Serum Levels of Oxidative Stress Markers in Patients with Type 2 Diabetes Mellitus and Non-alcoholic Steatohepatitis.

INTRODUCTION: Oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. The aim of this study was to evaluate the serum levels of oxidative stress markers in patients with type 2 diabetes mellitus (DMT2) and non-alcoholic steatohepatitis (NASH) and test their relationships with clinical and biochemical patient characteristics, compared to patients with DMT2 without non-alcoholic fatty liver disease (NAFLD), and controls. MATERIALS AND METHODS: In all, 60 consecutive patients with DMT2 and NASH, 55 with DMT2 without NAFLD, and 50 age-and-gender-matched healthy subjects participated in the study. The serum levels of protein carbonyls and 8-isoprostane were determined by ELISA methods, while the serum levels of malondialdehyde (MDA) were detected by means of the spectrophotometric method. Clinical, demographic, and laboratory parameters were examined for all the subjects included in the study. Multivariate logistic regression was used to test the independent predictive factors in the relationships investigated here. RESULTS: Patients with DMT2 and NASH displayed significantly higher serum levels of protein carbonyls (1.112 ± 0.42 nmol/dL), MDA (6.181 ± 1.81 ng/mL), and 8-isoprostane (338.6 ± 98.5 pg/mL) compared to patients with DMT2 without NAFLD, and controls. Results of multivariate logistic regression analyses indicate that in patients with DMT2 and NASH, the serum levels of oxidative stress markers were independently and positively associated with: HbA1c, duration of diabetes, the UKPDS cardiovascular risk score (for protein carbonyls); age, LDL-cholesterol (for 8-isoprostane); and triglycerides serum levels (for MDA). CONCLUSIONS: Our findings indicate that the process of oxidative stress tends to increase in patients with DMT2 and NASH, compared to patients with DMT2 without NAFLD, and controls. This evidence suggests that an antioxidant therapy might prove useful in the treatment of patients with DMT2 and NASH.

Prevalence of overweight/obesity, abdominal obesity and metabolic syndrome and atypical cardiometabolic phenotypes in the adult Romanian population: PREDATORR study.

PURPOSE: The objectives were to assess the prevalence of overweight/obesity, abdominal obesity and metabolic syndrome (MetS), and to evaluate the characteristics of the metabolically unhealthy lean (MUHL) and metabolically healthy overweight/obese (MHO) phenotypes in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological study with a stratified, cross-sectional, cluster random sampling design. Participants were classified into four cardiometabolic phenotypes based on the BMI, the cut-off value being 25 kg/m(2), and the presence of MetS (defined according to the Harmonization definition 2009): MUHL, MHO, metabolically healthy lean (MHL) and metabolically unhealthy overweight/obese (MUHO). RESULTS: Overall, 2681 subjects aged 20-79 years were included in the analysis. The overall age and sex-adjusted prevalence of obesity was 31.90 %, overweight was 34.7 %, abdominal obesity was 73.90 % and MetS was 38.50 %. The age- and sex-adjusted prevalence of MHO phenotype was 31.60 %, while MUHL phenotype prevalence was 3.90 %. MUHL and MHO participants had a cardiometabolic profile, kidney function and CVD risk intermediary between MHL and MUHO. MUHL had higher odds of being associated with CVD risk (OR 5.8; p < 0.001), abdominal obesity, prediabetes, diabetes, hypertriglyceridemia and hypo-HDL cholesterolemia than MHL, while MHO phenotype was associated with hypo-HDL cholesterolemia (OR 3.1; p = 0.002), prediabetes (OR 2.9; p < 0.001) and abdominal obesity. CONCLUSIONS: PREDATORR study showed a high prevalence of obesity/overweight, abdominal obesity and MetS in the adult Romanian population, and their association with kidney function and several cardiometabolic factors.

UPDATING THE CONCEPT OF METABOLICALLY HEALTHY OBESITY.

