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PubMed1997

Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys.

Estrogen replacement therapy (ERT) decreases the progression of coronary artery atherosclerosis in monkeys. Dietary soy protein also retards the progression of atherosclerosis relative to animal proteins such as casein. Soy protein contains weakly estrogenic compounds called isoflavones or phytoestrogens that may be responsible for the cardioprotective effects. This study was designed as a 2 x 2 factorial to determine the magnitude of soy protein's effects on cardiovascular risk factors relative to casein and lactalbumin, with or without estradiol treatment. Ovariectomized female monkeys were randomized to four treatment groups based on past dietary cholesterol consumption, their origin, and past reproductive history, and studied for 7 months. The animals were divided into (1) a group fed casein and lactalbumin as the protein source (n = 14), (2) a group fed casein and lactalbumin as the protein source plus 17 beta-estradiol (E2) (n = 13), (3) a group fed soybean protein isolate as the protein source (n = 11), and (4) a group fed soybean protein isolate as the protein source plus E2 (n = 10). Soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentrations, a significant improvement in insulin sensitivity and glucose effectiveness as determined by minimal-model analyses, and a decrease in arterial lipid peroxidation. E2-treated monkeys had a significant reduction in fasting insulin levels and insulin to glucose ratios, total body weight, and amounts of abdominal fat, and had smaller low-density lipoprotein (LDL) particles. In addition, E2 treatment resulted in a significant reduction (P = .001) in aortic cholesteryl ester content. A similar trend (P = .14) was found for soy protein compared with casein. There also was a significant interaction (P = .02) with soy and E2, such that animals consuming soy protein +E2 had the least arterial cholesteryl ester content. These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors. Interestingly, the two treatments affected different risk factors and together resulted in the greatest reduction in arterial cholesterol content. Further studies are needed to determine the active component of the soy protein and to assess its long-term effects on the cardiovascular system and other organ systems (such as the bones and reproductive system).

Aging↗
PubMed1996

Long-term assessment of glucose control by haemoglobin-AGE measurement.

BACKGROUND: Control of blood glucose is important in reducing both the incidence and the severity of complications in diabetes mellitus. One consequence of long- term hyperglycaemia is the formation and accumulation of advanced glycation end-products (AGEs) on tissue macromolecules. An AGE-modified form of human haemoglobin (Hb-AGE) present at high levels in the red cells of diabetic patients, differs from glucose-derived Amadori product HbA1c in being chemically irreversible and thus persisting for the circulating life of the red cell. We therefore compared Hb- AGE with HbA1c as indicators of long-term blood glucose control. METHODS: In an open study we measured circulating HbA1c and Hb-AGE concentrations in eight patients with poorly controlled non-insulin-dependent diabetes after a switch to subcutaneous insulin therapy and careful blood glucose monitoring. RESULTS: After 16 weeks of insulin therapy, the mean HbA1c had decreased from 13.3 (SD 1.2) to 7.3 (0.9)% and the mean Hb-AGE from 12.1 (1.5) to 7.3 (1.3) U/mg Hb. The rate of Hb-AGE decline was 23% slower than that of HbA1c (p=0.044). INTERPRETATION: The observation that Hb-AGE declines more slowly than HbA1c is consistent with the irreversible nature of the AGE product. Because of this property, Hb-AGE may prove superior to HbA1c as a long-term index of circulating glucose concentrations.

Blood Glucose↗
PubMed2002

Effect of hyperglycemia on the basal cytosolic free calcium level, calcium signal and tyrosine-phosphorylation in human T-cells.

In this study, we investigated the effect of in vitro hyperglycemia on the function of human T-cells (Jurkat cells). Hyperglycemic conditions caused concentration-dependent elevation of basal cytosolic free calcium level and reduced calcium signal (activation capacity), either after ionomycin or monoclonal anti-CD3 antibody treatments. Similar changes were observed if cells were treated with the calcineurin inhibitor Cyclosporin-A. We found that tyrosine-phosphorylation after anti-CD3 treatment was also impaired. High glucose concentrations in the tissue culture medium are also associated with increased non-enzymatic glycation of T-cell proteins. We propose that the increased glycation of proteins involved in calcium transport and/or intracellular signal transduction in T-cells accounts for the abnormal calcium sequestration and calcium mediated signal transduction.

