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PubMed2004

The anti-hyperglycemic activity of the fruiting body of Cordyceps in diabetic rats induced by nicotinamide and streptozotocin.

Little scientific evidence exists to support the numerous herbs used to improve diabetes-related metabolic disorders. Cordyceps, a Chinese herbal medicine with fruiting body and carcass, has been proposed to have multiple medicinal activities. The objective of this study was to investigate the effects of fruiting body and carcass of Cordyceps on hyperglycemia. Male Wistar rats administered with placebo (STZ group), 1 g of fruiting body (FB group), 1 g of carcass (CC group), or 1g of fruiting body plus carcass (CF group) of Cordyceps for four weeks (d1 to d28) were injected with nicotinamide (200 mg/kg) and streptozotocin (65 mg/kg) on d15. Animals fed with placebo and injected with saline acted as the controls (CON group). The results showed that water intake (d15 to d29), changes in fasting blood glucose concentration (d15 to d26), and serum concentrations of fructosamine (d29) were significantly greater in the STZ, CC and CF groups than in the CON and FB groups (one-way ANOVA, P < 0.05). The diabetic rats had significantly lower weight gain and higher blood glucose response in oral glucose tolerance test than the control rats; and these changes were significantly reduced by administrating the fruiting body of Cordyceps. Our results revealed that fruiting body, not carcass, of Cordyceps attenuated the diabetes-induced weight loss, polydipsia and hyperglycemia, and these improvements suggest that fruiting body of Cordyceps has a potential to be the functional food for diabetes.

Administration, Oral↗
PubMed2005

Effects of ingested fruiting bodies, submerged culture biomass, and acidic polysaccharide glucuronoxylomannan of Tremella mesenterica Retz.:Fr. on glycemic responses in normal and diabetic rats.

Mushroom polysaccharides have been shown to regulate glucose metabolism. Using male Wistar rats injected with saline (normal rats), streptozotocin (STZ-NT rats), or streptozotocin plus nicotinamide (STZ+NT rats), we investigated the hypoglycemic activity of orally ingested fruiting bodies (FB), submerged culture biomass (CM), or the acidic polysaccharide glucuronoxylomannan (GXM) of Tremella mesenterica, an edible jelly mushroom. Our results demonstrated that FB ingestion significantly attenuated the elevated blood glucose levels in an oral glucose tolerance test (OGTT) in STZ-NT rats. However, in STZ+NT rats, FB, CM, and GXM ingestion significantly attenuated the increases in food and water intake, 2-h postprandial blood glucose concentrations, and blood glucose levels in OGTT. Moreover, FB and GXM ingestion significantly decreased serum concentration of fructosamine in STZ+NT rats. Our results indicated that T. mesenterica might be developed as a potential oral hypoglycemic agent or functional food for diabetic patients and for persons with high risk for diabetes mellitus.

Agaricales↗
PubMed2005

Alpha-thiolamines such as cysteine and cysteamine act as effective transglycating agents due to formation of irreversible thiazolidine derivatives.

Non-enzymatic glycation of proteins and some phospholipids is considered to be an important factor in the genesis of diabetic complications. While this process has been viewed traditionally as entirely non-enzymatic and unidirectional, the discovery of fructosamine-3-phosphate (FN3K) and identification of FN3K-mediated deglycation mechanisms have made it apparent that non-enzymatic glycation is not unidirectional and that it can be reversed by deglycation reactions. While FN3K operates on ketosamines, the second intermediate in the non-enzymatic glycation cascade, we recently identified another potential deglycation mechanism that can operate on Schiff bases, the first intermediates of the non-enzymatic glycation process. The initial step in this postulated deglycation process is a transglycation reaction between a L.M.W. intracellular nucleophiles and a macromolecule-bound aldosamines, which regenerate unmodified proteins or phospholipids with a concomitant production of aldose-nucleophile transglycation byproducts. In vitro, transglycation occurs readily with amino acids, polyamines, thiols and thiolamines. There are indications that this reaction also occurs in vivo since in an initial GC/MS analysis of human urine we detected significant amounts of a transglycation product, glucose-cysteine (G-Cys), which was markedly increased in diabetics. Despite these encouraging early data, it is not yet clear to what extent transglycation is important in vivo and which intracellular nucleophiles are most relevant to this process. As discussed by us previously in this journal, one likely candidate for this role is glutathione since it is distributed universally and since there are well described mechanisms for removal of S-linked glutathione adducts from cells by the multi-drug-resistance (MDR) pumps. In this paper we report on another class of likely transglycating agents, alpha-thiolamines such as cysteine and cysteamine. While concentrations of these compounds in tissues are significantly lower than those of GSH, they react with Schiff bases more rapidly than GSH and, most significantly they form stable and irreversible thiazolidine products such as glucose-cysteine (G-Cys) and glucose-cysteamine (G-Ctm) that can subsequently be removed from cells. The possibility that alpha-thiolamines may play a physiological role as deglycating agents in vivo is very attractive since it suggests a possible strategy for inhibiting nonenzymatic glycation and diabetic complications that could be readily implemented through nutritional or pharmacological approaches. Such intervention is eminently feasible since there are at least three thiolamines already approved for human use. These include cysteamine used for the treatment of cystinosis; N-acetylcysteine utilized as a mucolytic and antioxidant agent, in the therapy of acetaminophen poisoning and radiocontrast-induced nephrotoxicity; and penicillamine used for treatment of Wilson's disease. Consequently, determining whether these compounds have the expected anti-glycating effects in vivo should be relatively straightforward.

