Soluble TNF receptors and albuminuria in non-obese Japanese type 2 diabetic patients.

The aim of this study was to investigate the relationships between albuminuria and tumor necrosis factor (TNF)-alpha or soluble TNF receptors (sTNF-R1, sTNF-R2) in eighty-eight non-obese Japanese type 2 diabetic patients stratified into two groups according to albuminuria status-microalbuminuria or normoalbuminuria. Patients with microalbuminuria were older and had significantly higher concentrations of sTNF-R1 and sTNF-R2 than those with normoalbuminuria. There was, however, no significant difference in sex, diabetes duration, smoking, BMI, systolic and diastolic blood pressure, HbA (1c), serum creatinine, and lipid profile between the two groups. Although serum TNF-alpha was positively correlated to serum sTNF-R1 and sTNF-R2, serum TNF-alpha level did not differ with respect to albuminuria. Univariate regression analysis showed that urinary albumin concentration was positively correlated to age (r=0.380, p<0.001), serum creatinine (r=0.214, p<0.05) and concentrations of sTNF-R1 (r=0.364, p<0.001) and sTNF-R2 (r=0.342, p<0.005). Other variables, including TNF-alpha, were not associated with albuminuria. Multiple regression analyses showed that urinary albumin concentration was independently predicted by the level of sTNF-R1 (F=32.1), which explained 26.3% of the variability of urinary albumin concentration. From these results, it can be concluded that serum soluble TNF receptor is an important independent factor associated with albuminuria in non-obese Japanese type 2 diabetic patients.     

Mitochondrial haplogroups associated with Japanese centenarians,Alzheimer＇s patients,Parkinson＇s patients,type 2 diabetic patients and healthy non-obese young males

The relationships between five classes of Japanese people （i.e., 96 centenarians, 96 Alzheimer＇s disease （AD） patients, 96 Parkinson＇s disease （PD） patients, 96 type 2 diabetic （T2D） patients, and 96 healthy non-obese young males） and their mitochondrial single nucleotide polymorphism （mtSNP） frequencies at individual mtDNA positions of the entire mitochondrial genome were examined using the radial basis function （RBF） network and the modified method. New findings of mitochondrial haplogroups were obtained for individual classes. The five classes of people were associated with the following haplogroups： Japanese centenarians-M7b2, D4b2a, and B5b; Japanese AD patients-G2a, B4cl, and N9b1; Japanese PD patients-M7b2, B4e, and B5b; Japanese T2D patients-B5b, M8al, G, D4, and F1; and Japanese healthy non-obese young males-D4g and D4b1b. From the points of common haplogroups among the five classes, the cente- narians have the common haplogroups M7b2 and B5b with the PD patients and common haplogroup B5b with the T2D patients. In addition, the 112 Japanese semi-supercentenarians （over 105 years old） recently reported were also examined by the method proposed. The results obtained were the haplogroups D4a, B4c1a, M7b2, F1, M1, and B5b. These results are different from the previously reported haplogroup classifications. As the proposed analysis method can predict a person＇s mtSNP constitution and the probabilities of becoming a centenarian, AD patient, PD patient, or T2D patient, it may be useful in initial diagnosis of various diseases.     

Effect of short-term low-intensity exercise on insulin sensitivity, insulin secretion, and glucose and lipid metabolism in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the effects of short-term physical exercise that did not change body mass on insulin sensitivity, insulin secretion, and glucose and lipid metabolism in 39 non-obese Japanese type 2 diabetic patients. Insulin sensitivity and insulin secretion were estimated with homeostasis model assessment insulin resistance (HOMA-IR) and HOMA-B-cell function proposed by Matthews et al., respectively. All patients were hospitalized and were engaged in low-intensity exercise that consisted of walking and dumbbell exercise for successive 7 days. There were no changes in hospital diet and the dose of any medications used throughout the study. Fasting glucose, insulin, and lipids were measured before and after exercise.After exercise, serum triglyceride levels significantly decreased, but no significant changes were observed in total and HDL cholesterol concentrations. Fasting glucose, insulin, and HOMA-IR levels significantly decreased after exercise, but HOMA-B-cell function did not change during the study. There was no significant difference between BMI levels before and after exercise.From these results, it can be concluded that short-term (7 days) low-intensity physical exercise combined with hospital diet reduces serum triglycerides, insulin resistance, and fasting glucose levels without affecting BMI in non-obese Japanese type 2 diabetic patients.     

