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In recent years, arsenic exposure has been linked to cardiovascular disease, (1) diabetes mellitus, (2) neurological dysfunction, (3) and cancer, all of which may be exacerbated by early life exposure. [...]

Diabetes dramatically increases the risk of cardiovascular complications. The endothelial dysfunction and diastolic heart dysfunction are associated with a decreasing level of hydrogen sulfide ([H.sub.2]S) and inhibition of the activity of endothelial nitric oxide synthase (NOS) in diabetes. The aim of this study is to investigate the effect of modulation of [H.sub.2]S synthesis on heart functions and vasorelaxation in diabetes. The DL- propargylglycine and L-cysteine were administered intraperitoneally. [H.sub.2]S content in the heart tissue, markers of oxidative stress, inducible NOS and constitutive NOS (cNOS) activities, endothelium-dependent vasorelaxation of the aortic rings, and heart function were studied. We demonstrate that our combination increased [H.sub.2]S synthesis 13 times and cNOS activity 5 times in the heart tissue of diabetic rats. Increasing NO and [H.sub.2]S production caused improvement and restoration of endothelium- dependent relaxation of aorta, effective arterial elastance, and diastolic heart function in diabetic rats. The endothelium- dependent relaxation increased 2.4 times; effective arterial elastance decreased by 47%. The end-diastolic myocardial stiffness decreased 2.2 times. Thus, modulation of [H.sub.2]S synthesis leads to increased cNOS activity by up to 5 times in the cardiovascular system. Increasing NO and [H.sub.2]S production restored endothelium-dependent relaxation of aorta and improved heart function in diabetes. Key words: hydrogen sulfide, diabetes, cNOS and iNOS activity, oxidative stress, DL-propargylglycine, L-cysteine, heart functions, endothelium-dependent relaxation. Le diabete entraine un accroissement spectaculaire du risque de complications cardiovasculaires. Les dysfonctionnements endothelial et diastolique du creur sont associes a un abaissement des taux de sulfure d'hydrogene ([H.sub.2]S) ainsi qu'a une inhibition de l'activite de la NO-synthase endotheliale dans le diabete. Ces travaux avaient pour but d'etudier l'effet de la modulation de la synthese du [H.sub.2]S sur le fonctionnement du creur et la vasorelaxation dans le diabete. Nous avons administre de la DL-propargylglycine et de la L-cysteine par voie intraperitoneale. Nous avons etudie les taux de [H.sub.2]S dans le tissu cardiaque, des marqueurs du stress oxydatif, l'activite de l'iNOS et de la cNOS, la vasorelaxation d'anneaux aortiques dependante de l'endothelium ainsi que le fonctionnement du creur. Nous montrons que notre association de composes entrainait une stimulation de la synthese de [H.sub.2]S par un facteur de 13 et de l'activite de la cNOS par un facteur de 5 dans le tissu cardiaque de rats atteints de diabete. Chez les rats atteints de diabete, l'augmentation de la production de NO et de [H.sub.2]S a permis l'amelioration et le retablissement de la relaxation de l'aorte dependante de l'endothelium, de l'elastance arterielle effective et de la fonction diastolique du creur. Nous avons observe une augmentation de la relaxation dependante de l'endothelium par un facteur de 2,4 avec une diminution de l'elastance arterielle effective de l'ordre de 47 %. Nous avons observe une diminution de la rigidite telediastolique par un facteur de 2,2. Par consequent, la modulation de la synthese du [H.sub.2]S mene a une augmentation de l'activite de la cNOS par un facteur de 5 dans le systeme cardiovasculaire. L'augmentation de la production de NO et de [H.sub.2]S permettait le retablissement de la relaxation de l'aorte dependante de l'endothelium et l'amelioration du fonctionnement du creur dans le diabete. [Traduit par la Redaction] Mots-cles : sulfure d'hydrogene, diabete, activite de la cNOS et de l'iNOS, stress oxydatif, DL-propargylglycine, L-cysteine, fonctionnement du creur, relaxation dependante de l'endothelium., 1. Introduction Worldwide, over 463 million people have diabetes. The number of patients with diabetes is projected to reach 700 million by 2045 (IDF Atlas 9th Edition and Other Resources [...]

