Markers of endothelial dysfunction and low-grade inflammation are associated in the offspring of type 2 diabetic subjects

The offspring of type 2 diabetic patients are at elevated risk for type 2 diabetes and cardiovascular disease. The aim of our study was to characterize the role of various biomarkers of endothelial activation in a cohort of offspring of type 2 diabetic subjects and to assess the association of adhesion molecules with inflammatory markers and metabolic parameters. Cytokine and adhesion molecule levels were measured in 19 healthy subjects and in 129 offspring of patients with type 2 diabetes (109 with normal glucose tolerance and 20 with impaired glucose tolerance). Insulin sensitivity was determined with the hyperinsulinemic-euglycemic clamp, insulin secretion with the intravenous glucose tolerance test, and abdominal fat distribution with computed tomography. The levels of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-Selectin and vascular adhesion protein-1 were not increased in offspring of type 2 diabetic subjects, but they correlated with inflammatory markers (C-reactive protein, tumor necrosis-alpha, interleukin-6, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin-8, interleukin-10 and interleukin-18). In conclusion, the levels of adhesion molecules were not elevated in the prediabetic state. Inflammatory markers and adhesion molecules were correlated suggesting that low-grade inflammation may precede the elevation of levels of adhesion molecules.     

Endothelial function and biochemical vascular markers in first-degree relatives of type 2 diabetic patients: the effect of exercise training

Endothelial dysfunction (ED) is associated with the presence of atherosclerosis. However, ED is also considered a sign of the early vascular changes preceding atherosclerosis. By measuring flow-mediated vasodilation (FMD) and circulating markers of endothelial function we sought to explore whether impaired endothelial function is already present in healthy subjects at increased risk of developing type 2 diabetes mellitus. Furthermore, we aimed to assess the impact of short-term lifestyle intervention (10 weeks endurance exercise) on the potentially primary defects of endothelial function. Twenty-nine healthy but insulin-resistant first-degree relatives of patients diagnosed with type 2 diabetes mellitus (33 +/- 5 years; body mass index, 26.3 +/- 1.6 kg/m2) were compared with 19 control subjects without a family history of diabetes mellitus (31 +/- 5 years; body mass index, 25.8 +/- 3.0 kg/m2). At baseline the von Willebrand factor was significantly increased in the relatives (P < .05). Furthermore, mannose-binding lectin (P = .06), soluble intercellular adhesion molecule 1 (P = .08), and osteoprotegerin (P = .08) tended to be increased in relatives. The following markers of endothelial function were comparable at baseline: FMD, C-reactive protein, plasminogen activator inhibitor 1, and soluble vascular cell adhesion molecule 1. Exercise training resulted in a decrease in mannose-binding lectin (P = .02) and osteoprotegerin (P < .01) in relatives only, whereas other biochemical markers were unaffected in both groups. Moreover, the relatively high-intensity exercise training tended weakly to reduce FMD in the relatives (P = .15). In conclusion, healthy subjects predisposed for type 2 diabetes mellitus show only minor signs of endothelial dysfunction. Under these almost normal vascular conditions, exercise training has little effect on endothelial function.     

血管内皮功能与血糖、胰岛素水平及心血管危险因素的相关性

目的 研究超重肥胖者血管内皮功能与血糖、胰岛素水平及心血管病危险因素的关系。方法 367例超重肥胖者被分成2型糖尿病组、糖耐量减低组、空腹血糖受损组、正常糖耐量组及单纯超重肥胖组，并与66例正常体重者对照。测定血管内皮依赖性舒张功能(血流介导)和内皮非依赖性舒张功能(硝酸甘油介导)，并测定体脂、血压、血糖、血脂和胰岛素抵抗指数(HOMA-IR)。结果 超重肥胖者的内皮依赖性舒张功能显著降低，合并代谢异常者降低更显著。血管内皮依赖性舒张功能与腰臀比、收缩压、HOMA-IR呈显著负相关。结论 超重肥胖者血管内皮功能受损，腰臀比、收缩压及HOMA—IR是影响内皮功能的主要因素。     

Changes in Cytokine Levels During Acute Hyperinsulinemia in Offspring of Type 2 Diabetic Subjects

Objective

To investigate the changes in the levels of cytokines and adhesion molecules in response to acute hyperinsulinemia in the offspring of type 2 diabetic subjects.