Cysteamine↗
PubMed2006

Biodistribution and catabolism of 18F-labeled N-epsilon-fructoselysine as a model of Amadori products.

Amadori products are formed in the early stage of the so-called Maillard reaction between reducing sugars and amino acids or proteins. Such nonenzymatic glycosylation may occur during the heating or storage of foods, but also under physiological conditions. N-epsilon-fructoselysine is formed via this reaction between the epsilon-amino group of peptide-bound lysine and glucose. Despite the fact that, in certain heated foods, up to 50% of lysyl moieties may be modified to such lysine derivatives, up to now, very little is known about the metabolic fate of alimentary administered Amadori compounds. In the present study, N-succinimidyl-4-[18F]fluorobenzoate was used to modify N-epsilon-fructoselysine at the alpha-amino group of the lysyl moiety. The in vitro stability of the resulting 4-[18F]fluorobenzoylated derivative was tested in different tissue homogenates. Furthermore, the 4-[18F]fluorobenzoylated N-epsilon-fructoselysine was used in positron emission tomography studies, as well as in studies concerning biodistribution and catabolism. The results show that the 4-[18F]fluorobenzoylated N-epsilon-fructoselysine is phosphorylated in vitro, as well as in vivo. This phosphorylation is caused by fructosamine 3-kinases and occurs in vivo, particularly in the kidneys. Despite the action of these enzymes, it was shown that a large part of the intravenously applied radiolabeled N-epsilon-fructoselysine was excreted nearly unchanged in the urine. Therefore, it was concluded that the predominant part of peptide-bound lysine that was fructosylated during food processing is not available for nutrition.

Animals↗
PubMed2005

Effects of propolis on blood glucose, blood lipid and free radicals in rats with diabetes mellitus.

The effects of ethanol (EEP) and water (WSD) extracts of propolis collected from north China on blood glucose, blood lipid and free radicals in rats with diabetes mellitus were studied. The results show that EEP and WSD led to decreased levels of blood glucose (FBG), fructosamine (FRU), malonaldehyde (MDA), nitric oxide (NO), nitric oxide synthetase (NOS), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) in serum of fasting rats; and to increased serum levels of high-density lipoprotein cholesterol (HDL-C) and superoxide dismutase (SOD). This suggests that propolis can control blood glucose and modulate the metabolism of glucose and blood lipid, leading to decreased outputs of lipid peroxidation and scavenge the free radicals in rats with diabetes mellitus.

Animals↗
PubMed2005

Altered redox status in patients with diabetes mellitus type I.

Diabetes mellitus is a complex metabolic disorder characterized by a disturbance in glucose metabolism. Recent evidences suggest that increased oxidative damage as well as deficits in antioxidants defence systems could be related to the complications in Diabetes patients' type I. The aim of this study was to investigate an extensive array of redox status indices: glutathione (GSH), malondialdehyde (MDA), peroxidation potential, superoxide dismutase (SOD), catalase (CAT), total hydroperoxide (TH) and advanced oxidation protein products (AOPP) in relation to blood glucose and glucose indicators control such as glycosylated haemoglobin (HbA1c) and fructosamine by spectophotometric techniques. Forty Diabetes Mellitus patients' type I and 40 healthy subjects were recruited. Both a reduction of GSH levels and an increase in MDA and TH levels were observed in the serum of patients. These patients also showed an increase of AOPP and PP levels as well as an increase of both CAT and SOD activity. Relatively to the control group, patients had significant differences in global indices of oxidant/antioxidant status and indicators of glycaemia control. These results contribute both to the evidences that substantial oxidative stress occurs during Diabetes Mellitus type I without early complications and to an integral overview of the oxidant/antioxidant balance in these patients.