Diabetes mellitus (DM) is a metabolic disorder that causes severe complications. Thus, the aims of this study were to investigate the influence of DM and folic acid treatment on liver and renal biomarkers, and heart remodeling through evaluation of cardiac matrix metalloproteinase (MMP) activity. There were 4 groups: control (physiological saline 1 mL/kg, i.p., 28 days), DM (streptozotocin [STZ] 100 mg/kg in physiological saline, i.p., 1 day), folic acid (FA; 5 mg/kg, i.p., 28 days), and DM+FA (STZ 100 mg/kg, i.p., 1 day and folic acid 5 mg/kg, i.p., 28 days). Our results demonstrated increased aminotransferase and alkaline phosphatase activity, urea and creatinine concentration, and decreased albumin and fibrinogen concentration in the DM group. MMP-2 relative activity was elevated in the DM and FA groups; MMP-9 was decreased in the DM and increased in the FA group. The folic acid treatment of diabetic rats did not change aminotransferase activity; it alleviated the increase in alkaline phosphatase and the decrease in albumin and fibrinogen concentration, and reduced MMP-2 activity; however, it increased urea and creatinine concentration. In conclusion, folic acid treatment of diabetic rats has cardio- and hepato-protective effects. However, its dosing should be carefully considered because of possible renal damage. Key words: diabetes mellitus, cardiac remodelling, matrix metalloproteinases, hepatic damage, renal damage, rat. Le diabete sucre (DS) est une maladie metabolique qui cause des complications graves. Par consequent, ces travaux avaient pour but d'etudier l'influence du DS et de l'administration d'acide folique (AF) sur les biomarqueurs hepatiques et renaux, ainsi que sur le remodelage du creur a l'aide de l'evaluation de l'activite des metalloproteinases matricielles cardiaques. Nous avons forme 4 groupes : temoin (solution physiologique a 1 ml/kg, i.p. pendant 28 jours), DS (streptozotocine [STZ] a 100 mg/kg dans une solution physiologique, i.p. pendant 1 jour), AF (a 5 mg/kg dans une solution physiologique, i.p. pendant 28 jours) et DS + AF (STZ a 100 mg/kg dans une solution physiologique, i.p. pendant 1 jour et AF a 5 mg/kg dans une solution physiologique, i.p. pendant 28 jours). Nos resultats ont montre une hausse de l'activite des aminotransferases et de la phosphatase alcaline, des concentrations d'uree et de creatinine, ainsi qu'un abaissement des concentrations d'albumine et de fibrinogene dans le groupe DS. Nous avons observe une hausse de l'activite relative de la MMP-2 dans les groupes DS et AF, ainsi qu'un abaissement de la MMP-9 dans le groupe DS, mais une hausse dans le groupe AF. L'administration AF n'a pas entraine de modification de l'activite des aminotransferases chez les rats diabetiques : il entrainait une attenuation de la hausse de la phosphatase alcaline, ainsi qu'un abaissement des concentrations d'albumine et de fibrinogene, avec une diminution de l'activite de la MMP-2; il entrainait toutefois une hausse des concentrations d'uree et de creatinine. En conclusion, l'administration AF permet d'obtenir des effets cardio- et hepatoprotecteurs chez des rats diabetiques. Cependant, il faudrait entreprendre une augmentation des doses AF avec prudence en raison de la possibilite d'observer des lesions renales. [Traduit par la Redaction] Mots-cles: diabete sucre, remodelage cardiaque, metalloproteinases matricielles, dommages hepatiques, dommages renaux, rat., Introduction Diabetes mellitus (DM) is a global public health problem with increasing incidence and prevalence (Danaei et al. 2011). It is a group of metabolic disorders characterized by hyperglycemia; altered [...]

