TRAIL Concentration and Diabetic Therapy
TRAIL Concentration and Diabetic Therapy
In the present study, our data demonstrated that plasma soluble TRAIL levels decreased dramatically at baseline and increased significantly after 6 months of treatment in newly diagnosed type 2 diabetes. Moreover, the changes of circulating TRAIL concentrations were positively correlated with FMD during the course of treatment in this study group. As far as we know, this is the first report on a relationship between TRAIL and endothelium in diabetic conditions.
TRAIL receptors (TRAIL-Rs) are widely expressed on many cell types, but the effects of TRAIL on normal human tissues have not been described, and the physiological function(s) of this novel TNF family member remains unclear completely. In nondiabetes, soluble TRAIL level in patients with cardiovascular disease (CVD) is reduced and this has been linked with increased risk of cardiovascular events, independently of conventional risk markers. Reduced circulating TRAIL in older patients with CVD is also associated with increased risk of death over a 6-year period. Furthermore, patients with myocardial infarction display reduced TRAIL levels compared with healthy controls, implicating a protective role for TRAIL in these clinical conditions. In diabetic subjects, the recent experimental works showed that TRAIL is able to reduce the accelerated atherosclerosis observed in streptozotocin-treated apolipoprotein E−/− mice and to ameliorate the natural history of type 1 diabetes mellitus, due to its pro-apoptotic properties against activated macrophages and T cells. Di Bartolo et al. have found that TRAIL−/− ApoE−/− mice on an high-fat diet gain more body weight and that they display higher fasting glucose and pro-inflammatory cytokines levels than ApoE−/− mice, and TRAIL delivery could reduce body weight, lower fasting glucose and pro-inflammatory cytokine levels, overall ameliorating type 2 diabetes. As expected, in the present study, our data showed that circulating soluble TRAIL level in newly diagnosed type 2 diabetic patients is significantly lower than healthy controls, which is in good agreement with one previous study. When taken together, these data apparently suggested that TRAIL may have protective roles for atherosclerosis in diabetes. However, one clinical study in type 2 diabetes did not found any relations between circulating soluble TRAIL levels and intima-media thickness (IMT) in carotid and femoral arteries. The reason for this discrepancy may be that the patients in this study were not newly diagnosed, nondrug using diabetic patients, the effects of drugs such as biguanide, insulin secretagogues, thiazolidinedione, 3-hydroxy-3-coenzyme A reductase inhibitors, on circulating TRAIL cannot be excluded. Therefore, we think, the authors cannot figure out the relation between circulating soluble TRAIL levels and atherosclerosis in type 2 diabetes.
Endothelial dysfunction is an early physiological event in atherosclerosis. In the present study, we found that TRAIL may have protective role on endothelial function in diabetes. The underlying mechanisms are unclear. The possible explanations are as follows: (i) Circulating TRAIL acts as a soluble cytokine interacting with 4 transmembrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3 and TRAIL-R4) belonging to the TNF-receptor family. The high-affinity TRAIL-R1 and TRAIL-R2 contain cytoplasmic 'death domains' and mediate proapoptotic signals but also can promote cell type-dependent prosurvival and proliferation signals. In this respect, it has been shown that both vascular endothelial cells and vascular smooth muscle cells (VSMCs) express TRAIL receptors and that recombinant TRAIL is able to promote their in vitro survival/proliferation by activating the Akt and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways. In addition, TRAIL exhibits endothelial protective properties, related at least in part to nitric oxide synthesis by endothelium itself. (ii) Increased levels of inflammatory biomarkers such as CRP, TNF-a, have been recently considered as potential contributors to inflammatory diseases including atherosclerosis as well as a marker of cardiovascular risk, and TRAIL has anti-inflammatory effects. Our present data showed that CRP level increased and circulating TRAIL decreased at baseline, and the absolute change of CRP is negatively correlated with change of TRAIL before and after 6 months treatment. (iii) Animal study showed that TRAIL treatment reduced significantly the increased adiposity associated with a high-fat diet. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a glucose tolerance test, and it improved significantly the peripheral response to insulin. Many studies have shown that hyperlipidaemia, hyperglycaemia and insulin resistance are frequently associated with endothelial dysfunction. In the present work, circulating TRAIL is negatively correlated with the FBG, 2-h BG and HbA1c levels. Taken together with our current findings, these studies demonstrate that TRAIL may have protective roles on endothelial function.
