 2 6 5例 2型糖尿病患者 ,其中未合并肾病者 10 6例 ,合并肾病者 15 9例 ,后者又分为蛋白尿者 12 2例 ,肾功能不全者 37例及 110例非糖尿病对照者的Apo E基因型。结果　 12型糖尿病合并肾病组与 2型糖尿病未合并肾病组相比 ,等位基因 ε2频率显著升高 (P=0 .0 0 894 ) ;基因型 E2 (E2 / 2 E2 / 3)组频率也显著升高 (P=0 .0 0 194 )。 2 2型糖尿病组与非糖尿病对照组相比基因型频率及等位基因频率均无显著性差异 (均 P>0 .0 5 )。结论　Apo E等位基因 ε2可能是 2型糖尿病合并肾病的危险因子。Apo E基因多态性与中国人 2型糖尿病发病无相关性     

Carbohydrate intake is associated with time spent in the euglycemic range in patients with type 1 diabetes

Aims/Introduction

Greater glycemic variability and lack of predictability are important issues for patients with type 1 diabetes. Dietary factors are one of the contributors to this variability, but how closely diet is linked to glycemic fluctuation on a daily basis has not been investigated. We examined the association between carbohydrate intake and glycemic excursion in outpatients.

Materials and Methods

A total of 33 patients with type 1 diabetes were included in the analyses (age 44.5 ± 14.7 years, diabetes duration 15.1 ± 8.3 years, 64% female, 30% using insulin pump, glycated hemoglobin 8.1 ± 1.3%). Time spent in euglycemia (70–180 mg/dL), hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) of consecutive 48-h periods of continuous glucose monitoring data were collected together with simultaneous records of dietary intake, insulin dose and physical activity. Correlation analyses and multiple regression analyses were used to evaluate the contribution of carbohydrate intake to time spent in the target glycemic range.

Results

In multiple regression analyses, carbohydrate intake (β = 0.53, P = 0.001), basal insulin dose per kg per day (β = −0.31, P = 0.034) and diabetes duration (β = 0.30, P = 0.042) were independent predictors of time spent in euglycemia. Carbohydrate intake (β = −0.51, P = 0.001) and insulin pump use (β = −0.34, P = 0.024) were independent predictors of time spent in hyperglycemia. Insulin pump use (β = 0.52, P < 0.001) and bolus insulin dose per kg per day (β = 0.46, P = 0.001) were independent predictors of time spent in hypoglycemia.

Conclusions

Carbohydrate intake is associated with time spent in euglycemia in patients with type 1 diabetes.