The bio-activities of separate Matricaria chamomilla (chamomile) and Origanum vulgare (oregano) are well studied; however, the combined effects of both natural products in animal diabetic models are not well characterized. In this study, alloxan-induced male albino rats were treated with single dose aqueous suspension of chamomile or oregano at dose level of either 150 or 300 mg/kg body mass or as equal parts as combination by stomach tube for 6 weeks. After treatment, blood samples were assessed for diabetic, renal, and lipid profiles. Insulin, amylase activity, and diabetic renal apoptosis were further evaluated. Treatment with higher dose of the extracts (300 mg/kg) as individual or as mixture of low doses (150 mg/kg of both the extracts) had significant mass gain, hypoglycemic effect (p [less than or equal to] 0.05) with decreased amylase activity and increased serum insulin levels. Restoration of renal profile, lipid profile with increase in HDL-c (p ≤ 0.05) along with reversal of pro-apoptotic Bax and antiapoptotic Bcl-2 were well observed with 300 mg/kg mixture, showing synergistic activity of the extracts compared with individual low dose of 150 mg/kg. Collectively, our results indicate that combination of chamomile and oregano extracts will form a new class of drugs to treat diabetic complications. Key words: diabetes mellitus, Matricaria chamomilla, Origanum vulgare, HbAtC, insulin, lipid profile, synergism. Les activites biologiques de Matricaria chamomilla (camomille) et d'Origanum vulgare (origan) ont ete bien etudiees individuellement. Cependant, les effets combines de ces deux produits naturels n'ont pas ete bien caracterises dans des modeles de diabete chez l'animal. Dans cette etude, nous avons administre par tube gastrique pendant 6 semaines a des rats albinos sous alloxane des doses uniques de camomille ou d'origan en suspension aqueuse individuellement (150 ou 300 mg/kg) ou en association a parties egales. Apres le traitement, nous avons evalue les profils diabetique, renal et lipidique a l'aide d'echantillons sanguins. Nous avons aussi evalue les taux d'insuline, l'activite de l'amylase et l'apoptose dans les reins d'animaux diabetiques. L'administration de doses elevees d'extraits (a 300 mg/kg) individuellement ou de doses faibles du melange (150 mg/kg pour chacun des extraits) entrainait une augmentation notable du poids et de l'effet hypoglycemiant (p ≤ 0,05) avec une diminution de l'activite de l'amylase ainsi qu'une augmentation des taux d'insuline seriques. Avec le melange dose a 300 mg/kg, nous avons observe precisement la recuperation des profils renal et lipidique (augmentation des taux de c-HDL (p ≤ 0,05)) ainsi que l'annulation de l'augmentation des taux de proteines Bax et Bcl-2 (respectivement pro- et anti-apoptotiques), ce qui montre la presence d'une synergie entre l'activite des extraits par rapport aux doses faibles (150 mg/kg) des extraits administres separement. Dans l'ensemble, nos resultats montrent que l'association d'extraits de camomille et d'origan constitue une nouvelle classe de medicaments destines au traitement des complications du diabete. [Traduit par la Redaction] Mots-cles: diabete sucre, Matricaria chamomilla, Origanum vulgare, HbA1C, insuline, profil lipidique, synergie., Introduction Diabetes mellitus (DM) is characterized by hyperglycemia, altered metabolism of lipids, carbohydrates, and proteins which in turn leads to chronic complications including diabetic nephropathy (Davis and Granner 1996). As [...]