Antibodies, Monoclonal↗
PubMed2002

Tumor necrosis factor system in insulin resistance in gestational diabetes.

OBJECTIVE: The aim of the study was to investigate the pathophysiological role of the tumor necrosis factor (TNF) system in insulin resistance in patients with gestational diabetes (GDM) and during the course of normal pregnancy. PATIENTS AND METHODS: Thirty women with GDM (16-39 gestational weeks), 35 healthy pregnant women (15 first, nine second and 11 third trimester) and 25 healthy age-matched non-pregnant women were studied. Serum TNF-alpha, and its soluble receptors 1 and 2 (sTNFR-1 and -2) were measured. RESULTS: In non-diabetic pregnant women in the third trimester all measures were significantly higher (P<0.05 or less) than in the first trimester and in non-pregnant women (BMI 27.6 +/- 4.1 (+/- S.D.), 24.1 +/- 2.6, 22.4 +/- 2.4 kg/m(2)), serum TNF-alpha (4.6 +/- 0.6, 4.1 +/- 0.4, 4.1 +/- 0.4 ng/l), sTNFR-1 (2.7 +/- 0.9, 2.0 +/- 0.5, 2.0 +/- 0.1 microg/l), sTNFR-2 (5.6 +/- 2.6, 4.6 +/- 2.1, 3.3 +/- 0.2 microg/l), C-peptide (3.1 +/- 1.7, 1.1 +/- 0.7, 1.1 +/- 0.8 microg/l), and C-peptide:blood glucose ratio (0.6 +/- 0.2, 0.2 +/- 0.1, 0.2 +/- 0.1 microg/mmol). In GDM these measures were even higher than in any subgroup of healthy pregnant women (BMI) (33.4 +/- 6.4 kg/m(2), TNF-alpha) (6.3 +/- 0.6 microg/l), sTNFR-1 (3.0 +/- 0.5 microg/l), sTNFR-2 (10.0 +/- 6.9 microg/l, C-peptide 6.0 +/- 2.7 microg/l, C-peptide:blood glucose ratio: 1.2 +/- 0.5 microg/mmol, P<0.01). Significant (P<0.01) positive linear correlations were found in gestational diabetic and non-diabetic women between serum TNF-alpha, C-peptide levels, and BMI. In gestational diabetic women, in multivariate analysis studying the dependency of C-peptide only BMI remained significant (r(2)=0.67, P=0.01). CONCLUSIONS: Our observation emphasizes the obesity-related component of insulin resistance driven by adipocytokines, such as TNF-alpha and its receptors during the course of normal pregnancy and GDM.

Antigens, CD↗
PubMed1997

Effect of an alpha-glucosidase inhibitor on glomerular basement membrane anionic sites in streptozotocin induced mildly diabetic rats.

The present study was conducted in order to examine the effect of acarbose, a potent alpha-glucosidase inhibitor, on renal function in rats with mild streptozotocin-diabetes. Male Wistar rats were made mildly diabetic by intravenous injection of streptozotocin (40 mg/kg) and were supplied a standard solid chow containing 0.1% acarbose for 8 weeks. Diabetic rats showed mild hyperglycemia under non-fasting condition and their urine albumin excretion (UAE) rate was markedly increased compared to non-diabetic control rats, while acarbose treatment resulted in a significant suppression of blood glucose level and UAE in diabetic rats. Examination by electron microscope revealed that the number of anionic sites in the lamina rara externa per 1000 nm of glomerular basement membrane (GBM) was significantly decreased in diabetic rats compared to control value (15.7 +/- 0.9 vs. 20.9 +/- 0.3 P < 0.001), whereas, significant recovery (19.6 +/- 0.6 P < 0.01) was observed after 8 weeks of acarbose treatment. In conclusion, acarbose treatment suppressed blood glucose level of mildly-insulin deficient animal model without insulin treatment and prevented from a reduction in the number of anionic sites in GBM which might ameliorate an increased permeability of GBM leading to albuminuria.