Similar incretin secretion in obese and non-obese Japanese subjects with type 2 diabetes

Incretin secretion and effect on insulin secretion are not fully understood in patients with type 2 diabetes. We investigated incretin and insulin secretion after meal intake in obese and non-obese Japanese patients with type 2 diabetes compared to non-diabetic subjects. Nine patients with type 2 diabetes and 5 non-diabetic subjects were recruited for this study. Five diabetic patients were obese (BMI ? 25) and 4 patients were non-obese (BMI < 25). In response to a mixed meal test, the levels of immunoreactive insulin during 15-90 min and C-peptide during 0-180 min in non-obese patients were significantly lower than those in obese patients. Total GLP-1 and active GIP levels showed no significant difference between obese and non-obese patients throughout the meal tolerance test. In addition, there were no significant differences between diabetic patients and non-diabetic subjects. In conclusion, incretin secretion does not differ between Japanese obese and non-obese patients with type 2 diabetes and non-diabetic subjects.     

Soluble LDL-immune complexes in type 2 diabetes and vascular disease.

BACKGROUND AND AIMS: The oxidative modification of LDL has been shown to affect its clearance and to exert cytotoxic and immunogenic effects. The objective of our study was to analyse markers of LDL oxidation-soluble LDL containing immune complexes (LDL-ICs) in type 2 diabetes with micro- and macrovascular disease. PATIENTS AND METHODS: The study included 69 diabetic patients with coronary artery disease (DM + CAD), 78 non-diabetics with CAD, 47 controls, and 27 diabetics with nephropathy and 36 free from complications. OxLDL antibodies and advanced glycated end-products were measured by ELISA, and LDL-IC apo B content after PEG precipitation. RESULTS: Determination of a broad range of oxLDL antibody activity in all study groups showed no significant differences. In contrast, the content of apo B, a component of the antigen moiety of oxLDL-ICs, was higher in CAD and diabetes (+ CAD) than in LDL-ICs isolated from controls (p < 0.001). LDL-ICs did not differ between patients with CAD + DM and CAD patients free from diabetes. LDL-IC levels in diabetic patients with or without microangiopathy were significantly higher than in healthy volunteers (PEG-apo B 0.278 +/- 0.107 vs. 0.165 +/- 105 g/l, p < 0.002; PEG-IgG 151.7 +/- 76 vs. 115.4 +/- 62 g/l, p < 0.05). However, there was no significant difference in the level of circulating LDL-ICs between the subgroup of diabetic patients with nephropathy/retinopathy and patients free of microvascular disease (Ab-oxLDL 27.7 +/- 10.4 vs. 27.1 +/- 9.3 AU, NS; PEG-apo B 0.324 +/- 0.111 vs. 0.287 +/- 0.124 g/l, NS; PEG-IgG 1.68 +/- 0.68 vs. 1.42 +/- 0.80 g/l, NS). There was a statistically significant positive correlation between AGE content and LDL-ICs (r = 0.35, p < 0.009). A significant but inverse correlation was recorded between triglyceride concentration and level of LDL-ICs in DM + CAD (r = - 0.32, p < 0.016) and CAD patients (r = - 0.35, p < 0.002). A highly significant negative correlation between triglycerides and circulating LDL-ICs (r = - 0.54, p < 0.039) was observed in patients with early nephropathy, but not in those with physiological proteinuria. It is known that at a high triglyceride level in type 2 diabetes, the majority of LDL are small and dense, thus being more susceptible to oxidative modification. This could be a possible mechanism explaining why more LDL-ICs, with a level inversely correlating with triglyceride concentration, are generated in diabetes. CONCLUSION: The increased level of circulating LDL-ICs is a risk factor for the general population, including those with diabetes. Our results suggested the contribution of LDL-ICs to the development of atherosclerosis to probably be more significant than the direct contribution of oxLDLAb itself.     