Methods

Forty healthy offspring of type 2 diabetic subjects and 19 control offspring of healthy parents were included in the study. Twenty offspring had normal glucose tolerance (NGT) and twenty offspring impaired glucose tolerance (IGT). Insulin sensitivity was determined by the hyperinsulinemic euglycemic clamp and insulin secretion with the intravenous glucose tolerance test. The levels of cytokines and adhesion molecules were measured before and at the end of the clamp.

Results

Acute hyperinsulinemia induced by the euglycemic hyperinsulinemic clamp reduced the levels of TNF-α, IL-8, IL-10 and IL-18 in healthy controls but not in the offspring of type 2 diabetic subjects having NGT or IGT. In response to insulin, levels of hs-CRP decreased and levels of IL-6 increased significantly in all study groups. The levels of adhesion molecules (ICAM-1, VCAM-1, E-Selectin) remained unchanged in response to hyperinsulinemia.

Conclusions

The suppression of cytokine levels (particularly proinflammatory cytokines) during acute hyperinsulinemia observed in healthy controls was not present in offspring of type 2 diabetic patients. This emphasizes the crucial role of low-grade inflammation in insulin resistance in subjects with high risk of developing diabetes.     

Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.     

Relationship between serum resistin concentrations and inflammatory markers in patients with type 2 diabetes mellitus

To examine whether serum resistin concentrations are associated with metabolic or inflammatory markers in patients with type 2 diabetes mellitus, we examined serum concentrations levels and metabolic or inflammatory markers in 56 patients with type 2 diabetes mellitus and 41 healthy subjects. Serum levels of resistin, serum amyloid A, and soluble vascular cell adhesion molecule-1 were measured by enzyme-linked immunosorbent assay. Serum resistin levels were significantly elevated in diabetic patients compared with those in healthy subjects. Serum resistin concentrations did not correlate with body mass index; however, there was a significant positive correlation between resistin and soluble vascular cell adhesion molecule-1 in diabetic patients. Based on the present results, we conclude that resistin appears to be associated with vascular inflammatory markers in patients with type 2 diabetes mellitus.     

Endothelial dysfunction in metabolic syndrome: Prevalence,pathogenesis and management

The metabolic syndrome (MetS) is characterized by the presence of central obesity, impaired glucose metabolism, dyslipidemia and hypertension. Several studies showed that MetS is associated with increased risk for type 2 diabetes mellitus (T2DM) and vascular events. All components of MetS have adverse effects on the endothelium. Endothelial dysfunction plays a role in the pathogenesis of atherosclerosis and might also increase the risk for insulin resistance and T2DM. We review the prevalence and pathogenesis of endothelial dysfunction in MetS. We also discuss the potential effects of lifestyle measures and pharmacological interventions on endothelial function in these patients. It remains to be established whether improving endothelial function in MetS will reduce the risk for T2DM and vascular events.     

Monocytic expression of CD14 and CD18, circulating adhesion molecules and inflammatory markers in women with diabetes mellitus and impaired glucose tolerance

Aims/hypothesis Type 2 diabetes is a major risk factor for cardiovascular disease. Monocyte recruitment and inflammatory activation are crucial steps in the development of atherosclerosis and several receptors are involved in these processes. The aim of this study was to investigate levels of CD14 and the ₂-integrin subunits CD11b and CD18 on monocytes from women with diabetes or impaired glucose tolerance.Methods A population-based sample of 112 Swedish women, who were aged 64 years and had diabetes mellitus or impaired or normal glucose tolerance, was investigated. Cell surface receptors were analysed with flow cytometry and serum inflammation markers and soluble adhesion molecules with enzyme-linked methods.Results The monocytic CD14 expression and serum levels of C-reactive protein, IL-6 and soluble adhesion molecules were higher in the diabetes group than in the group with normal glucose tolerance. Monocytic CD18 was elevated both in the diabetes and in the impaired glucose tolerance groups. The levels of monocytic surface markers correlated with BMI and to a lesser extent with glycaemic control.Conclusions/interpretation The increased monocytic expression of important surface receptors together with elevated serum inflammation markers supports the concept of increased inflammation in type 2 diabetes and may be an important factor for the risk of atherosclerosis.The authors state that no conflicts of interest exist.     

Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease

Impaired insulin signaling is central to development of the metabolic syndrome and can promote cardiovascular disease indirectly through development of abnormal glucose and lipid metabolism, hypertension, and a proinflammatory state. However, insulin's action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications of diabetes mellitus. Recent advances in our understanding of the complex pathophysiology of insulin's effects on vascular tissues offer new opportunities for preventing these cardiovascular disorders.     

Circulating vascular endothelial growth factor is unaffected by acute hyperglycemia and hyperinsulinemia in type 1 diabetes mellitus

BACKGROUND: Circulating levels of vascular endothelial growth factor (VEGF) may predict microvascular complications in type 1 diabetes mellitus and are elevated when metabolic control is poor. We tested whether serum VEGF is influenced by prevailing glucose and insulin levels. METHODS: In 15 type 1 diabetic patients, serum VEGF, plasma von Willebrand factor antigen (vWF-Ag), and serum soluble intercellular adhesion molecule-1 (s-ICAM) levels were measured after 210 min of hyperglycemia (blood glucose target 12.0 mmol/l) and hyperinsulinemia (insulin infused at 120 mU/kg/h), alone and in combination. These were then compared with the levels obtained at the end of a 210-min normoglycemic (blood glucose target 5.0 mmol/l) standard insulin clamp (insulin infused at 30 mU/kg/h). RESULTS: VEGF (p>0.60) as well as vWF-AG (p>0.80) and s-ICAM (p>0.20) remained unchanged at the end of the three intervention periods. CONCLUSION: These findings suggest that no special precautions, in terms of concurrent measurement of glucose or timing of insulin administration, are necessary when interpreting circulating VEGF in this patient category.     

Consequences of fetal exposure to maternal diabetes in offspring

CONTEXT: Type 2 diabetes is the result of both genetic and environmental factors. Fetal exposure to maternal diabetes is associated with a higher risk of abnormal glucose homeostasis in offspring beyond that attributable to genetic factors, and therefore, may participate in the excess of maternal transmission of type 2 diabetes. Evidence acquisition: A MEDLINE search covered the period from 1960-2005. EVIDENCE SYNTHESIS: Human studies performed in children and adolescents suggest that offspring who had been exposed to maternal diabetes during fetal life exhibit higher prevalence of impaired glucose tolerance and markers of insulin resistance. Recent studies that directly measured insulin sensitivity and insulin secretion have shown an insulin secretory defect even in the absence of impaired glucose tolerance in adult offspring. In animal models, exposure to a hyperglycemic intrauterine environment also led to the impairment of glucose tolerance in the adult offspring. These metabolic abnormalities were transmitted to the next generations, suggesting that in utero exposure to maternal diabetes has an epigenetic impact. At the cellular level, some findings suggest an impaired pancreatic beta-cell mass and function. Several mechanisms such as defects in pancreatic angiogenesis and innervation, or modification of parental imprinting, may be implicated, acting either independently or in combination. CONCLUSION: Thus, fetal exposure to maternal diabetes may contribute to the worldwide diabetes epidemic. Public health interventions targeting high-risk populations should focus on long-term follow-up of subjects who have been exposed in utero to a diabetic environment and on a better glycemic control during pregnancy.     

短期胰岛素泵强化治疗对初发2型糖尿病患者血浆vaspin水平的影响

目的 观察短期胰岛素泵强化治疗对初发2型糖尿病患者血浆内脏脂肪组织来源的丝氨酸蛋白酶抑制物vaspin水平的影响,探讨其与胰岛素敏感性的关系.方法 30例初发2型糖尿病患者使用胰岛素泵强化治疗2周,治疗前后采用高胰岛素-正葡萄糖钳夹术评价其胰岛素敏感性,用酶免法测定血浆vaspin及相关代谢指标.结果 2型糖尿病组空腹血浆vaspin水平高于正常糖耐量(NGT)组和糖调节受损(IGR)组.2型糖尿病组经胰岛素泵强化治疗后葡萄糖代谢率升高[(5.10±0.51对2.99±0.42)mg·kg-1·min-1,P＜0.05],稳态模型评估的胰岛素抵抗指数(HOMA-IR)降低[2.30(1.09～7.20)对4.28(1.70～6.47),P＜0.05],同时血浆vaspin水平也显著降低[(1.19±0.57对1.83±0.55)ng/ml,P＜0.05],且vaspin水平的降低与HOMA-IR的改变呈明显正相关.结论 胰岛素泵强化治疗能有效改善2型糖尿病患者的胰岛素敏感性,降低血浆vaspin水平;且血浆vaspin水平与2型糖尿病患者胰岛索敏感性有关.     