Acarbose↗
PubMed1998

The use of Acarbose in Type 2 diabetic patients in secondary failure: effects on glycaemic control and diet induced thermogenesis.

Acarbose, an alpha-glucosidase inhibitor, delays the absorption of complex carbohydrates and sucrose, thereby lowering post-prandial blood glucose. In this study, we evaluated the effects of Acarbose on glycaemic control in Type 2 diabetic patients in secondary oral hypoglycaemic agent failure. Due to its mode of action, we also used indirect calorimetry to examine its effects on energy expenditure (EE), diet induced thermogenesis (DIT) and respiratory quotient (RQ) after a standard breakfast (440 calories with 60 g carbohydrates). A total of 12 patients (male/female, 8/4; age, 56+/-9 years; duration of diabetes 10.1+/-4.6 years; body mass index (BMI) 29.6 + 2.7 kg/m2) with poor glycaemic control (HbA1c, 8.8+/-0.9%) completed 8 weeks treatment with Acarbose (100 mg). After treatment, HbAlc was lower compared to the baseline (8.8+/-0.9% vs. 8.0+/-0.9%; t = 2.7; P = 0.02). Acarbose acutely lowered post-prandial blood glucose and insulin area under the curve by a mean of 16.9% and 9.2%, respectively. Long term changes in HbA1c correlated strongly with acute changes in blood glucose area due to Acarbose administration (r = 0.87; P < 0.01). There was a significant effect of Acarbose on EE and DIT for the first 120 min post meal (F3,92 = 3.4; P = 0.03, F2,69 = 6.3; P = 0.008, respectively). After Acarbose treatment, RQ was lower at 30 min compared to the baseline (0.86+/-0.04 before, and 0.83+/-0.05 after; t = 2.8; P = 0.02). In conclusion, Acarbose improves glycaemic control and changes post-prandial energy expenditure of Type 2 diabetic patients in secondary failure. The magnitude of long term reduction in hyperglycaemia differs amongst individuals. This is largely due to intrinsic variations in patients' response to Acarbose rather than differences in medication compliance or dietary composition.

Acarbose↗
PubMed2001

Kinetic studies, mechanism, and substrate specificity of amadoriase I from Aspergillus sp.

Amadoriase is a flavoenzyme that catalyzes the oxidative deglycation of Amadori products (fructosyl amino acids or aliphatic amines) to yield free amine, glucosone, and hydrogen peroxide. The mechanism of action of amadoriase I from Aspergillus sp. has been investigated by stopped-flow kinetic studies using fructosyl propylamine and O(2) as substrates in 10 mM Tris HCl, pH 7.9, 4 degrees C. Using both substrate analogues and fast kinetic techniques, the active configuration of the substrate was found to be the beta-pyranose form. Stopped-flow studies showed that the reductive half-reaction is triphasic and generates intermediates that absorb at long wavelengths and is consistent either with (i) the reaction of the substrate with the flavin followed by iminium deprotonation or hydrolysis and then product release or with (ii) the formation of flavin reduction intermediates (carbanion equivalents or adducts), followed by product release. The rate of product release after flavin reduction is lower than the aerobic turnover rate, 14.4 s(-1), suggesting that it is not involved in the catalytic cycle and that reoxidation of the reduced enzyme occurs in the E(red)-product complex. In the oxidative half-reaction, the reduced flavin is oxidized by O(2) in a single phase. The observed rate constant has a linear dependence on oxygen concentration, giving a bimolecular rate constant of 4.9 x 10(4) M(-1) s(-1) in the absence of product, and 3.6 x 10(4) M(-1) s(-1) when the product is bound. The redox potentials of amadoriase have been measured at pH 7.0, 25 degrees, giving values of +48 and -52 mV for the oxidized enzyme/anionic semiquinone and anionic semiquinone/reduced enzyme couples, respectively.

Amino Acid Oxidoreductases↗
PubMed2002

Alteration of substrate selectivity through mutation of two arginine residues in the binding site of amadoriase II from Aspergillus sp.