Waist-to-height ratio and coronary artery disease in Taiwanese type 2 diabetic patients

Waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHeiR), and BMI are indicators for obesity. This study examined the usefulness of these indicators for coronary artery disease (CAD) in Taiwanese type 2 diabetic patients. A total of 1,345 (646 men and 699 women) patients aged 63.3 +/- 11.5 years were studied. CAD was defined by history or Minnesota-coded electrocardiogram. The relative importance was evaluated by the magnitude of adjusted odds ratio per 1-s.d. increment, the decrease in -2 log likelihood after adding the index to the logistic model, the c-index, and the Akaiki's information criterion (AIC). Results showed that the four indices were highly intercorrelated and except BMI for men, all indices differed significantly between patients with and without CAD in either sex. In logistic regressions, the respective adjusted odds ratios for WC, WHR, WHeiR, and BMI for every 1-s.d. increment were 1.209 (1.010-1.448), 1.109 (0.935-1.316), 1.231 (1.027-1.474), and 1.207 (0.997-1.461) for men; and were 1.176 (0.995-1.390), 1.105 (0.923-1.322), 1.280 (1.079-1.518), and 1.277 (1.083-1.507) for women. Only WHeiR was significant for both sexes and it also showed the greatest decrease in -2 log likelihood, the largest magnitude of odds ratio, and the smallest AIC while compared with the other indices in either sex. It is concluded that WHeiR has the superiority of independent association with CAD and the highest magnitude of association than WC, WHR, and BMI in both sexes. The usefulness of WHeiR should not be neglected in clinical practice.     

Blood-soluble Fas levels are increased in type 2 diabetic patients with peripheral vascular disease.

AIM: To investigate the possible utility of plasma sFas (soluble Fas) levels as a marker of peripheral vascular disease (PVD) in type 2 diabetic patients, and the relationship between classical cardiovascular risk factors and sFas levels in these patients. MATERIALS AND METHODS: sFas levels were measured in 57 type 2 diabetic patients with and 60 without PVD matched for age and sex. Diagnosis of PVD was established in presence of at least one of the following criteria: leg or foot amputation of vascular cause, lower-extremity arterial angioplasty or surgical by-pass, or ankle-braquial index (ABI) less than 1 in at least one side of the body. ELISA was used to measure sFas levels. RESULTS: None of the risk factors assessed total cholesterol, HDL cholesterol, triglycerides, CRP, ACE, fibrinogen, Lp(a) and homocysteine was significantly different between both groups of patients. However, patients with PVD had higher plasma sFas levels than the group without PVD (10.25+/-3.7 ng/ml VS. 8.86+/-2.6 ng/ml; p=0.02). Levels of sFas were 1.45 ng/ml (95% CI: 0.32-2.58; p=0.013) higher in PVD patients when adjusting by age, total, HDL and LDL cholesterol, triglycerides, homocysteine, CRP, ACE, arterial hypertension and tobacco smoking. Using multiple logistic regression sFas is a predictor of PVD, although not potent. CONCLUSION: Plasma sFas may be an independent marker of PVD in type 2 diabetes mellitus patients.     

Association between osteoprotegerin gene polymorphisms and cardiovascular disease in type 2 diabetic patients

Osteoprotegerin (OPG) gene polymorphisms (T245G, T950C and G1181C) have been associated with osteoporosis and early predictors of cardiovascular disease. The aim of this study was to evaluate whether these polymorphisms contribute to cardiovascular disease (CVD) in type 2 diabetic patients. We performed a case-control study with 178 CVD subjects with diabetes and 312 diabetic patients without CVD to assess the impact of variants of the OPG gene on the risk of CVD. The OPG gene polymorphisms were analyzed by using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). There was no significant association between the T245G and G1181C polymorphisms and CVD in the additive genetic model (OR = 0.96, 95% CI 0.64–1.45, p = 0.79; OR = 1.06, 95% CI 0.81–1.39, p = 0.65, respectively). However, the C allele of the T950C polymorphism was independently associated with a risk of CVD in type 2 diabetic patients in this genetic model (OR = 1.38, 95% CI 1.07–1.80, p = 0.01). This study provides evidence that the C allele of the T950C polymorphism is associated with increased risk of CVD in diabetic patients. However, well-designed prospective studies with a larger sample size are needed to validate these results.     