Adult↗
PubMed2004

Augmentation of inhibitory effects of glycoprotein IIb-IIIa antagonists in patients with diabetes.

BACKGROUND: Patients with diabetes mellitus and acute coronary syndromes (ACS) derive enhanced benefit from treatment with glycoprotein (GP) IIb-IIIa inhibitors. To determine mechanisms potentially responsible we characterized the binding of fibrinogen to platelets from patients with and without diabetes in the presence and absence of GP IIb-IIIa antagonists. METHODS: GP IIb-IIIa antagonists (tirofiban, eptifibatide, and abciximab) were added in vitro to blood from patients with and without diabetes. Binding of fibrinogen to activated GP IIb-IIIa was assessed with the use of flow cytometry. The kinetics of binding of I(125)-abciximab and I(125)-fibrinogen to washed platelets from subjects with and without diabetes mellitus were determined. Glycation of platelet membrane proteins was measured with the fructosamine assay. RESULTS: In the presence of GP IIb-IIIa antagonists, activation-induced binding of fibrinogen to platelets was reduced to a greater extent (p<0.02) in blood from patients with diabetes. The greater inhibition in blood from patients with diabetes was seen with pharmacologic concentrations of tirofiban (50 ng/ml, by 27%), eptifibatide (1.5 microg/ml, by 24%), and abciximab (2 mg/ml, by 12%). Whereas the binding of I(125)-abciximab was similar to platelets from patients with diabetes and those without, the rate of binding of I(125)-fibrinogen was decreased with platelets from patients with diabetes. Binding after 5 min was reduced by 46% in those with diabetes (p<0.05). Platelet membrane proteins from patients with diabetes were glycated to a greater extent compared with those without diabetes. CONCLUSION: GP IIb-IIIa antagonists inhibit platelet activation to a greater extent in blood from patients with diabetes. The decreased rate of binding of fibrinogen early after activation of platelets appears to be a consequence of glycation and may promote inhibition by GP IIb-IIIa antagonists.

Abciximab↗
PubMed2004

Islet of Langerhans allogeneic transplantation at the University of Geneva in the steroid free era in islet after kidney and simultaneous islet-kidney transplantations.

AIMS: We report a single-center experience of islet allogeneic transplantation in islet after kidney (IAK) and simultaneous islet-kidney (SIK) type 1 diabetic recipients using a steroid-free immunosuppressive regimen. METHODS: Eight patients received 12 islet infusions in 5 IAK and 3 SIK procedures. Median age was 51 years (range, 30-58 years) with a male:female ratio of 2:6. IAK was considered only for patients with a stable kidney function and a creatinine clearance level >60 mL/min. SIK was considered for patients with a counterindication for simultaneous kidney-pancreas transplantation. Immunosuppression was based on sirolimus/tacrolimus combined with daclizumab induction. Two consecutive infusions of >5000 islet equivalents (IEQ)/kg were planned. RESULTS: Five patients completed the transplantation course, whereas 3 patients received only 1 islet infusion. All patients have functional grafts (C-peptide >166 pmol/L) at 6-month median follow-up. Of 5 patients who completed their transplantation course 4 became insulin independent. HbA1c and fructosamine decreased over time, showing improved metabolic control. Severe adverse events were observed in 4 patients. One SIK patient died after OKT-3 treatment of severe kidney rejection. CONCLUSIONS: The Edmonton immunosuppressive protocol can be applied for patients undergoing either IAK or SIK procedures, with a high rate of graft function and insulin independence. Morbidity is higher than among patients undergoing solitary islet transplantation for type 1 brittle diabetes.

Adult↗
PubMed2004

The effects of different anticoagulants on routine canine plasma biochemistry.