Obesity is a well-recognized risk factor for type 2 diabetes, cardiovascular disease, and several types of cancer. However, a proportion of the obese individuals display a significantly lower risk for metabolic complications than expected for their degree of body mass index, and this subtype of obesity was described as "metabolically healthy obesity" (MHO). No universally accepted criteria for the diagnosis of MHO exists and the prevalence of this subtype of obesity varies largely according to criteria used. Broadly, MHO is characterized by a lower amount of visceral fat, a more favorable inflammatory profile, and less insulin resistance as compared to the metabolically unhealthy obesity. Currently, controversies exist regarding the risk of cardiovascular events and all-cause mortality associated with MHO as compared to metabolically-healthy non-obese individuals. Further research is needed in order to identify the MHO phenotype and if MHO is truly healthy for a long period of time or if it is a transient state from normal metabolic/normal weight to abnormal metabolic/obese state. This review will discuss the MHO definition criteria; the differences between MHO and metabolically unhealthy obesity; the possible underlying mechanisms and clinical implications of MHO.

Low plasma adiponectin levels predict increased urinary albumin/creatinine ratio in type 2 diabetes patients.

BACKGROUND: Experimental studies have shown that adiponectin has antiproteinuric and nephroprotective effects. The purpose of the study was to assess the value of plasma adiponectin as a predictor of proteinuria in type 2 diabetes (T2D) patients. METHODS: In this one-year prospective follow-up study, we included T2D patients with positive visual test for microalbuminuria (Micral) and negative visual test for proteinuria. Exclusion criteria were: glomerular filtration ratio (GFR) < 30 ml/min, acute infection/inflammation, uncontrolled hypertension, and atherosclerotic complications. The main outcome measure was the change in urinary albumin/creatinine ratio (UACR) after 1 year follow-up (Δ UACR). RESULTS: Fifty-six patients (66% males) completed the study. Their initial mean UACR was 81.58 ± 26.42 mg/g and mean GFR was 81.15 ± 3.96 ml/min. At baseline, simple regression disclosed significant correlations between UACR and plasma adiponectin (r = 0.54, P = 0.00002) and GFR (r = -0.28, P = 0.03); in multiple regression analysis, plasma adiponectin remained the only predictor of UACR (P = 0.00007). Baseline plasma adiponectin was significantly correlated to body mass index (r = -0.28, P = 0.04), waist circumference (r = -0.27, P = 0.05), HDL cholesterol (r = 0.35, P = 0.01), and LDL cholesterol (r = 0.27, P = 0.04). Baseline plasma adiponectin significantly correlated in simple (r = -0.38, P = 0.004) and multiple regression (P = 0.04) to Δ UACR. When patients were divided according to Δ UACR in nonprogressors (Δ UACR < 0) and progressors (Δ UACR > 0), logistic regression showed that baseline GFR (OR = 1.04, CI95%: 1.00-1.09, P = 0.04) and plasma adiponectin (OR = 1.16, CI95%: 1.02-1.32, P = 0.02) were the only factors that predicted whether the patient would be a progressor or not. CONCLUSION: In T2D patients, lower plasma adiponectin levels seem to be predictive of increased UACR.

Effect of two starting insulin regimens in patients with type II diabetes not controlled on a combination of oral antihyperglycemic medications.

In an open-label, 24-week, parallel-group study, 135 patients inadequately controlled with oral antihyperglycemic medications (OAMs) were treated with maximally tolerated doses of metformin and glibenclamide for at least 8 weeks and then randomized to bedtime neutral protamine Hagedorn (NPH) insulin plus maximally tolerated dose of glibenclamide BID (glib/NPH group) or insulin lispro mix 50 (50% lispro, 50% insulin lispro protamine suspension [ILPS]) pre-breakfast and lispro mix 25 (25% lispro, 75% ILPS) pre-dinner (LM50/LM25 group) (both OAMs discontinued). The LM50/LM25 group had significantly lower 2-hour postprandial BG (both meals combined) compared with glib/NPH after 12 (11.70+/-3.40 mmol/L vs. 13.15+/-2.44 mmol/L, p=0.010) and 24 weeks (11.13+/-3.31 mmol/L vs. 14.46+/-2.93 mmol/L, p =0.0001). Both regimens significantly decreased HbA1c. The reduction was greater with LM50/LM25 (-1.31+/-2% vs. -0.5+/-1.6%; P=0.01). At endpoint, the overall hypoglycemia rate increased with LM50/LM25 and decreased with glib/NPH compared with baseline (0.22+/-0.9 vs. -0.08+/-0.72 episodes/patient/30 days; p =0.037). Treatment with LM50/LM25 compared with glib/NPH in patients with inadequate control on combined OAMs yielded better postprandial and overall glycemic control with a higher rate of hypoglycemia.

Early insulin treatment to prevent cardiovascular disease in prediabetes and overt diabetes.