Amadoriases I and II are deglycation isoenzymes from Aspergillus sp. of potential relevance for treatment of diabetic complications resulting from excessive protein glycation. Amadoriase II has a preference for anionic substrate with a K(m) of 0.23 and 2.53 mM for fructosylglycine and fructosylpropylamine, respectively. In contrast, the corresponding K(m) values for amadoriase I are 9.75 and 0.023 mM, respectively. Chemical modification of amadoriase II with p-hydroxyphenylglyoxal, a specific arginine-modifying reagent, resulted in an inhibition of enzyme activity toward fructosylglycine, while having less effect on the enzymatic activity toward fructosylpropylamine. Peptide mapping and subsequent mass spectrometry analysis suggest that Arg(112) is one of the sites of p-hydroxyphenylglyoxal modification. Sequence alignment between amadoriase I and amadoriase II revealed that two glutamic acids in amadoriase I align to Arg(112) and Arg(114) in amadoriase II. Site-directed mutation of amadoriase II (R112E, R114E) resulted in reversal of the enzymatic activities toward fructosylglycine and fructosylpropylamine. Our results suggested that Arg(112) and Arg(114) are responsible for the high affinity of amadoriase II toward anionic substrates and determine the substrate selectivity of the enzyme.

Amino Acid Oxidoreductases↗
PubMed1999

Superoxide free radical generation by Amadori compounds: the role of acyclic forms and metal ions.

Generation of oxygen free radicals by glycated proteins is widely believed to be one of the causes of oxidative stress in diabetes and aging. Metal ion catalysis is regarded as an essential part of the oxidative mechanism. In this work, we also considered an alternative "metal-free" superoxide radical formation by a number of fructose-amino acids (Amadori compounds) derived from glycine and lysine, which represent the simplest models for early glycated proteins. In the superoxide dismutase-dependent cytochrome c assay, 1 mM Chelex-treated aqueous solutions of monofructose-amino acids 4-6 generated 0.9-3.6 x 10(-10) M s-1 O2*- at pH 7. Surprisingly, the rates of superoxide radical formation in the solutions of difructose-amino acids 7-9 were significantly higher (0.75-5.8 x 10(-9) M s-1 O2*-). The percentage of acyclic sugar anomers (</=0. 8-85%) and their "enolization" rate constants (5 x 10(-6) to 2 x 10(-3) s-1) varied broadly for the compounds studied and positively correlated with the rates of superoxide radical formation. The presence of Cu2+ markedly increased the rate of superoxide radical formation at metal concentrations higher than 1 microM, while Fe3+ did not accelerate the reaction even at 100 microM. Therefore, in addition to the metal ion-catalyzed oxygen free radical formation, metal-free enol oxidation of fructosyl groups on glycated amino acid residues may contribute to the generation of oxygen free radicals and their subsequent oxidative damage to proteins.

Copper↗
PubMed1998

Pancreatic bile-salt-dependent lipase activity in serum of diabetic patients: is there a relationship with glycation?

1. Pancreatic bile-salt-dependent lipase has been detected in human plasma where it has the capability to modify normal low- and high-density lipoprotein composition and structure and to reduce the atherogenicity of oxidized low-density lipoprotein (Shamir R, Johnson WJ, Morlock-Fitzpatrick K, Zolfaghari R, Li L, Mas E, Lombardo D, Morel DW, Fisher EA. Pancreatic carboxyl ester lipase: a circulating enzyme that modifies normal and oxidized lipoproteins in vitro. J Clin Invest 1996; 97: 1696-704). 2. In the present study, we investigated the effect of glycation and particularly that of human serum albumin on the activity of bile-salt-dependent lipase. In vitro, bile-salt-dependent lipase activity decreased in the presence of human serum albumin; however, this was less pronounced in the presence of glycated human serum albumin. In vivo, bile-salt-dependent lipase specific activity was about 2-fold higher in the sera of diabetic patients than in the sera of normal subjects. 3. A significant increase in the specific activity of bile-salt-dependent lipase related to the serum level of glycation was observed. The increase in bile-salt-dependent lipase specific activity was not related to the glucose concentration in serum suggesting that glycation of bile-salt-dependent lipase could not be involved in the observed effects. Although the stability of serum bile-salt-dependent lipase was important enough to allow a systemic action of the enzyme on lipoproteins, it could not explain the higher activity of the enzyme in diabetic serum. 4. We concluded that bile-salt-dependent lipase could be helpful against the premature development of atherosclerosis in diabetes.