The effects of heparin, ethylenediaminetetraacetic acid (EDTA), sodium citrate and sodium fluoride/potassium oxalate on plasma biochemistry results in dogs were studied and compared with serum. Blood specimens from 10 apparently clinical healthy dogs were collected and placed in different tubes containing each anticoagulant tested. Differences in albumin, acetylcholinesterase, ionized calcium and potassium were found between serum and heparinized plasma. Most metabolites and enzymes did not show any variation, but significant decreases in electrolytes, alkaline phosphatase, acetylcholinesterase, bile acids, fructosamine and albumin were found when EDTA was used. Sodium citrate produced a 10-15% decrease in most metabolites and enzymes, possibly due to a sample dilution effect. Sodium fluoride/potassium oxalate produced haemolysis which may have influenced changes in some biochemical parameters.

Animals↗
PubMed2001

Calcium antagonists as inhibitors of in vitro low density lipoprotein oxidation and glycation.

The peroxidation step in lipid transformation is considered to be essential in the pathogenesis of atherosclerosis. Calcium antagonists (CA) appear to have antioxidant effects in addition to their potent vasorelaxant properties. In the present study, we compared the antioxidative efficacy of CA (amlodipine, lacidipine, nifedipine, isradipine, diltiazem, and semotiadil) in the copper-catalysed oxidation of low-density lipoprotein (LDL) with that of glycated(g)/glycoxidated(go) LDL. This issue is of great importance when considering the potential therapeutic use of antioxidant drugs in diabetes-associated vasculopathy. Oxidation of native LDL was inhibited most efficiently (>90%) by lacidipine and semotiadil in the concentration range 10(-4)-10(-3) M. We found, however, a dramatic decrease in antioxidant activity towards g/goLDL as compared to native LDL in all the CA tested. Only lacidipine significantly inhibited copper-mediated oxidation of g/goLDL in the whole concentration range tested (10(-5) M-10(-3) M). This probably resulted from the increased auto-oxidative potential introduced by early and advanced glycation end products (AGE) into the g/goLDL. We noted that coincubation of LDL with 10(-3) M CA and 0.5 M glucose under oxidative/non-oxidative conditions partially or fully restored the antioxidant capacity of the different CA to inhibit the subsequent copper-catalysed oxidation of the modified LDL. This is a clear indication that CA inhibit glycative or glycoxidative LDL changes during the preceding long-term glycation period. The notion that both oxidative changes and long-term glycation effects were reduced by CA was corroborated by fluorescence analysis, AGE-ELISA, quantitation of lipid peroxidation, and thiobarbituric acid reactive substance (TBARS) measurement of long-term g/goLDL. The strongest antioxidative effects during long-term glycation of LDL were seen with isradipine, lacidipine, nifedipine, and semotiadil. Diltiazem was the only CA that could not prevent TBARS formation in LDL during the long-term glycation period. In contrast, Amadori product formation, as measured by the generation of fructosamines, was not significantly reduced by any CA tested. Thus CA, like other antioxidants, significantly retard AGE formation, while initial glycation reactions, such as Amadori product formation, are only weakly inhibited.

Antioxidants↗
PubMed1999

Metal complexes as allosteric effectors of human hemoglobin: an NMR study of the interaction of the gadolinium(III) bis(m-boroxyphenylamide)diethylenetriaminepentaacetic acid complex with human oxygenated and deoxygenated hemoglobin.

The boronic functionalities on the outer surface of the Gd(III) bis(m-boroxyphenylamide)DTPA complex (Gd(III)L) enable it to bind to fructosamine residues of oxygenated glycated human adult hemoglobin. The formation of the macromolecular adduct can be assessed by NMR spectroscopy via observation of the enhancement of the solvent water proton relaxation rate. Unexpectedly, a strong binding interaction was also observed for the oxygenated unglycated human adult hemoglobin, eventually displaying a much higher relaxation enhancement. From relaxation rate measurements it was found that two Gd(III)L complexes interact with one hemoglobin tetramer (KD = 1.0 x 10(-5) M and 4.6 x 10(-4) M, respectively), whereas no interaction has been observed with monomeric hemoproteins. A markedly higher affinity of the Gd(III)L complex has been observed for oxygenated and aquo-met human adult hemoglobin derivatives with respect to the corresponding deoxy derivative. Upon binding, a net change in the quaternary structure of hemoglobin has been assessed by monitoring the changes in the high-resolution 1H-NMR spectrum of the protein as well as in the Soret absorption band. On the basis of these observations and the 11B NMR results obtained with the diamagnetic La(III)L complex, we suggest that the interaction between the lanthanide complex and deoxygenated, oxygenated, and aquo-met derivatives of human adult hemoglobin takes place at the 2, 3-diphosphoglycerate (DPG) binding site, through the formation of N-->B coordinative bonds at His143beta and His2beta residues of different beta-chains. The stronger binding to the oxygenated form is then responsible for a shift of the allosteric equilibrium toward the high-affinity R-state. Accordingly, Gd(III)L affinity for oxygenated human fetal hemoglobin (lacking His143beta) is significantly lower than that observed for the unglycated human adult tetramer.