Type 2 diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD), and CVD represents the leading cause of death in people with type 2 DM. The cardiovascular risk is increased long before diabetes is diagnosed, in the prediabetes stage, when impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) develop. These stages are characterized by dysglycemia, defined as any elevated fasting or postprandial glycemia, extending from the normal range into diabetic range, associated with an increased risk of CVD. Due to metabolic memory demonstrated for type 2 DM as well, early interventions addressed to achieve and maintain glycemic control are required for long-term benefits in terms of both microvascular and macrovascular complications. The recommendation of early insulin therapy in type 2 DM is sustained by its pleiotropic effects, which may be cardioprotective and potentially anti-atherosclerotic. Insulin therapy in prediabetes and earlier in type 2 DM, could be a strategy in preventing cardiovascular disease and type 2 DM progression. To test this hypothesis, a large trial has been designed. Outcome Reduction with an Initial Glargine Intervention trial (ORIGIN) is an international, multicenter, randomized controlled, 2 x 2 factorial trial, investigating the possibility to prevent cardiovascular morbidity and mortality in people with type 2 DM, IGT, and/or IFG, and high cardiovascular risk by treating the normoglycemia with either insulin glargine or omega-3 fatty acid, compared to the standard intervention.

Insulin glargine provides greater improvements in glycaemic control vs. intensifying lifestyle management for people with type 2 diabetes treated with OADs and 7-8% A1c levels. The TULIP study.

AIM: To determine whether earlier administration of insulin glargine (glargine) vs. the intensification of lifestyle management (LM) improves glycaemic control in type 2 diabetes patients with A1c 7-8% treated with oral therapy. METHODS: TULIP [Testing the Usefulness of gLargine when Initiated Promptly in type 2 diabetes mellitus (T2DM)] was a 9-month, 12-visit, open-label, multinational, multicentre, randomized study to evaluate starting glargine or intensifying LM in T2DM patients aged 40-75 years, body mass index (BMI) 24-35 kg/m2 and A1c 7-8%, treated with maximum doses of metformin and sulphonylurea for > or = 2 years. Glargine was injected once daily (evening) and titrated to fasting blood glucose 0.7-1.0 g/l. In the LM arm, dietary and physical activity counselling recommended stable weight for people with BMI < 27 kg/m2 or weight loss of 3 kg for patients with BMI > or = 27 kg/m2. A total of 215 patients were randomized to glargine (n = 106) or LM (n = 109). The primary objective was patients achieving A1c < 7% at endpoint. Secondary endpoints included changes in A1c, in fasting plasma glucose (FPG), body weight and hypoglycaemia incidence. RESULTS: Two hundred and eleven (52.6% male) patients were randomized and treated; mean (+/- s.d.) age 60.7 +/- 7.9 years, weight 84.5 +/- 13.1 kg, BMI 29.9 +/- 3.5 kg/m2 and A1c 7.6 +/- 0.4%. More patients reached A1c < 7% (66 vs. 38%; p < 0.0001) or < 6.5% (34 vs. 11%; p = 0.0001) with glargine vs. LM. The change in FPG from baseline to study endpoint was significantly greater in the glargine vs. the LM arm (-0.50 +/- 0.47 vs. -0.05 +/- 0.39 g/l respectively; p < 0.0001). Compared with the glargine group, the LM group showed a decrease in weight (+0.9 +/- 2.9 vs. -2.5 +/- 3.2 kg; p < 0.0001), as well as the expected lower symptomatic hypoglycaemia (55.3 vs. 25.0%; p < 0.0001) and nocturnal hypoglycaemia (20.4 vs. 5.6%; p = 0.0016). No significant changes were observed from baseline to study endpoint in any of the lipid parameters tested. CONCLUSIONS: In patients with T2DM with A1c 7-8%, who were previously treated by conventional LM and OAD therapy, adding glargine resulted in greater improvements in glycaemic control vs. intensifying LM.

Reverse cholesterol transport and atherosclerosis. A mini review.