Adult↗
PubMed2005

Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds.

Increased formation of MG (methylglyoxal) and related protein glycation in diabetes has been linked to the development of diabetic vascular complications. Diabetes is also associated with impaired wound healing. In the present study, we investigated if prolonged exposure of rats to MG (50-75 mg/kg of body weight) induced impairment of wound healing and diabetes-like vascular damage. MG treatment arrested growth, increased serum creatinine, induced hypercholesterolaemia (all P < 0.05) and impaired vasodilation (P < 0.01) compared with saline controls. Degenerative changes in cutaneous microvessels with loss of endothelial cells, basement membrane thickening and luminal occlusion were also detected. Acute granulation appeared immature (P < 0.01) and was associated with an impaired infiltration of regenerative cells with reduced proliferative rates (P < 0.01). Immunohistochemical staining indicated the presence of AGEs (advanced glycation end-products) in vascular structures, cutaneous tissue and peripheral nerve fibres. Expression of RAGE (receptor for AGEs) appeared to be increased in the cutaneous vasculature. There were also pro-inflammatory and profibrotic responses, including increased IL-1beta (interleukin-1beta) expression in intact epidermis, TNF-alpha (tumour necrosis factor-alpha) in regions of angiogenesis, CTGF (connective tissue growth factor) in medial layers of arteries, and TGF-beta (transforming growth factor-beta) in glomerular tufts, tubular epithelial cells and interstitial endothelial cells. We conclude that exposure to increased MG in vivo is associated with the onset of microvascular damage and other diabetes-like complications within a normoglycaemic context.

Animals↗
PubMed2000

Eicosapentaenoic acid stimulates nitric oxide production and decreases cardiac noradrenaline in diabetic rats.

1. The aim of the present study was to investigate whether long-term oral administration of eicosapentaenoic acid increases nitric oxide (NO) production and affects cardiac sympathetic activity in rats with diabetes mellitus. 2. We measured changes in urinary excretion of NO3-, a stable NO metabolite, and cardiac noradrenaline (NA) concentrations in non-diabetic rats and streptozotocin-induced diabetic rats treated with either ethyl icosapentate (EPA-E; 100 mg/kg per day; n = 10), a purified ethyl esterification product of eicosapentaenoic acid, or vehicle (distilled water; n = 10) for 6 weeks. The effects of N(G)-nitro-L-arginine (L-NNA), a NO synthase inhibitor, on urinary NO3- excretion and cardiac NA concentrations were also investigated in diabetic rats treated with EPA-E. 3. Urinary NO3- excretion was higher at weeks 5 and 6 in diabetic rats treated with EPA-E than in diabetic rats treated with vehicle (week 5: 120+/-8 vs 51+/-11 micromol/g per day, respectively (P<0.01); week 6: 279+/-83 vs 73+/-9 micromol/g per day, respectively (P<0.01)). Cardiac NA concentrations were higher in diabetic rats than in non-diabetic rats and were decreased in the left atrium and both ventricles in diabetic rats treated with EPA-E compared with control. Systemic administration of L-NNA abolished the increase in urinary excretion of NO3- and the decrease in cardiac NA concentrations in diabetic rats treated with EPA-E. 4. Long-term oral administration of EPA-E may stimulate NO production and increased NO is likely to play a role in inhibiting enhanced cardiac sympathetic activity in diabetic rats.

Animals↗
PubMed2000

Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes.