Adult↗
PubMed1997

Investigation of the mechanism underlying the variability of glycated haemoglobin in non-diabetic subjects not related to glycaemia.

The Islington Diabetes Survey identified two groups of non-diabetic individuals, low and high glycators, who remained consistently classified 4.4 +/- 0.2 years after the original study. To investigate the mechanism for this grouping, 12 original subjects, 5 with low and 7 with high levels of glycated haemoglobin relative to their 2 h blood glucose, were studied. Glycated albumin and fructosamine measurements gave comparable classifications, with three individuals being misclassified for each measurement; in addition glycated albumin was positively correlated with mean blood-glucose concentration (r = 0.53; P < 0.05). Fasting plasma glucose concentration was greater than the intra-erythrocyte concentration (P < 0.05), but their ratio was reduced in low compared to high glycators (0.77 +/- 0.12 and 0.94 +/- 0.13, P < 0.0001). No differences between groups were found for plasma insulin, urea or non-esterified fatty acids; plasma or intra-erythrocyte inorganic phosphate or vitamin C; nor plasma, erythrocyte or urinary total amino acids. Erythrocyte 2,3-diphosphoglycerate, a catalyst of glycation, was elevated in high compared to low glycators (5.61 +/- 0.26 and 4.81 +/- 0.24 mmol/l, P < 0.001). Mean centile glycated haemoglobin was positively correlated with intra-erythrocyte pH (r = 0.55; P < 0.05) and negatively with plasma total amino acids (r = -0.57, P < 0.05). These data indicate that the intra-erythrocyte environment of high glycators favours glycation of haemoglobin. This could have important consequences for diabetic patients in terms of monitoring their glycaemic control and in the progression of those complications related to non-enzymic glycation of intracellular proteins.

Blood Glucose↗
PubMed1997

Diagnostic performance of red cell sorbitol assay in a Nigerian teaching hospital.

The analytical linearity, detection limit, precision and accuracy, as well as diagnostic sensitivity, specificity and predictive values of red cell sorbitol (RCS) assay were evaluated using the fluorimetric enzymatic technique with the available laboratory facilities in a Nigerian Teaching Hospital. The assay was linear up to 40.0 nmol/ml. The detection limit was 0.55 nmol/ml. The within-assay coefficients of variation (CV) from low to high concentrations were in the range of 2.82% to 5.48% while the corresponding values for the between-assay variation were 3.60% to 6.05%. The mean recovery was 90.4%. High concentrations of some common blood constituents and drugs did not cause significant interference. An evaluation of the diagnostic sensitivity and specificity of RCS in 102 out-patients revealed a sensitivity of 94.4%, specificity of 98.8% and efficiency of 98.0%. The predictive value of a positive test was 94.4% while that of a negative test was 98.8%. The mean value of red cell sorbitol in patients confirmed to have diabetes mellitus (23.1 +/- 1.13 SE nmol/g Hb) was significantly higher (P < 0.001) than the corresponding value (11.0 +/- 0.0.27 SE nmol/g Hb) for those without diabetes and for control subject. A similar observation was also made for plasma glucose and fructosamine. These observations demonstrate that RCS assay could be adopted in a third world laboratory for clinical applications.

Adolescent↗
PubMed2002

NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs.