Eryptosis and oxidative damage in type 2 diabetic mellitus patients with chronic kidney disease

It has been suggested that oxidative stress may participate in the progression of diabetes and its complications. Long-term complications of type 2 diabetes mellitus (T2DM) include retinopathy, atherosclerosis, shortened life span of erythrocytes, nephropathy, and chronic kidney disease (CKD). Oxidative damage has been associated with erythrocyte apoptosis induction in other pathological conditions. Our aim was to study the presence of eryptosis and its possible relationship with oxidative damage in patients with T2DM without CKD (T2DM/CKD(-)) and in patients with T2DM and CKD (T2DM/CKD(+)).Oxidative damage of lipids erythrocytes were increased in diabetic patients. The highest lipoperoxidation was found in T2DM/CKD(+). Likewise, the lower plasma total antioxidant capacity, GSH/GSSG ratio, and GSH in erythrocytes were found in T2DM/CKD(+) patients. A negative correlation was found between plasma total antioxidant capacity and oxidative damage. Phosphatidylserine (PS) externalization was measured in erythrocytes to evaluate eryptosis. Annexin binding in erythrocytes of T2DM/CKD(+) patients was higher than in healthy subjects and T2DM/CKD(-) patients. A positive correlation between lipoperoxidation and PS externalization in erythrocytes was found. This work showed that the erythrocytes of diabetic patients have increased oxidative damage, a reduction of antioxidant systems and more erythrocyte PS externalization. The duration of diabetes and the presence of CKD increase both oxidative damage and eryptosis. It is possible that a longer time of evolution induces an increase in erythrocyte oxidative damage and the consumption of blood antioxidant systems, adding to the osmotic stress in CKD and so contributes to an increase in PS externalization in diabetic patients.     

Soluble interleukin 2 receptor in atopic eczema.

OBJECTIVE--To determine whether serum soluble interleukin 2 receptor concentrations are related to disease activity in atopic eczema. DESIGN--Single cohort longitudinal study with controls. SETTING--Outpatient and general medicine departments in secondary referral centre. PATIENTS--Of 15 patients aged 17-57 with severe atopic eczema, all with acute exacerbations of disease, 13 were admitted to hospital and two treated as outpatients until the skin lesions had resolved or greatly improved. Nineteen controls gave single blood samples. INTERVENTIONS--Daily skin dressing with betamethasone valerate (0.025%) and ichthammol paste and tubular dressings. END POINT--Resolution of or considerable improvement in skin lesions. MEASUREMENTS AND MAIN RESULTS--Enzyme linked immunosorbent assays (ELISA) were used to measure serum soluble interleukin 2 receptor concentrations in blood samples taken on admission, at intervals subsequently, and on discharge. Clinical scores of disease activity were also made. Median concentrations on admission were significantly higher (770 U/ml) in the patients than the controls (300 U/ml). Concentrations fell significantly during treatment. In 25 assessments made at different times in 13 patients serum soluble interleukin 2 receptor concentration correlated significantly (R = 0.73) with clinical disease activity. CONCLUSIONS--Cellular immunopathogenic mechanisms contribute to atopic eczema. Immune activation can be measured in atopic eczema by measurements of soluble interleukin 2 receptor, and this should facilitate assessment of response to treatment.     

Oxidative protein damage in plasma of type 2 diabetic patients.

In this study, we evaluated protein oxidation in 84 patients with Type 2 diabetes with no complications and in 61 healthy volunteers who formed the control group, whose ages matched those of the patients. We determined plasma carbonyl and plasma thiol levels as markers of oxidative protein damage and erythrocyte glutathione, plasma ceruloplasmin and transferrin as markers of free radical scavengers. The concentrations (mean +/- SD) of both of plasma carbonyl (1.24 +/- 0.46 vs. 0.72 +/- 0.17 nmole/mg protein; p < 0.0001) and lipid hydroperoxides (1.8 +/- 0.63 vs. 1.3 +/- 0.21 micromole/l; p < 0.0001) were increased, and the concentration of plasma transferrin (3.85 +/- 0.65 vs. 4.59 +/- 0.79 g/l; p < 0.05) was decreased, respectively, in Type 2 diabetic patients compared with those of the controls. There were no significant differences in the concentrations of plasma thiol (0.0064 +/- 0.001 vs. 0.0068 +/- 0.001 micromole/mg protein), erythrocyte glutathione (2.54 +/- 0.57 vs. 2.65 +/- 0.56 mg/g Hb), plasma ceruloplasmin (548 +/- 107.30 vs. 609 +/- 93.34 mg/l) between the patients and the controls. These changes observed in diabetic patients contribute to the imbalance in the redox status of the plasma. We attribute this imbalance to oxidative protein damage in Type 2 diabetic patients clinically free of complications.     