Vitamin D ratio and glycaemic control in individuals with type 2 diabetes mellitus: A systematic review

Several studies have suggested a favorable role for vitamin D in glycaemic metabolism and its potential as adjuvant treatment of type 2 diabetes mellitus. This review discusses the role of vitamin D in the glycaemic control of individuals with type 2 diabetes mellitus and evaluates the effect of vitamin D supplementation on glycaemic markers in this population. Literature searches were performed in the BIREME, LILACS, and PubMed databases using the Medical Subject Headings and words related to vitamin D, type 2 diabetes mellitus, and glycaemic control. Interventional and observational studies were considered eligible. The evaluation of the included studies was independently performed by 2 evaluators at all stages of selection, data extraction, and bias risk assessment. The primary outcome was the relationship between vitamin D levels and glucose metabolism markers in type 2 diabetes mellitus individuals. The secondary outcome was the effect of vitamin D supplementation on the glycaemic control markers in individuals with type 2 diabetes mellitus. The inverse relationship between vitamin D and variables of glucose metabolism was verified. Interventional studies revealed that vitamin D supplementation did not alter glycaemic control markers in most studies. Few studies have shown positive effects with a significant reduction in the percentage of glycated haemoglobin, insulin, and glucose concentrations, and changes in homeostatic model assessment–insulin resistance and beta cell, and quantitative insulin sensitivity check index. Therefore, despite the association of vitamin D with glucose metabolism, there is insufficient evidence of the beneficial effects of its supplementation on the metabolic control of type 2 diabetes mellitus.     

Level of serum IL-12 and its correlation with endothelial dysfunction, insulin resistance, proinflammatory cytokines and lipid profile in newly diagnosed type 2 diabetes

Aim

This study was an attempt to evaluate and correlate serum interleukin-12 (IL-12) with different circulating markers in newly diagnosed type-2 diabetes mellitus (T2DM) for possible progression of atherosclerosis.

Methods

For this study, we recruited 1968 family members of diabetics and 349 had abnormal glucose. Out of 349 subjects, 197 were T2DM as per American Diabetes Association guidelines and further investigated for cardiovascular abnormalities. 63 T2DM have high sensitive C-reactive protein (hsCRP) > 3.0 mg/l and cardiovascular complications. Overall, 150 subjects, 50 healthy, 50 T2DM (D1) and 50 T2DM with cardiovascular complications (D2) were enrolled and investigated for soluble markers.

Results

The levels of serum glucose, proinflammatory cytokines (IL-6, IL-12, tumor necrosis factor), endothelial dysfunction markers [vascular cell adhesion molecule-1 (VCAM-1), inter-cellular adhesion molecule-1 (ICAM-1), nitric oxide] and lipid abnormality were highest in D2 group. Correlation and regression study showed that IL-12 was dependent on hsCRP, insulin resistance, VCAM-1, ICAM-1 and lipids. The multivariate stepwise regression analysis demonstrates that hsCRP contributes significantly for variance of IL-12.

Conclusion

This study reveals that, even first-time diagnosis of T2DM, subjects with higher insulin resistance and abnormal lipids have elevated IL-12, endothelial dysfunction and proinflammatory markers. Further increased hsCRP enhance IL-12 which up-regulate cardiovascular disease progression.     

Role of endogenous androgen against insulin resistance and athero- sclerosis in men with type 2 diabetes

Age-related decline in serum testosterone and dehydroepiandrosterone sulfate concentrations occur in men. Low concentrations of these endogenous androgens have been linked with insulin resistance, which is an important upstream driver for metabolic abnormalities such as hyperglycemia, hypertension, or hyperlipidemia, and increased cardiovascular risk. Moreover, men with diabetes have significantly less circulating androgen than nondiabetic men. Here, we summarize how androgen affects insulin resistance and atherosclerosis in men with type 2 diabetes. Low serum concentrations of endogenous androgens are associated with visceral fat accumulation. Androgen deprivation by castration to treat prostate cancer increases insulin resistance, while testosterone administration in type 2 diabetic men with androgen deficiency improves glucose homeostasis and decreases visceral fat, in addition to alleviating symptoms of androgen deficiency including erectile dysfunction. Androgen correlates inversely with severity of atherosclerosis and has beneficial effects upon vascular reactivity, inflammatory cytokine, adhesion molecules, insulin resistance, serum lipids, and hemostatic factors. Because men with type 2 diabetes have relative hypogonadism, testosterone supplementation could decrease both insulin resistance and atherosclerosis.     