Glucagon-like peptide-1 (GLP-1) is an effective anti-diabetic agent, but its metabolic instability makes it therapeutically unsuitable. This study investigated the pharmacodynamics of a long-acting GLP-1 derivative (NN2211: (Arg(34)Lys(26)-(N- epsilon -(gamma-Glu(N-alpha-hexadecanoyl)))-GLP-1(7-37)), after acute and chronic treatment in hyperglycaemic minipigs. During hyperglycaemic glucose clamps, NN2211 (2 micrograms kg(-1) i.v.) treated pigs required more (P < 0.005) glucose than control animals (5.8 +/- 2.1 vs. 2.9 +/- 1.8 mg kg(-1) min(-1)). Insulin excursions were higher (P < 0.01) after NN2211 (15,367 +/- 5,438 vs. 9,014 +/- 2,952 pmol l(-1) min), and glucagon levels were suppressed (P < 0.05). Once-daily injections of NN2211 (3.3 micrograms kg(-1) s.c.) reduced the glucose excursion during an oral glucose tolerance test, to 59 +/- 15% of pre-treatment values by 4 weeks (P < 0.05), without measurable changes in insulin responses. Fructosamine concentrations were unaltered by vehicle, but decreased (from 366 +/- 187 to 302 +/- 114 micromol l(-1), P = 0.14) after 4 weeks of NN2211. Gastric emptying was reduced (P < 0.05) by NN2211. NN2211 acutely increases glucose utilization during a hyperglycaemic glucose clamp and chronic treatment results in better daily metabolic control. Therefore, NN2211, a GLP-1 derivative that can be administered once daily, holds promise as a new anti-diabetic drug with a minimal risk of hypoglycaemia.

Animals↗
PubMed1998

Oxidative damage of vascular smooth muscle cells by the glycated protein-cupric ion system.

To clarify the mechanism of cellular injury through the nonenzymatic reaction of glucose with proteins, we studied the cytotoxic effect of glycated bovine serum albumin on cultured smooth muscle cells in the presence of cupric ion. Glycated proteins were prepared by incubating bovine serum albumin with 0.5 M D-glucose in 0.3 M sodium phosphate buffer at 37 degrees C for 2, 4 and 16 weeks (g-BSA-2, g-BSA-4 and g-BSA-16, respectively). Early glycation products, such as fructosamine, were formed more than two weeks after incubation. However, the immunoreactivity of glycated proteins to anti-AGE antibody was 12-fold higher in g-BSA-16 than in g-BSA-2. Both g-BSA-2 and g-BSA-16 showed a concentration-dependent cytotoxicity in smooth muscle cells in the presence of 80 microM cupric ion by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) dye reduction assay and dye exclusion test. Flow cytometry and spectrofluorophotometry using dihydrorhodamine 123 showed that the extracellular generation of oxidants was dose-dependently enhanced with increasing concentrations of g-BSA-2 or g-BSA-16 in the presence of cupric ion. However, no difference was observed in the intracellular generation of oxidants between the presence and absence of glycated proteins by flow cytometry using 2', 7'-dichlorofluorescein diacetate. Cytotoxicity and oxidant generation were prevented by catalase and tiron, but not by superoxide dismutase or mannitol, a hydroxyl radical scavenger. These results indicate that smooth muscle cells may be damaged by reactive oxygen species which are produced extracellularly by the interaction with the early glycation products and cupric ion, and suggest that hydrogen peroxide may be a candidate for reactive oxygen species which contribute to such oxidative damage of smooth muscle cells.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2000

In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques.

Although there have been suggestions that the glycation and oxidation of low density lipoprotein (LDL) might increase its atherogenic potential, little is known about the presence of glycoxidative LDL in human atherosclerotic lesions. We developed specific antibodies against different immunological epitopes of AGE structures, including N(epsilon)-(carboxymethyl)lysine-protein adduct (CML), a glycoxidation product, and structure(s) other than CML (nonCML), and a monoclonal antibody against oxidized phosphatidylcholine (oxPC), as an epitope of oxidized LDL. Immunohistochemical analysis demonstrated that the CML- and oxPC-epitopes were accumulated mainly in macrophage-derived foam cells in atherosclerotic lesions, including fatty streaks and atherosclerotic plaques. On the other hand, the nonCML-epitope and apolipoprotein B were localized mainly in extracellular matrices of atherosclerotic lesions. The CML- and oxPC-epitopes were characterized by a model antigen-generating system using the copper ion-induced peroxidation and/or glucose-induced glycation of LDL. The glycoxidation of LDL caused the formation of CML-epitope with increasing concentrations of copper ion and glucose. It was also formed to some extent in LDL incubated with high concentrations (500 mM) of glucose. However, no CML-epitope was observed in oxidized LDL induced by copper ion alone. On the other hand, the formation of oxPC-epitope in LDL was dependent on copper ion-induced peroxidation, but independent of glucose-induced glycation. The addition of chelators, ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, reduced the increase in electrophoretic mobility and TBARS caused by the peroxidation and glycoxidation of LDL, but had no effects on the formation of fructosamine caused by the glycation and glycoxidation of LDL. Chelators as well as aminoguanidine protected the formation of CML-epitope in glycated or glycoxidative LDL. Although the formation of oxPC-epitope was completely inhibited by the addition of chelators, it was partially protected by aminoguanidine. These in vitro results suggest that the glycoxidative modification of LDL may occur in the arterial intima, and may contribute to the development of human atherosclerotic lesions.