Metformin increases blood flow and forearm glucose uptake in a group of non-obese type 2 diabetes patients.

The present study was designed to determine the effects of metformin on the forearm glucose uptake and blood flow after an oral glucose challenge. Eleven normal subjects, and ten non-obese type 2 diabetes patients without medication of anti-hyperglycemic drug and with medication of metformin for four weeks, were studied after an overnight fast (12-14 h) and 3 hours after ingestion of 75 g of glucose. Peripheral glucose metabolism was analyzed by the forearm technique combined with indirect calorimetry. The forearm glucose uptake increased in diabetes patients taking metformin (63.5+/-9.1 VS. 39.1+/-5.3 mg/100 ml FA. 3 h). The increase of forearm glucose uptake was due to increase of blood flow. The glucose oxidation was greater in the group treated with metformin, compared to the same group without anti-hyperglycemic drug (19.3+/-2.6 VS. 7.7+/-2.6 mg/100 ml FA. 3 hrs). The free fatty acids were higher in diabetes patients, which normalized after taking metformin. In conclusion, it was found that in these participants metformin acts in insulin resistance; it increases glucose muscle uptake and blood flow. The enhancement of blood flow and lower free fatty acids, not described yet, could be direct effects of the drug or due to reduced glucose toxicity. These positive effects must be responsible for the improvement in vascular function.     

Protein carbonyl content in erythrocyte membranes in type 2 diabetic patients.

Protein carbonyl groups result from free radical-induced protein oxidation; their level in tissues and plasma is a relatively stable marker of oxidative damage. Protein carbonyl contents in erythrocyte membranes were investigated in the type 2 diabetic patients with good (n = 16) and poor (n = 30) glycemic control. Diabetic patients were classified as patients with (n = 20) and without (n = 26) angiopathy. Protein carbonyl content was evaluated using the 2,4-dinitro-phenyl-hydrazine method. Protein carbonyl content and GHb levels were significantly higher in both patients with poor and good glycemic control than in control subjects (p < 0.001 in each case). There was a significant difference in protein carbonyl content between patients with poor and good glycemic control (p < 0.001). Diabetic patients with angiopathy had significantly higher protein carbonyl content and GHb levels than the diabetic patients without angiopathy (p < 0.001). These results suggest that impaired glycemic control is connected to protein oxidation, and protein oxidation may be related to underlying metabolic abnormalities and complications of diabetes.     

TNF type 2 receptor (p75) lowers the threshold of T cell activation.

T cell activation requires a threshold amount of TCR-mediated signals, an amount that is reduced by signals mediated through costimulatory molecules expressed on the T cell surface. Here the role of TNFR2 (p75) as a putative costimulatory receptor for T cell activation was examined. It was found that p75 deficiency in CD8(+) T cells increased the requirements for TCR agonist approximately 5-fold. Furthermore, p75(-/-) T cells display a marked reduction in the proliferative response to TCR agonist. This hypoproliferative response was associated with delayed kinetics of induction of the acute activation markers CD25 and CD69 as well as a marked decrease in the production of IL-2 and IFN-gamma. The net result is that very few cells are recruited into the dividing population. Interestingly, CD28 costimulation was only partially effective in rescuing the proliferative defect of p75(-/-)CD8(+) T cells. Thus, p75 provides an important costimulatory signal in addition to that provided by CD28 toward optimal T cell proliferation.     