In accordance with other studies in type 2 diabetes, we found FMD and HDL-C at baseline in diabetic patients were significantly lower than those in control, and BMI, DBP, SBP, total cholestrol (TC), LDL-C, triglyceride (TG), UAER, FBG, 2-h BG and HbA1c were significantly higher than those in control. In addition, similar to our previous findings, we also found in the present work that endothelial function was improved and TC, LDL-C, TG and CRP levels were decreased significantly after 6-month treatment. It has been suggested that metformin treatment can decrease TC, LDL-C, TG levels in type 2 diabetes. Metformin also has long been known to reduce the development of atherosclerotic lesions in animal models, and clinical studies have shown the drug to reduce surrogate measures such as carotid intima-media thickness. Therefore, metformin treatment in the present study can at least partially contribute to the significant changes of TC, LDL-C, TG, TRAIL as well as FMD in diabetic patients during treatment period.
Some limitations of the current study should be mentioned here. First, we did not measure the corresponding levels of osteoprotegerin. It has been well established that the ratio of TRAIL to osteoprotegerin carries the more relevant information. Second, we did not detect the TRAIL expression in different tissues (such as endothelial cells and vascular smooth muscle cells) under different conditions (high concentrations of glucose, insulin, metformin and lipids, etc), so we cannot explain the changes of circulating TRAIL during treatment course. Third, Weng et al. reported early intensive insulin therapy in patients with newly diagnosed type 2 diabetes has favourable outcomes on recovery and maintenance of β-cell function and protracted glycaemic remission compared with treatment with oral hypoglycaemic agents. Therefore, we have performed early intensive therapy for this study group. However, we did not measure the β-cell function for all patients, such we cannot figure out relation between plasma TRAIL concentrations and β-cell function.
In conclusion, our data demonstrated that plasma soluble TRAIL levels decreased dramatically at baseline and increased significantly after 6 months of diabetic treatment in newly diagnosed type 2 diabetes. Moreover, the changes of circulating TRAIL concentrations were positively correlated with FMD during the course of insulin plus metformin treatment in this study group. These results indicate that TRAIL may have protective effects on endothelium in diabetes. Further studies are warranted to determine the functional role of circulating TRAIL in the development of atherosclerosis in diabetic patients.
Discussion
In the present study, our data demonstrated that plasma soluble TRAIL levels decreased dramatically at baseline and increased significantly after 6 months of treatment in newly diagnosed type 2 diabetes. Moreover, the changes of circulating TRAIL concentrations were positively correlated with FMD during the course of treatment in this study group. As far as we know, this is the first report on a relationship between TRAIL and endothelium in diabetic conditions.
TRAIL receptors (TRAIL-Rs) are widely expressed on many cell types, but the effects of TRAIL on normal human tissues have not been described, and the physiological function(s) of this novel TNF family member remains unclear completely. In nondiabetes, soluble TRAIL level in patients with cardiovascular disease (CVD) is reduced and this has been linked with increased risk of cardiovascular events, independently of conventional risk markers. Reduced circulating TRAIL in older patients with CVD is also associated with increased risk of death over a 6-year period. Furthermore, patients with myocardial infarction display reduced TRAIL levels compared with healthy controls, implicating a protective role for TRAIL in these clinical conditions. In diabetic subjects, the recent experimental works showed that TRAIL is able to reduce the accelerated atherosclerosis observed in streptozotocin-treated apolipoprotein E−/− mice and to ameliorate the natural history of type 1 diabetes mellitus, due to its pro-apoptotic properties against activated macrophages and T cells. Di Bartolo et al. have found that TRAIL−/− ApoE−/− mice on an high-fat diet gain more body weight and that they display higher fasting glucose and pro-inflammatory cytokines levels than ApoE−/− mice, and TRAIL delivery could reduce body weight, lower fasting glucose and pro-inflammatory cytokine levels, overall ameliorating type 2 diabetes. As expected, in the present study, our data showed that circulating soluble TRAIL level in newly diagnosed type 2 diabetic patients is significantly lower than healthy controls, which is in good agreement with one previous study. When taken together, these data apparently suggested that TRAIL may have protective roles for atherosclerosis in diabetes. However, one clinical study in type 2 diabetes did not found any relations between circulating soluble TRAIL levels and intima-media thickness (IMT) in carotid and femoral arteries. The reason for this discrepancy may be that the patients in this study were not newly diagnosed, nondrug using diabetic patients, the effects of drugs such as biguanide, insulin secretagogues, thiazolidinedione, 3-hydroxy-3-coenzyme A reductase inhibitors, on circulating TRAIL cannot be excluded. Therefore, we think, the authors cannot figure out the relation between circulating soluble TRAIL levels and atherosclerosis in type 2 diabetes.