Reverse cholesterol transport (RCT) is a complex process ensuring the efflux of cholesterol from peripheral cells and its transport back in the liver for its metabolism and biliary excretion. Cholesterol efflux results by the interaction of a cellular free cholesterol and phospholipid transporter, the ABC-AI, with lipid poor apoAI, endowed HDL particles. The free cholesterol taken up by HDL is then esterified by lecithin:cholesterol acyltransferase (LCAT) and the hydrophobic cholesteryl esters are retained into the core of HDL, so that new cholesterol molecules can be translocated on the HDL surface. The generated cholesteryl esters are partially transferred to triglyceride rich apoB containing lipoprotein through a nonenzymatic process mediated by cholesteryl ester transfer protein (CETP) in exchange for triglyceride. The hepatic uptake of the cholesterol released from peripheral cells may thus proceed via an HDL-receptor, the SR-BI and through the LDL receptor route. Hepatic lipase (HL) facilitates the selective uptake of cholesteryl esters by the hepatocytes by exerting a lipolytic effect and a ligand-binding effect, bridging the lipoprotein particles to the heparan sulfate proteoglycans on cells surface and allowing the transcytosis of cholesteryl esters. Studies on genetically modified animals and on humans with severe genetic deficiencies demonstrated that abnormalities of the various components of RCT would accelerate atherogenesis. Clinical studies revealed that the development of coronary artery disease (CAD) may by delayed by increased HL activity in patients with familial hypercholesterolemia (heterozygotes), while in hypertriglyceridemic patients an increased plasma CETP and HL levels would favor the generation of less lipidated HDL and of small dense atherogenic LDL particles.

Effect of abdominal obesity on prothrombotic tendency in type 2 diabetes. Behavior of clotting factors VII and VIII, fibrinogen and von Willebrand Factor.

Patients with type 2 diabetes and abdominal fat patterning displayed higher plasma activities of clotting factors VII and VIII as well as increased plasma levels of fibrinogen and von Willebrand factor antigen, when compared with not only healthy normal weight controls, but also with diabetic patients at normal body weight. Mechanisms associating abdominal obesity with the above mentioned prothrombotic changes are only partially elucidated and may differ according to the individual haemostatic variable. Actually, according to data in the literature and authors' observations increased plasma factor VII activity is mainly associated with increased plasma triglyceride level, while the hepatic synthesis of fibrinogen as well as the synthesis and release of endothelia-derived von Willebrand factor are stimulated by cytokines originating in the visceral adipose tissue. The relationship between the presently investigated hemostatic variables and features of the metabolic syndrome are less obvious than in the previously recorded association of metabolic risk factors with plasma levels of plasminogen activator inhibitor.

Metabolic syndrome--practical approach.

The diagnosis of metabolic syndrome is based on identification of the following parameters: abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, fasting glycemia, as recommended by ATP III. In order to simplify the clinical practice, at least two parameters should be screened for. The most frequent couple, easy to be determined in practice, is hypertensive waist, followed by hypertriglyceridemic waist, hypertensive dyslipidemia, dysglycemic dyslipidemia and hypertensive dysglycemia. Based on these couples the next step would be to identify the triads that diagnose the metabolic syndrome. A global assessment of cardiovascular risk should be made. Suggested method is to apply the Framingham Score. Therapeutic intervention is structured according to levels of cardiovascular risk. Clinical management is structured on THEME Programs (therapy, education, monitoring, evaluation), applied to all risk factors.

Metabolic syndrome--new insights into a growing entity.

Metabolic syndrome is a cluster of cardiovascular risk factors. Pathogenesis of metabolic syndrome implies 3 potential etiological mechanisms: obesity and adipose tissue disorders, insulin resistance, and a constellation of independent factors. Clinical recognition of the metabolic syndrome is based on finding several well-recognized signs in clinical practice: abdominal obesity, elevated triglycerides, reduced HDL cholesterol, raised blood pressure, and elevated plasma glucose. In addition, other components commonly aggregate with the major components: elevated apolipoprotein B, small LDL particles, insulin resistance and hyperinsulinemia, impaired glucose tolerance (IGT), elevated C-reactive protein (CRP), and variation in coagulation factors (plasminogen activator inhibitor [PAI]-I and fibrinogen). Cardiovascular disease (CVD) is the primary clinical outcome of metabolic syndrome. Additionally, risk for type 2 diabetes is higher. Diabetes is itself a major risk factor for CVD. ATP III criteria for diagnosis of metabolic syndrome provide a practical tool to identify patients at increased risk for CVD. World Health Organization (WHO) and American Association of Clinical Endocrinologists (AACE) criteria require further oral glucose testing if IFG and diabetes are absent. IGT on OGTT denotes greater risk for diabetes than does metabolic syndrome without elevated fasting glucose.

