Effect of a multidisciplinary team approach in patients with diabetic foot ulcers on major adverse limb events (MALEs): systematic review and meta-analysis for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

The treatment of patients with diabetic foot ulcers (DFUs) is extremely complex, requiring a comprehensive approach that involves a variety of different healthcare professionals. Several studies have shown that a multidisciplinary team (MDT) approach is useful to achieve good clinical outcomes, reducing major and minor amputation and increasing the chance of healing. Despite this, the multidisciplinary approach is not always a recognized treatment strategy. The aim of this meta-analysis was to assess the effects of an MDT approach on major adverse limb events, healing, time-to-heal, all-cause mortality, and other clinical outcomes in patients with active DFUs. The present meta-analysis was performed for the purpose of developing Italian guidelines for the treatment of diabetic foot with the support of the Italian Society of Diabetology (Società Italiana di Diabetologia, SID) and the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD). The study was performed using the Grading of Recommendations Assessment, Development, and Evaluation approach. All randomized clinical trials and observational studies, with a duration of at least 26 weeks, which compared the MDT approach with any other organizational strategy in the management of patients with DFUs were considered. Animal studies were excluded. A search of Medline and Embase databases was performed up until the May 1st, 2023. Patients managed by an MDT were reported to have better outcomes in terms of healing, minor and major amputation, and survival in comparison with those managed using other approaches. No data were found on quality of life, returning-to-walking, and emergency admission. Authors concluded that the MDT may be effective in improving outcomes in patients with DFUs.

Development of the Italian clinical practice guidelines for the treatment of diabetic foot syndrome: design and methodological aspects.

AIMS: Diabetic foot syndrome (DFS) and its complications are a growing public health concern. The Italian Society of Diabetology (SID) and the Italian Association of Clinical Diabetologists (AMD), in collaboration with other scientific societies, will develop the first Italian guidelines for the treatment of DFS. METHODS: The creation of SID/AMD Guidelines is based on an extended work made by 19 panelists and 12 members of the Evidence Review Team. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology has been used to decide aims, reference population, and target health professionals. Clinical questions have been created using PICO (Patient, Intervention, Comparison, Outcome) conceptual framework. The definition of questions has been performed using a two-step web-based Delphi methodology, a structured technique aimed at obtaining by repeated rounds of questionnaires a consensus opinion from a panel of experts in areas wherein evidence is scarce or conflicting, and opinion is important. RESULTS: The mean age of panelists (26.3% women) was 53.7 ± 10.6 years. The panel proposed 34 questions. A consensus was immediately reached for all the proposed questions, 32 were approved and 2 were rejected. CONCLUSIONS: The areas covered by clinical questions included diagnosis of ischemia and infection, treatment of ischemic, neuropathic, and infected ulcers, prevention of foot ulceration, organization and education issues, and surgical management. The PICO presented in this paper are designed to provide indications for healthcare professionals in charge of diabetic foot treatment and prevention, primarily based on clinical needs of people with diabetic foot syndrome and considering the existing organization of health care.

Diabetic foot disease during the COVID-19 pandemic: lessons learned for our future.

The COVID-19 pandemic has had a strong impact on the treatment of all diseases, especially chronic ones, and diabetic foot is no exception. The COVID-19 pandemic has favored the adoption of a new model of assistance delivery to facilitate the delivery of remote assistance to patients. The standard model based on face-to-face visits has been integrated by a hybrid model of telemedicine, home care and face-to-face visits to keep patients at home to minimize the number of in-person visits to clinics and admissions except for complicated DFUs. However, telemedicine is not always possible or suitable for various reasons (patients not digital, need for practical treatment of the foot etc.). In this review, we looked at the different approaches to diabetic foot ulcer management and the indirect impact of the COVID-19 pandemic on diabetes-related lower extremity complications and the lessons we have learned for the future.

Photodynamic Topical Antimicrobial Therapy for Infected Diabetic Foot Ulcers in Patients With Diabetes: A Case Series.