Distinct differences between TNF receptor 1- and TNF receptor 2-mediated activation of NFkappaB

Tumor necrosis factor (TNF) signaling is mediated via two distinct receptors, TNFR2 and TNFR1, which shows partially overlapping signaling mechanisms and biological roles. In the present study, TNFR2 and TNFR1 signal transduction mechanisms involved in activation of NFkappaB and CMV promoter-enhancer were compared with respect to their susceptibility towards inhibitors of intracellular signaling. For this, we used SW480 cells, where we have shown that TNF-signaling can occur independently through each of the two receptors. The TNFR1 response was inhibited by D609, bromophenacyl bromide (BPB), nordihydroguararetic acid (NDGA), and by sodium salicylate, while TNFR2-mediated activation of NFkappaB and CMV promoter-enhancer was resistant to these compounds. The signaling mechanisms known to be affected by these inhibitors include phospholipases as well as redox- and pH-sensitive intracellular components. Our results imply that TNFR2 signaling involved in NFkappaB activation proceeds independently of these inhibitor-sensitive signaling components, indicating distinct signaling pathways not shared with TNFR1.     

Thiazolidinediones improve beta-cell function in type 2 diabetic patients

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved beta-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P<0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7 (PIO+drug-na?ve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2 (ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.     

Tumor necrosis factor (TNF) receptor type 2 is an important mediator of TNF alpha function in the mouse ovary

It is believed that a finite pool of primordial follicles is established during embryonic and neonatal life. At birth, the mouse ovary consists of clusters of interconnected oocytes surrounded by pregranulosa cells. Shortly after birth these structures, termed germ cell cysts or nests (GCN), break down to facilitate primordial follicle formation. Tumor necrosis factor alpha (TNF) is a widely expressed protein with myriad functions. TNF is expressed in the ovary and may regulate GCN breakdown in rats. We investigated whether it participates in GCN breakdown and follicle formation in mice by using an in vitro ovary culture system as well as mutant animal models. We found that TNF and both receptors (TNFRSF1A and TNFRSF1B) are expressed in neonatal mouse ovaries and that TNF promotes oocyte death in neonatal ovaries in vitro. However, deletion of either receptor did not affect follicle endowment, suggesting that TNF does not regulate GCN breakdown in vivo. Tnfrsf1b deletion led to an apparent acceleration of follicular growth and a concomitant expansion of the primordial follicle population. This expansion of the primordial follicle population does not appear to be due to decreased primordial follicle atresia, although this cannot be ruled out completely. This study demonstrates that mouse oocytes express both TNF receptors and are sensitive to TNF-induced death. Additionally, TNFRSF1B is demonstrated to be an important mediator of TNF function in the mouse ovary and an important regulator of folliculogenesis.     

The effect of etomoxir on insulin sensitivity in type 2 diabetic patients.

Oral application of 50 mg Etomoxir caused a significant rise (33.1%) of insulin-mediated glucose uptake. This was shown in a placebo-controlled, double-blind randomized study in 8 type 2 diabetic patients by using the euglycemic clamp technique. The mean metabolic clearance rate of glucose (MCR) was raised from 4.1 +/- 0.9 mg/(kg.min) to 5.4 +/- 1.2 mg/(kg.min) (x +/- SEM, P = 0.039). Plasma levels of free fatty acids (FFA), glucose counterregulatory hormones, lipids and C-peptide values during the clamps were not different after verum and placebo. We conclude that Etomoxir improves insulin sensitivity in type 2 diabetic patients.     

Lack of association between an ecNOS gene polymorphism and diabetic nephropathy in type 2 diabetic patients with proliferative diabetic retinopathy.

The development of diabetic nephropathy shows remarkable variation among individuals. Therefore, not only hyperglycemia but also genetic factors may contribute to the development of diabetic nephropathy. The aim of the present study was to examine the contribution of the 27-bp repeat polymorphism in intron 4 of the endothelial constitutive nitric oxide synthase gene (ecNOS4) to the development of diabetic nephropathy. For this purpose, we analyzed this polymorphism in 167 Japanese type 2 diabetic patients with proliferative diabetic retinopathy consisting of 102 patients with diabetic nephropathy (with macroalbuminuria) and 65 patients without diabetic nephropathy (with normoalbuminuria). The genotype and allele frequencies were not significantly different between patients with diabetic nephropathy and those without diabetic nephropathy (ecNOS4 "b/b" 79.4% vs. 84.6%, ecNOS4 "b/a" 20.6% vs. 15.4%, "b" allele 89.7% vs. 92.3%, "a" allele 10.3% vs. 7.7%). We conclude that the ecNOS4 polymorphism does not contribute to the development of diabetic nephropathy.