Heart failure and diabetes.

Diabetes substantially increases the risk of heart failure both in men and women, being included in the Stage A classification of heart failure by the American Societies of Cardiology. The main etiological factors contributing to heart failure in diabetes are coronary artery disease, systemic hypertension and diabetic cardiomyopathy, the latter being invoked in case of heart failure where the first two factors are missing. Renal insufficiency and obesity may also play a role. The diagnosis will follow the same steps as in non-diabetic subjects: careful and periodic assessment for signs and symptoms of heart failure in all diabetic patients, echocardiography to assess the systolic and diastolic function of the left ventricle, and B-type natriuretic peptide level (as a marker of left ventricular dysfunction). The therapeutic approach will include non-pharmacological measures and pharmacological treatment. Patients with diabetes and heart failure benefit of the same drugs as non-diabetic subjects, including beta-blockers, which should not be avoided in patients with diabetes. The antihyperglycemic agents that should not be used in patients with heart failure are biguanides and thiazolidindiones (pioglitazone can be used in NYHA I and II classes). Approaches that were proven to reduce the risk of heart failure in diabetes are blood pressure and lipid control, treatment with ACE inhibitors in patients with diabetes and other cardiovascular risk factors and improvement of the glycemic control.

Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes.

This trial compared the efficacy and safety of basal-bolus therapy using either the soluble basal insulin analogue insulin detemir (IDet) in combination with meal-time rapid-acting analogue insulin aspart (IAsp), or NPH insulin (NPH) in combination with meal-time regular human insulin (HSI). This was a 22-week, multinational, open-labelled, symmetrically randomised, parallel group trial including 395 people with type 2 diabetes (IDet + IAsp: 195, NPH + HSI: 200). At 22 weeks, HbA1c was comparable between treatments (IDet + IAsp: 7.46%, NPH + HSI: 7.52%, P = 0.515) with decreases from baseline of 0.65% and 0.58%, respectively. Treatment with IDet + IAsp was associated with a significantly lower within-person variation in self-measured fasting plasma glucose (FPG) (SD:1.20 versus 1.54 mmol/L, p < 0.001), as well as a lower body weight gain (0.51 versus 1.13 kg, p = 0.038) than with NPH + HSI. The risk of nocturnal hypoglycaemia was 38% lower with IDet + IAsp than with NPH + HSI, but statistical significance was not attained (P = 0.14). The overall safety profile was similar between the two treatments. Basal-bolus treatment with IDet + IAsp is an effective and well tolerated insulin regimen in people with type 2 diabetes, resulting in glycaemic control comparable to that of NPH + HSI, but with the advantages of less weight gain and a lower day-to-day within-person variation in FPG.

Diet and coronary heart disease in diabetes.

Persons with diabetes mellitus have an increased cardiovascular morbidity and mortality and therefore it is imperative to identify and treat aggressively all cardiovascular risk factors. The first line of intervention aiming to reduce the cardiovascular burden is dietary therapy along with other recommendations for lifestyle modification. Compliance with life-long dietary changes is a major issue and therefore emphasis should be placed on whole foods and dietary consumption habits. Also, dietary changes should be individualised according to patient's nutritional needs, lifestyle, cultural eating habits, taking into consideration all risk factors and existing comorbidities. Nevertheless, at least two main strategies have been proven to be effective in preventing coronary heart disease: 1). modification of fat quality through substitution of saturated fat, dietary cholesterol and trans- fatty acids with non-hydrogenated mono-and poly-unsaturated fats and increased consumption of omega-3 fatty acids; 2). modification of carbohydrate quality by choosing high-cereal fiber and low-glycaemic load intakes instead of refined grain products. Although the best diet for reducing cardiovascular risk remains uncertain, a combination of dietary interventions offers great benefits in preventing coronary events.

Serum cholinesterase activity correlates with serum insulin, C-peptide and free fatty acids levels in patients with type 2 diabetes.