Diabetic foot ulcers (DFUs) are common, complex, costly complications, associated with frequent recurrences and increased morbidity and mortality. DFUs can be prevented and their healing can be mostly influenced by appropriately and aggressively managing any infection, but the role of antiseptic therapies in reducing healing time lacks sufficient evidence. Several therapeutic interventions have been developed based on the principles of photomedicine to overcome the issue of poor drug circulation in infected areas, with the aim of killing microbial agents while leaving the surrounding host cells unharmed. Such techniques use absorption of photons by specific chromophores. Among these, RLP068 is a tetracationic Zn(II) phthalocyanine derivative activated by exposure to red light, used as a topical treatment for superficial bacterial and fungal infections. The photoactivation of RLP068 results in the production of singlet oxygen and other reactive oxygen species, able to affect a range of cellular targets, including cell membrane and/or wall, cytoplasm, and cellular components, resulting in a rapid, broad range, bactericidal and fungicidal effect. The phase IIa study showed that photoactivated RPL068 is capable of inducing a dose-dependent reduction in total and pathogen microbial load in infected diabetic foot ulcers. In this article, a case series of 22 DFU treated with photoactivated RLP068 at 5 different centers in Italy is presented. Considering microbial agents reduction, ulcer healing facilitation, healing rate (9 DFUs out of 22), and amputation rate (only 1 case over 22), the decrease in the cost of DFU seems to be a point in favor of RLP068 and its cost-effectiveness.

Update on prevention of diabetic foot ulcer.

The diabetic foot ulcer is the most important reason for non-traumatic limb amputation. Based on recent data, it has been estimated that up to 34% of type 2 diabetes patients may develop diabetic foot ulcers once in their lifetime. Risk factors for developing foot ulcers are distal sensorimotor peripheral neuropathy, peripheral arterial disease, previous ulcers, and/or amputations. Understanding the factors that place patients with diabetes mellitus at high ulceration risk and the early treatment of risk factors, and continuous education of the patient (and/or caregivers) are essential for the prevention and management of diabetic foot complications. Implementing strategies to prevent these complications is a key aspect of diabetes care, but the most effective strategy in prevention has to be investigated. More evidence from well-designed studies is needed on this topic.

Barriers to diabetic foot management in Italy: A multicentre survey in diabetic foot centres of the Diabetic Foot Study Group of the Italian Society of Diabetes (SID) and Association of Medical Diabetologists (AMD).

BACKGROUND AND AIMS: Diabetic foot (DF) disease is a current health and social burden. The authors aimed to identify the barriers to the DF management across Italy. METHODS AND RESULTS: A questionnaire was submitted to Italian centres dedicated to DF care. The questionnaire was composed of 12 questions focused on the barriers to the DF management including timing of referral, hospital management, and community follow-up. Each centre could answer by choosing a score from 1 to 5 for every item with the following numerical variables: 1 = never; 2 = rarely; 3 = sometimes; 4 = often; 5 = always. Accordingly, for each item a national and regional score was reported and a comparison between regions was carried out. National and regional scores were estimated using the total score for each item as a numerator and the number of national centres included as a denominator. Among 102 centres, 99 were included and 3 were excluded due to missing data. The 99 centres belonged to 16 regions with the following distribution: Calabria 4, Campania 5, Emilia-Romagna 14, Friuli-Venezia-Giulia 4, Lazio 12, Liguria 4, Lombardy 10, Marche 1, Molise 1, Piedmont 5, Apulia 5, Sardinia 5, Sicily 4, Tuscany 11, Veneto 9, Umbria 5. The items with the highest score were late referral (3.3) and urgent surgery (3.2). The regions with the highest score were Molise (3.9) and Calabria (3.5). CONCLUSION: The main issues across Italy were late referral and the requirement for urgent surgery for acute DF. In the regional scenario, the southern central areas showed more barriers than northern regions.

The Complexity of Diabetic Foot Management: From Common Care to Best Practice. The Italian Expert Opinion by Delphi Survey.

Diabetic foot is a major public health issue, driven by diabetes complications (neuropathy, peripheral vascular disease, foot deformity, and abnormal leucocyte function), which may lead to leg amputation, thus resulting in severe disability, reduced quality of life, and high health costs. The prevention of diabetes complications and the early detection and proper management of diabetic foot wounds are the milestones to avoid major amputations. Unfortunately, in many areas, the prevention of diabetic foot lesions is inadequate and wounds may proceed toward infection and chronicity, with limb- and life-threatening results. Using the Delphi method, we conducted a survey on diabetic foot among Italian experts, selected across different Italian clinical centers. This method was used to achieve a consensus on current opinion and clinical leanings on the diagnosis and management of diabetic foot ulcers. Specifically, the aim of the survey was to evaluate the current management of the diabetic foot syndrome; highlight the differences in the approach among a group of experts; evaluate the role of wound bed preparation and antisepsis; and discuss any areas of disagreement in which evidences are sparse and the clinical judgment plays a crucial role in the decision-making process.