Effects of the prostaglandin I2 analogue,beraprost sodium,on vascular cell adhesion molecule-1 expression in human vascular endothelial cells and circulating vascular cell adhesion molecule-1 level in patients with type 2 diabetes mellitus

Beraprost sodium is an orally active prostaglandin (PG)I(2) analogue, which has antiplatelet and vasodilating properties. In this study, we investigated the effects of beraprost on the expression of vascular cell adhesion molecule-1 (VCAM-1), one of the key molecules involved in atherosclerosis, in cultured vascular endothelial cells. In addition, we examined the effects of beraprost on circulating VCAM-1 level and atherosclerosis progression in patients with type 2 diabetes mellitus. Beraprost significantly decreased tumor necrosis factor-alpha (TNF-alpha)-induced VCAM-1 expression in human vascular endothelial cells. Beraprost also repressed human monocytoid U937 cell adhesion to the vascular endothelial cells. Twenty-five patients with type 2 diabetes mellitus who had atherosclerotic change of carotid arteries were enrolled for an open prospective study: 11 patients received beraprost for 3 years, while the other 14 did not. The 3-year changes of circulating VCAM-1 level, as well as those of carotid arterial intima-media thickness (IMT) were significantly lower in the patients receiving the beraprost treatment than that in the patients without the treatment. Thus, beraprost had an ability to repress the expression of VCAM-1 in human vascular endothelial cells. In addition, beraprost lowered circulating VCAM-1 level and prevented the increase of carotid IMT in patients with type 2 diabetes mellitus. Considering that circulating VCAM-1 and IMT are predictive of future vascular events, beraprost may have a beneficial effect on progression of atherosclerosis in diabetic patients.     

Levels of plasma fibrinogen and d-dimer in patients with impaired fasting glucose.

BACKGROUND: Cardiovascular risk associated with impaired fasting glucose has been examined in various studies with conflicting results. During the last 10 years, several risk markers for atherosclerosis such as fibrinogen and D-dimer have been identified. The present study was designed to evaluate plasma fibrinogen and D-dimer levels in patients with impaired fasting glucose compared with normal subjects and those with type 2 diabetes mellitus. METHODS: Age-, sex-, and body mass index-matched 30 normal subjects, 30 patients with impaired fasting glucose (fasting glucose 110 to 125 mg/dl), and 30 patients with type 2 diabetes mellitus (fasting glucose >/= 126 mg/dl) were included in the study. RESULTS: The levels of plasma fibrinogen in patients with type 2 diabetes mellitus, impaired fasting glucose, and normal subjects were 449 (306 - 605) mg/dl, 348 (264 - 468) mg/dl, and 216 (179 - 260) mg/dl, respectively. Patients with impaired fasting glucose had significantly lower plasma fibrinogen levels than patients with type 2 diabetes mellitus (p < 0.05). There were significantly higher plasma fibrinogen levels in patients with impaired fasting glucose than in normal subjects (p < 0.05). The levels of plasma D-dimer in patients with type 2 diabetes mellitus, impaired fasting glucose, and normal subjects were 615 (505 - 768) mg/l, 518 (412 - 664) mg/l, and 424 (356 - 557) mg/l, respectively. Patients with impaired fasting glucose had significantly lower plasma D-dimer levels than patients with type 2 diabetes mellitus (p < 0.05). There were significantly higher plasma D-dimer levels in patients with impaired fasting glucose than in normal subjects (p < 0.05). The levels of plasma fibrinogen and D-dimer were related to fasting glucose in type 2 diabetes mellitus and impaired fasting glucose groups (p < 0.05). We also detected positive correlation between plasma fibrinogen levels and age in study groups (p < 0.05). CONCLUSION: Our data suggest that patients with impaired fasting glucose pose a hypofibrinolytic status and cardiovascular risk, although this was lower than in patients with type 2 diabetes mellitus.     