When compared with values recorded in 14 control subjects, the 15 overweight patients with type 2 diabetes displayed significantly increased activities of serum alanineaminotransferase (172% of mean values in controls), gamma-glutamyltransferase (253%) and cholinesterase (139%). A much wider dispersion of individual values for the two firstly mentioned enzymes was however noted so that their correlation with serum triglycerides levels were weaker (r = 0.373; p < 0.05 and r = 0.451; p < 0.05 respectively) than the same correlation obtained for serum cholinesterase (r = 0.760; p < 0.001). In two other studies including 28 controls and 30 diabetic patients serum cholinesterase was found to be significantly correlated with serum levels of insulin (r = 0.622; p < 0.001), C-peptide (r = 0.652; p < 0.001) and free fatty acid (r = 0.821; p < 0.001). Circumstantial evidence is provided that insulin resistance and an increased flux of free fatty acids from adipose tissue to the liver would stimulate the hepatic synthesis of serum cholinesterase.

Lipoprotein (a) concentrations in patients with familial combined hyperlipidemia and hypertension.

BACKGROUND: Lipoprotein (a) (Lp(a)) is an independent risk factor for coronary heart disease (CHD), and its association with hyperlipidemia and/or hypertension greatly increases the risk of premature CHD. METHODS: The present study assessed plasma concentrations of Lp(a) in hyperlipidemic subjects from families with well-defined familial combined hyperlipidemia (FCH) (n = 262) and from patients with hypertension (n = 168), and to compare it with Lp(a) plasma levels in healthy volunteers (n = 371). Lp(a) concentrations were measured using a specific radioimmunoassay. RESULTS: The Lp(a) plasma concentrations were similar in FCH patients (median 204 mg/l, range 16-2163 mg/l) and in the control group (155, 16-1846 mg/l; P > 0.05). The Lp(a) levels in patients with hypertension (157, 10-1985 mg/l) did not differ from those of controls (P > 0.05). The Lp(a) concentrations were similar in patients with essential hypertension (EH) and normal lipid levels, and in hyperlipidemic EH patients. A tendency towards higher levels of Lp(a) was observed in patients with secondary hypertension due to renal artery stenosis (RAS) (n = 26, Lp(a) 232, 16-1110 mg/l), but this was not statistically significant. CONCLUSIONS: Plasma concentrations of Lp(a) are similar in patients with FCH, with EH, either normo- or hyperlipidemic, and with RAS, when compared with healthy controls. However, measuring the Lp(a) levels in patients with either hyperlipidemia or hypertension remains important for assessing the risk potential for severe atherosclerosis in these patients.

High glucose concentrations increase the tumor necrosis factor-alpha production capacity by human peripheral blood mononuclear cells.

The proinflammatory cytokines tumor necrosis factor-a (TNF) and interleukin-1b (IL-1) play an important role in the pathogenesis of insulin-dependent diabetes mellitus, while TNF is also involved in promoting insulin resistance. It has been recently shown that glucose can induce the synthesis of TNF and IL-6 in human monocytes. The aim of the present study was to investigate the effect of glucose on unstimulated and lipopolysaccharide (LPS)-induced TNF and IL-1 production by human peripheral blood mononuclear cells (PBMC). No effect of glucose on spontaneous release of TNF or IL-I could be observed. The LPS-stimulated production of TNF was enhanced when cells were preincubated with increasing glucose concentrations. In contrast, no effect of glucose preincubation on LPS-induced IL-I synthesis was found. In conclusion, high glucose concentrations can increase the stimulated TNF production capacity, with possible important consequences for patients with diabetes mellitus.

Interleukin 1 beta, tumour necrosis factor-alpha and interleukin 1 receptor antagonist in newly diagnosed insulin-dependent diabetes mellitus: comparison to long-standing diabetes and healthy individuals.

Interleukin 1 beta (IL-1) and tumour necrosis factor alpha (TNF) are important for the beta cell lysis in insulin-dependent diabetes mellitus (IDDM), while IL-1 receptor antagonist (IL-1ra) is considered protective by blocking the effects of IL-1. Serum concentrations and ex-vivo production of IL-1, TNF and IL-1ra were examined in 10 newly diagnosed IDDM (ND-IDDM) patients, and compared with 11 long-standing IDDM (LS-IDDM) patients and 14 healthy volunteers. Ex-vivo LPS-stimulated production of IL-1 in ND-IDDM patients was significantly increased compared with LS-IDDM patients and healthy controls, while TNF and IL-1ra synthesis did not differ significantly. IL-1ra/IL-1 ratio was significantly decreased in ND-IDDM, and returned to normal values in the LS-IDDM group. Circulating concentrations of IL-1ra in LS-IDDM patients were increased. These data suggest a proinflammatory imbalance in ND-IDDM patients and this may play an important role in beta cell loss.