The protective effect of rosuvastatin in human umbilical endothelial cells exposed to constant or intermittent high glucose.

In diabetes the exposure of the vascular endothelium to high glucose levels results in increased oxidative insult and in vascular dysfunction. We have investigated the effects of rosuvastatin on oxidative stress and apoptosis induced in human umbilical vein endothelial cells (HUVECs) by constant and intermittent high glucose levels. HUVECs were incubated for 14 days in either low (5 mM) or high (20 mM) glucose concentrations, or intermittent high and low glucose on a daily basis. Constant high glucose levels increased p47-phox, p67-phox, and p22-phox expression [components of the Nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase complex]; endothelial nitric oxide synthase, nitric oxide, and O(2)(-) production; nitrotyrosine, 8-hydroxy-2'-deoxyguanosine, and caspase-3 expression; and reduced Bcl-2 expression. These effects were significantly greater under intermittent compared to constant high/low glucose conditions. The effect of rosuvastatin (1 microM) in the presence or absence of mevalonate (200 microM) was evaluated in the cells under both constant and intermittent glucose conditions. Rosuvastatin almost normalized all these parameters. These effects of rosuvastatin were prevented when mevalonate was also added, demonstrating the link to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. These data suggest that rosuvastatin has the potential to prevent damage to and apoptosis of HUVECs induced by high glucose exposure, by reducing oxidative stress. The action of rosuvastatin on antioxidant pathways is related to the inhibition of the overexpression of components of NAD(P)H oxidase induced by the two conditions of high glucose.

Use of a retrograde nail for ankle arthrodesis in Charcot neuroarthropathy: a limb salvage procedure.

BACKGROUND: Charcot neuroarthropathy is a serious complication associated with diabetic neuropathy. This complication probably is most serious when the ankle is involved because of the instability and progressive deformity, which often leads to ulceration, osteomyelitis, and amputation. Arthrodesis before the ulcerated lesion appears is considered a limb salvage treatment. One of the most effective techniques for an unstable ankle in Charcot neuroarthropathy is retrograde transcalcaneal nailing. METHODS: Eighteen diabetic patients, without a history of ulceration, were treated from July, 2003, to November, 2005, with panarthrodesis of the ankle using intramedullary retrograde transcalcaneal nailing. The average follow up was 14 +/- 10.1 months. All patients completed the unloaded postoperative period with a fiberglass cast (3 months nonweightbearing and 3 months partial weightbearing) and commenced walking in shoes with a stiff rocker sole and a molded insole. RESULTS: During the followup period there were no major complications. In three patients, removal of one of the proximal screws used for anchoring the nail to the tibia was done because of protrusion causing skin breakdown. Fourteen patients had a stable fusion and four patients had fibrous union. The percentage of limb salvage was 100% in the followup period. CONCLUSIONS: Our study confirms that this operative technique is effective and safe.

Primary role of superoxide anion generation in the cascade of events leading to endothelial dysfunction and damage in high glucose treated HUVEC.

AIM: The aim of the study was to elucidate the chain of events leading to oxidative damage in endothelial cells exposed to high glucose. METHOD: The nitric oxide synthase (NOS) cofactor tetrahydrobiopterin (BH4), the peroxynitrite decomposition catalyst FP15, the inhibitor of mitochondrial complex II thenoyltrifluoroacetone (TTFA) and the antioxidant superoxide dismutase (SOD) mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP) were individually added to human umbilical vein endothelial cells (HUVEC) cultured in high glucose. This study was designed to establish the possible sequence of action of NOS, peroxynitrite and superoxide anion in the oxidative damage cascade. RESULTS: We found that in high glucose, nitrotyrosine, 8OHdG, NO (+40%) and O2- (+300%) production, eNOS and caspase-3 expression increased, while Bcl-2 expression decreased. MnTBAP and TTFA were able to normalize all the parameters assayed. FP15 caused an increase in NO production, did not interfere with eNOS expression and O2- generation, but was able to reduce apoptosis and to normalize nitrotyrosine and 8OHdG formation. BH4 enrichment was able to reduce O2- generation, nitrotyrosine and 8OHdG formation and apoptosis. The addition of this cofactor did not affect eNOS expression, but increased NO formation, more than FP15. CONCLUSION: These data show the starting role of superoxide anion generated at mitochondrial level in the cascade of events leading to hyperglycemia generated apoptosis.

Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction.

BACKGROUND: It has been previously shown that hyperglycemia enhances free radical production, inducing oxidative damage, which in its turn activates the death pathways implicated in cell apoptosis and necrosis. But the possible involvement of this pathway in the hyperglycemia-induced apoptosis of endothelial cells has not yet been reported. METHODS: To verify a possible connection between mitochondrial ROS production and apoptosis induced by both stable and oscillating high glucose, SOD, MnTBAP and TTFA was added to HUVEC cell culture medium. We measured nitrotyrosine and 8OHdG as oxidative stress parameters and Bcl-2 expression and Caspase-3 expression and activity as apoptosis indicators. RESULTS: Our results show that hyperglycemia, both stable or oscillating, increases oxidative stress and endothelial cell apoptosis through ROS overproduction at the mitochondrial transport chain level. CONCLUSION: The prevention of mitochondrial oxidative damage seems to be a future important therapeutic strategy in diabetes.

Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production.

In this study the effects of stable and intermittent high glucose concentrations on ICAM-1, VCAM-1 and E-selectin production, PKC activity and PKCbetaI, betaII and delta isoforms expression in cultured HUVEC have been examined. In stable high glucose ICAM-1, VCAM-1 and E-selectin concentration and mRNA expression increased, and this effect was even more evident in intermittent high glucose. PKC activity increased in fluctuating glucose compared to stable high glucose, due to an over-expression of betaI, betaII and delta isoforms. ICAM-1, VCAM-1 and E-selectin, after the adding of total PKC inhibitor bisindolylmaleimide-I (BIMI-I) and LY379196, a specific inhibitor of PKCbeta, were equally reduced. 8-Hydroxydeoxyguanosine (8-OHdG), a sensitive indicator of oxidative damage to DNA, increased in stable and even more in intermittent high glucose and was reduced by both BIMI-I and LY379196. However, when thenoyltrifluoroacetone (TTFA), an inhibitor of mitochondrial complex II and the SOD mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP) were added, all adhesion molecules, any PKC isoforms expression and 8-hydroxydeoxyguanosine were normalized in both constant and oscillating glucose. In conclusion intermittent high glucose induces a greater expression of the adhesion molecules than stable high glucose; this effect seems to be related to an activation of PKCbeta, but completely dependent from mitochondrial free radicals over-production.

[Postprandial hyperglycemia and diabetic complications]. / Iperglicemia post-prandiale e complicanze diabetiche.

There is increasing evidence that the postprandial state is an important contributing factor to the development of atherosclerosis. In diabetes, the postprandial phase is characterized by a rapid and large increase in blood glucose levels, and the possibility that the postprandial hyperglycemic spikes may be relevant to the pathophysiology of late diabetic complications has received recently much more attention. The oral glucose tolerance test, although non-physiological, has been used highly as model of the postprandial state. Epidemiological studies have shown that, when impaired, oral glucose tolerance is associated with an increased risk of cardiovascular disease, being the glycemia after two hours of the glucose challenge a direct and independent risk factor. Moreover, the possibility that postprandial hyperglycemia is a risk factor for cardiovascular disease also in diabetic patients has been reported. Most of the cardiovascular risk factors are modified in the postprandial phase in diabetic subjects and directly affected by an acute increase of glycemia. The mechanisms through which acute hyperglycaemia exerts its effects may be identified in labile non-enzymatic glycation and in production of free radicals. It is likely that the two mechanisms co-operate in causing the disorders induced by acute hyperglycemia. Correction of the postprandial hyperglycemia can be part of the strategy for the prevention and management of cardiovascular diseases in diabetes.

Molecular targets of diabetic vascular complications and potential new drugs.

In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive "causal" antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase beta isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.

Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients.