Endothelial dysfunction is an early physiological event in atherosclerosis. In the present study, we found that TRAIL may have protective role on endothelial function in diabetes. The underlying mechanisms are unclear. The possible explanations are as follows: (i) Circulating TRAIL acts as a soluble cytokine interacting with 4 transmembrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3 and TRAIL-R4) belonging to the TNF-receptor family. The high-affinity TRAIL-R1 and TRAIL-R2 contain cytoplasmic 'death domains' and mediate proapoptotic signals but also can promote cell type-dependent prosurvival and proliferation signals. In this respect, it has been shown that both vascular endothelial cells and vascular smooth muscle cells (VSMCs) express TRAIL receptors and that recombinant TRAIL is able to promote their in vitro survival/proliferation by activating the Akt and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways. In addition, TRAIL exhibits endothelial protective properties, related at least in part to nitric oxide synthesis by endothelium itself. (ii) Increased levels of inflammatory biomarkers such as CRP, TNF-a, have been recently considered as potential contributors to inflammatory diseases including atherosclerosis as well as a marker of cardiovascular risk, and TRAIL has anti-inflammatory effects. Our present data showed that CRP level increased and circulating TRAIL decreased at baseline, and the absolute change of CRP is negatively correlated with change of TRAIL before and after 6 months treatment. (iii) Animal study showed that TRAIL treatment reduced significantly the increased adiposity associated with a high-fat diet. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a glucose tolerance test, and it improved significantly the peripheral response to insulin. Many studies have shown that hyperlipidaemia, hyperglycaemia and insulin resistance are frequently associated with endothelial dysfunction. In the present work, circulating TRAIL is negatively correlated with the FBG, 2-h BG and HbA1c levels. Taken together with our current findings, these studies demonstrate that TRAIL may have protective roles on endothelial function.
In accordance with other studies in type 2 diabetes, we found FMD and HDL-C at baseline in diabetic patients were significantly lower than those in control, and BMI, DBP, SBP, total cholestrol (TC), LDL-C, triglyceride (TG), UAER, FBG, 2-h BG and HbA1c were significantly higher than those in control. In addition, similar to our previous findings, we also found in the present work that endothelial function was improved and TC, LDL-C, TG and CRP levels were decreased significantly after 6-month treatment. It has been suggested that metformin treatment can decrease TC, LDL-C, TG levels in type 2 diabetes. Metformin also has long been known to reduce the development of atherosclerotic lesions in animal models, and clinical studies have shown the drug to reduce surrogate measures such as carotid intima-media thickness. Therefore, metformin treatment in the present study can at least partially contribute to the significant changes of TC, LDL-C, TG, TRAIL as well as FMD in diabetic patients during treatment period.
Some limitations of the current study should be mentioned here. First, we did not measure the corresponding levels of osteoprotegerin. It has been well established that the ratio of TRAIL to osteoprotegerin carries the more relevant information. Second, we did not detect the TRAIL expression in different tissues (such as endothelial cells and vascular smooth muscle cells) under different conditions (high concentrations of glucose, insulin, metformin and lipids, etc), so we cannot explain the changes of circulating TRAIL during treatment course. Third, Weng et al. reported early intensive insulin therapy in patients with newly diagnosed type 2 diabetes has favourable outcomes on recovery and maintenance of β-cell function and protracted glycaemic remission compared with treatment with oral hypoglycaemic agents. Therefore, we have performed early intensive therapy for this study group. However, we did not measure the β-cell function for all patients, such we cannot figure out relation between plasma TRAIL concentrations and β-cell function.
In conclusion, our data demonstrated that plasma soluble TRAIL levels decreased dramatically at baseline and increased significantly after 6 months of diabetic treatment in newly diagnosed type 2 diabetes. Moreover, the changes of circulating TRAIL concentrations were positively correlated with FMD during the course of insulin plus metformin treatment in this study group. These results indicate that TRAIL may have protective effects on endothelium in diabetes. Further studies are warranted to determine the functional role of circulating TRAIL in the development of atherosclerosis in diabetic patients.