Endothelial dysfunction,inflammation, and insulin resistance: A focus on subjects at risk for type 2 diabetes

Subjects with obesity, family history of type 2 diabetes, polycystic ovary syndrome, previous gestational diabetes, dyslipidemia, hypertension, impaired glucose tolerance or impaired fasting glucose, and those with metabolic syndrome are at risk for the development of type 2 diabetes. Some of them are also at risk for cardiovascular disease. Some underlying abnormalities such as insulin resistance, endothelial dysfunction, and low-grade chronic inflammation are frequently present and closely associated in all these groups. The flow of substrates, hormones, and cytokines from visceral fat to skeletal muscle and to the endothelial cells, along with some genetic abnormalities that lead to impaired insulin action in the peripheral tissues and to impaired insulin-stimulated nitric oxide production in endothelial cells, may play a role in establishing these shared metabolic and vascular derangements. Weight loss, thiazolidinediones, and metformin improve vascular function in subjects at risk for type 2 diabetes and may prove to reduce cardiovascular events in these individuals.     

Susceptibility of low-density lipoprotein to oxidation and circulating cell adhesion molecules in young healthy adult offspring of parents with type 2 diabetes

Relatives of subjects with type 2 diabetes carry an increased risk for diabetes and cardiovascular disease. Oxidative modification of low-density lipoprotein (LDL) and proinflammatory processes are believed to have central roles in atherogenesis. We have investigated the susceptibility of LDL to oxidation and circulating cell adhesion molecules in healthy, glucose-tolerant adults (aged 18 to 38 years) with (12 men, 2 women) and without (controls; 12 men, 2 women) a parental history of type 2 diabetes. From fasting blood samples, oxidation of LDL was initiated with copper ions and adhesion molecules were measured using immunoassays. Groups were similar with respect to age, body mass index (BMI), blood pressure, plasma glucose, and serum lipids. Resistance of LDL to oxidation was reduced in offspring of parents with type 2 diabetes (time to Vmax, 80.1 +/- 2.2 v 91.4 +/- 2.6 minutes, P =.003). Plasma hydroperoxides did not differ between groups (1.2 +/- 0.1 v 1.1 +/- 0.1 micromol/L). Soluble intracellular adhesion molecule-1 (sICAM1) was elevated in offspring compared with controls (571 +/- 20 v 447 +/- 20 microg/L, P =.0002). Soluble vascular cell adhesion molecule-1 (sVCAM-1) (1,184 +/- 76 v 1084 +/- 56 microg/L, P =.31) and E-selectin (53 +/- 8 v 53 +/- 7 microg/L, P =.98) did not differ between groups. Reduced resistance of LDL to oxidation and increased circulating sICAM-1 in young healthy adult offspring of parents with type 2 diabetes may be intrinsic to increased risk of atherosclerosis in these subjects.     

Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus

Several in vitro investigations showed that serum paraoxonase 1 (PON1) that is located on high-density lipoprotein reduces or prevents low-density lipoprotein (LDL) oxidation and therefore retards atherosclerosis. Accordingly, the well documented loss of PON1 activity in patients with overt diabetes mellitus was causally related to the development of micro- and macroangiopathy in the disease course. Because vascular complications start already in prediabetic states, e.g. impaired glucose tolerance (IGT), we investigated serum PON1 activities and circulating levels of oxidized LDL (oxLDL) in 125 IGT subjects, 75 patients with newly diagnosed diabetes mellitus type 2, and 403 individuals with normal glucose tolerance. Using three different substrates (paraoxon, phenylacetate, p-nitrophenylacetate) we found that PON1 activity is not significantly altered in IGT and diabetes mellitus subjects, respectively, when compared with normoglycemic controls. Both IGT subjects and diabetes mellitus patients had significantly increased levels of oxLDL in the circulation. However, serum PON1 activity variations and glutamine/arginine phenotype were not related to the levels of oxLDL. The data suggest that 1) PON1 activity loss is an event occurring later in the course of diabetes mellitus; and 2) PON1 does not affect oxidation of circulating LDL, at least in early diabetes mellitus.