The principal metabolic effect of metformin-an oral antihyperglycaemic agent-is the improvement in the sensitivity of peripheral tissues and liver to insulin. This study examined the effect of metformin monotherapy on antioxidative defence system activity in erythrocytes and plasma in diabetic patients. We studied the effect of metformin treatment on the activities of Cu, Zn-superoxide dismutase (EC 1. 15. 1. 1.), catalase (EC 1. 11. 1. 6.) and glutathione peroxidase (EC 1. 11. 1. 9.) in relation to lipid peroxidation products and reduced glutathione level in plasma and erythrocytes. In this study we also examined erythrocytes' susceptibility to H2O2-induced oxidative stress during metformin therapy. Although metformin monotherapy ameliorated the imbalance between free radical-induced increase in lipid peroxidation (by reducing the MDA level in both erythrocytes and plasma) and decreased plasma and cellular antioxidant defences (by increasing the erythrocyte activities of Cu, Zn, SOD, catalase and GSH level) and decreased erythrocyte susceptibility to oxidative stress, it had negligible effect to scavenge Fe ion-induced free radical generation in a phospholipid-liposome system.

Blood Glucose↗
PubMed1999

Effect of pravastatin on erythrocyte rheological and biochemical properties in poorly controlled Type 2 diabetic patients.

AIMS: The rheological properties of erythrocytes are impaired in diabetes mellitus, especially because of changes in their membrane lipid composition. In hypercholesterolaemic patients, lowering plasma cholesterol is associated with an improvement of the erythrocyte rheological parameters. The aim of this study was to investigate the relationship between erythrocyte deformability, plasma lipids, lipid membrane composition and cytosolic cations in poorly controlled Type 2 diabetic patients and to test the effects of a cholesterol-lowering treatment on these parameters. METHODS: We compared 37 poorly controlled Type 2 diabetic patients with 26 controls. In 22 of the diabetic patients who showed an impairment in erythrocyte deformability (filtration index >10.5 on the Hanss' haemorheometer), a double-blind randomized trial compared the effect of the inhibitor of HMG CoA reductase pravastatin 20 mg per day for 4 months vs. placebo on the erythrocyte parameters. RESULTS: Compared with controls, diabetic patients had higher filtration index (FI), erythrocyte sodium and calcium contents and lower free cholesterol-phospholipids ratio in erythrocyte membranes. Erythrocyte sodium content correlated positively with the FI and the membrane free cholesterol-phospholipids ratio. In the pravastatin-treated group (11 patients), fibrinogen decreased significantly, FI reached a normal value (<10) in six patients. Four of the five other patients who still had abnormal FI after 4 months of treatment had either a high plasma triglycerides (> or =4.60 mmol/l) or a high plasma fibrinogen (> or =4 g/l) level at baseline. Only two of the 11 placebo-treated patients achieved a normal FI. CONCLUSION: These data suggest that in poorly controlled Type 2 diabetic patients there is a link between the chemical composition and the rheological properties of erythrocytes. Erythrocyte deformability may be improved by lowering plasma cholesterol with a statin.

Anticholesteremic Agents↗
PubMed1999

Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance.

AIMS: This study was initiated to test the hypothesis that metformin treatment leads to enhanced glucose disposal at ambient insulin concentrations. METHODS: Nineteen obese patients with impaired glucose tolerance (IGT) were treated with either metformin or placebo in a randomized, double-blind, placebo-controlled, cross-over study. Insulin secretion and insulin resistance were quantified using the homeostasis model assessment (HOMA) and insulin-stimulated glucose disposal were measured by determining the steady-state plasma glucose (SSPG). RESULTS: The average benefit of metformin was 0.6 mmol/l for glucose (95% confidence interval (CI) 0.2-0.9 P = 0.002), 2.8 pmol/l for insulin (95% CI 0.2-5.4, P = 0.019). Insulin resistance, as quantified by HOMA, was improved by 1.1 (95% CI 0.2-2.0, P = 0.004), without any change in insulin secretion. Basal and insulin-stimulated glucose oxidation were comparable in the placebo and metformin-treated groups at the end of each treatment period, as was the SSPG concentration. However, both systolic and diastolic blood pressures fell significantly following metformin administration as compared to treatment with placebo. CONCLUSIONS: These results indicate that metformin administration to patients with IGT is associated with enhanced glucose disposal at baseline insulin concentrations and a fall in blood pressure. In contrast, neither glucose oxidation nor glucose disposal were increased in association with metformin treatment under conditions of physiological hyperinsulinaemia.

Blood Glucose↗