BACKGROUND: Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction and inflammation through oxidative stress. Statins and angiotensin type 1 receptor blockers have been shown to reduce oxidative stress and inflammation, improving endothelial function. METHODS AND RESULTS: Twenty type 2 diabetic patients ate 3 different test meals: a high-fat meal, 75 g glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, endothelial function, nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6 were assayed during the tests. Subsequently, diabetics took atorvastatin 40 mg/d, irbesartan 300 mg/d, both, or placebo for 1 week. The 3 tests were performed again between 5 and 7 days after the start of each treatment. High-fat load and glucose alone produced a decrease in endothelial function and increases in nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6. These effects were more pronounced when high-fat load and glucose were combined. Short-term atorvastatin and irbesartan treatments significantly counterbalanced these phenomena, and their combination was more effective than either therapy alone. CONCLUSIONS: This study confirms an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function and inflammation, suggesting oxidative stress as a common mediator of such an effect. Short-term treatment with atorvastatin and irbesartan may counterbalance this phenomenon; the combination of the 2 compounds is most effective.

Antioxidant therapy in diabetic complications: what is new?

In diabetes oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolysis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. Classic antioxidants, like vitamin E, failed to show beneficial effects on diabetic complications probably due to their only "symptomatic" action. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. Statins increase NO bioavailability and decrease superoxide production, probably interfering with NAD(P)H activity and modulating eNOS expression. ACE inhibitors and AT-1 blockers prevent hyperglycemia-derived oxidative stress modulating angiotensin action and production. This effect is of particular interest because hyperglycemia is able to directly modulate cellular angiotensin generation. Calcium channel blockers inhibit the peroxidation of cell membrane lipids and their subsequent intracellular translocation. Thiazolinediones bind and activate the nuclear peroxisome proliferator-activated receptor gamma, a nuclear receptor of ligand-dependent transcription factors. The inhibition of this receptors lead to inhibition of the inducible nitric oxide synthase and consequently reduction of peroxynitrite generation. This preventive activity against oxidative stress generation can justify a large utilization and association of this compound for preventing complications in diabetic patients, where antioxidant defences have been shown to be defective.

Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment.

Adhesion molecules, particularly intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, have been associated with cardiovascular disease. Elevated levels of these molecules have been reported in diabetic patients. Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease, and evidence suggests that postprandial hypertriglyceridemia and hyperglycemia may induce an increase in circulating adhesion molecules. However, the distinct role of these two factors is a matter of debate. Thirty type 2 diabetic patients and 20 normal subjects ate three different meals: a high-fat meal, 75 g of glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, plasma nitrotyrosine, ICAM-1, VCAM-1, and E-selectin were assayed during the tests. Subsequently, diabetic subjects took simvastatin 40 mg/day or placebo for 12 weeks. The three tests were performed again at baseline, between 3 and 6 days after starting the study, and at the end of each study. High-fat load and glucose alone produced an increase of nitrotyrosine, ICAM-1, VCAM-1, and E-selectin plasma levels in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters, but reduced the effect on adhesion molecules and nitrotyrosine, which was observed during every different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations in ICAM-1, VCAM-1, E-selectin, and nitrotyrosine during the tests. This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on ICAM-1, VCAM-1, and E-selectin plasma levels, suggesting oxidative stress as a common mediator of such effects. Simvastatin shows a beneficial effect on oxidative stress and the plasma levels of adhesion molecules, which may be ascribed to a direct effect in addition to the lipid-lowering action of the drug.

Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment.

BACKGROUND: Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction through oxidative stress; however, the distinct role of these two factors is a matter of debate. METHODS AND RESULTS: Thirty type 2 diabetic patients and 20 normal subjects ate 3 different meals: a high-fat meal; 75 g glucose alone; and high-fat meal plus glucose. Glycemia, triglyceridemia, nitrotyrosine, and endothelial function were assayed during the tests. Subsequently, diabetics took 40 mg/d simvastatin or placebo for 12 weeks. The 3 tests were performed again at baseline, between 3 to 6 days after the start, and at the end of each study. High-fat load and glucose alone produced a decrease of endothelial function and an increase of nitrotyrosine in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters but reduced the effect on endothelial function and nitrotyrosine observed during each different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations of endothelial function and nitrotyrosine during the tests. CONCLUSIONS: This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect. Simvastatin shows a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as the lipid-lowering action of the drug.