Adolescent↗
PubMed1999

Prevention of processes coupled with free radical formation prevents also the development of calcium-resistance in the diabetic heart.

Recently it was shown that besides their negative role in pathogenesis of diabetes, reactive oxygen species (ROS) and particularly the products of non-enzymatic glycation of proteins (NEGP) may also participate in some processes of adaptation of the myocardium to diabetes, such as in the mechanism of development of calcium resistance of the heart. Our study revealed that the hearts of rats with experimentally induced diabetes (single dose of streptozotocin, 45 mg/kg i.v., 6 U/kg insulin daily) develop considerable resistance against calcium overload (induced by means of Ca-paradox). On the day 63 after the beginning of experiment, when the diabetic cardiomyopathy became fully developed but the hearts were still not failing, their calcium resistance was increased to 83.33%. Our results provide evidence that, when applied in a special regimen, resorcylidene aminoguanidine (RAG, 4 mg/kg) prevented both, the formation of fructosamine (a source of ROS generation), and also that of the advanced Maillard products, in the heart sarcolemma of diabetic rats. The effect of RAG was accompanied by a decrease in calcium resistance in the group of rats with chronic diabetes (63 days) from 83.3 to 46.7%. It is concluded that NEGP and ROS formation are inevitably needed for development of calcium resistance in the diabetic hearts.

Animals↗
PubMed1998

Long-term effects of a sustained-release preparation of acipimox on dyslipidemia and glucose metabolism in non-insulin-dependent diabetes mellitus.

Elevated circulating plasma nonesterified fatty acids (NEFA) may contribute to the insulin resistance and hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM), and decreasing plasma NEFA could provide a therapeutic benefit. A sustained-release preparation of acipimox, a lipolysis inhibitor, was used in an attempt to decrease circulating plasma NEFA levels long-term, and the effects on glycemic control, insulin resistance, and serum lipids were measured. Sixty NIDDM patients (43 males and 17 females) took part in a randomized controlled trial of acipimox or placebo for 12 weeks. Fasting plasma NEFA levels did not change in acipimox-treated patients (baseline v 12 weeks, 0.84 +/- 0.35 v 0.88 +/- 0.55 mmol x L(-1), mean +/- SD). Fasting blood glucose was unchanged (mean difference v placebo, -0.5 mmol x L(-1); 95% confidence interval [CI], -1.4 to 0.3 mmol x L[-1]), but serum fructosamine decreased (mean difference v placebo, -26 micromol x L(-1); 95% CI, -51 to 0 mmol x L[-1]), as did the standardized hemoglobin A1 ([HbA1] mean difference v placebo, -1.4%; 95% CI, -3.0% to -0.1%). Insulin resistance measured as steady-state plasma glucose during an insulin-dextrose infusion test was unchanged (mean difference v placebo, -1.4 mmol x L(-1); 95% CI, -3.2 to 0.5 mmol x L[-1]). Serum total cholesterol (mean difference v placebo, -0.4 mmol x L(-1); 95% CI, -0.6 to -0.1 mmol x L[-1]), serum apolipoprotein B ([apo B] mean difference v placebo, -0.19 g x L(-1); 95% CI, -0.3 to -0.1 g x L[-1]), and serum triglycerides (mean difference v placebo for pretreatment v posttreatment ratio, 0.59; 95% CI, 0.40 to 0.88) were all lower with acipimox. Serum high-density lipoprotein (HDL) cholesterol (mean difference v placebo, 0.10 mmol x L(-1); 95% CI, -0.05 to 0.3 mmol x L[-1]), serum apo A1 (mean difference v placebo, 0.03 g x L(-1); 95% CI, -0.04 to 0.1 g x L[-1]), and serum lipoprotein(a) ([Lp(a)] acipimox v placebo, 154 (0 to 1,574) v 71 (0 to 1,009), median and range) were unchanged. Despite the lack of change in fasting plasma NEFA levels, acipimox caused a modest beneficial improvement in overall glycemic control and plasma lipids in NIDDM patients and could be a useful agent in the treatment of dyslipidemic NIDDM patients.

Apolipoprotein A-I↗