The cause and effect relationship between diabetes and zinc is complex and unclear. This animal study has examined the potential of zinc supplementation in beneficial modulating hyperglycemia, insulin secretion, and metabolic abnormalities associated with diabetes. The study was conducted in streptozotocin-induced diabetic rats. Groups of hyperglycemic rats were subjected to dietary interventions for 6 weeks with zinc supplementation (5 times and 10 times the normal level). Supplemental-zinc-fed diabetic groups showed significant control on hyperglycemia and hypoinsulinemia. There was a significant reduction in protein glycosylation, glucosuria, and urinary excretion of proteins and urea in diabetic animals maintained on a zinc- supplemented diet. Diabetic rats showed significantly higher plasma albumin and lower plasma urea and creatinine levels upon zinc supplementation. Significant alterations in insulin sensitivity indices HOMA-IR, HOMA-B, and QUICKI were also indicated by zinc supplementation. The pathological abnormalities in pancreatic islets of diabetic animals were significantly alleviated by dietary zinc intervention. This study provides the first evidence that zinc supplementation can partially ameliorate the severity of diabetic hyperglycemia and associated metabolic abnormalities, hypoinsulinemia, insulin resistance, and altered pancreatic morphology. Thus, zinc supplementation may offer a significant potential for clinical application in managing diabetic hyperglycemia and related metabolic complications. Key words: diabetes mellitus, zinc supplementation, hyperglycemia, insulin sensitivity index, metabolic abnormalities. La relation de cause a effet entre le diabete et le zinc est complexe et nebuleuse. Dans cette etude chez l'animal, nous avons etudie la capacite de la supplementation en zinc de moduler avantageusement l'hyperglycemie, la secretion d'insuline et les anomalies metaboliques associees au diabete. Nous avons utilise un modele de diabete provoque par la streptozotocine chez le rat. Nous avons procede a des interventions sur le regime alimentaire de groupes de rats hyperglycemiques a l'aide d'une supplementation en zinc de 6 semaines (de 5 a 10 fois les quantites normales). Les groupes de rats diabetiques auxquels etaient administres des supplements de zinc ont presente une maitrise appreciable de l'hyperglycemie et de l'hypoinsulinemie. Nous avons observe une diminution notable de la glycosylation des proteines, de la glycosurie, et de l'excretion urinaire de proteines et de l'uree chez les animaux diabetiques auxquels etait administre un regime alimentaire d'entretien supplemente en zinc. Chez les rats diabetiques, les taux d'albumine plasmatique etaient augmentes et les taux d'uree et de creatinine plasmatiques etaient diminues avec la supplementation en zinc. La supplementation en zinc etait aussi associee a des modifications sur le plan des indices de sensibilite a l'insuline suivants: HOMA-IR, HOMA-B et QUICKI. L'ajout de zinc au regime alimentaire a aussi permis d'attenuer les anomalies pathologiques au sein des ilots pancreatiques des animaux diabetiques. Cette etude fournit les premiers indices qui permettent de dire que la supplementation en zinc permet en partie de diminuer la gravite de l'hyperglycemie associee au diabete et d'attenuer les anomalies metaboliques, l'hypoinsulinemie, la resistance a l'insuline et les modifications morphologiques du pancreas qui y sont associees. Par consequent, la supplementation en zinc pourrait jouer un role important comme application clinique dans la prise en charge de l'hyperglycemie associee au diabete et des complications metaboliques qui y sont liees. [Traduit par la Redaction] Mots-cles: diabete sucre, supplementation en zinc, hyperglycemie, indice de sensibilite a l'insuline, anomalies metaboliques., Introduction Diabetes mellitus is a metabolic disorder mainly manifested by hyperglycemia resulting from defective insulin secretion from the β-cells of pancreas or impaired response of the body even though in [...]

Hyperglycemia affects male and female vascular beds differently. We have previously shown that 1 week after the induction of diabetes with streptozotocin (STZ), male and female rats exhibit differences in aortic endothelial function. To examine this phenomenon further, aortic responses were studied in male and female rats 8 weeks after the induction of diabetes (intermediate stage). Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh) was measured in phenylephrine (PE) pre-contracted rat aortic rings. Concentration response curves to PE were generated before and after L-NAME, a nitric oxide synthase (NOS) inhibitor. Furthermore, mRNA expression of endothelial nitric oxide synthase (eNOS) and NADPH oxidase subunit (Nox1) were determined. At 8 weeks, diabetes impaired EDV to a greater extent in female than male aortae. Furthermore, the responsiveness to PE was significantly enhanced only in female diabetic rats, and basal NO, as indicated by the potentiation of the response to PE after L-NAME, was reduced in female diabetic rat aortae to the same levels as in males. In addition, eNOS Mrna expression was decreased, while the Nox1 expression was significantly enhanced in diabetic female rats. These results suggest that aortic function in female diabetic rats after 8 weeks exhibits a more prominent impairment and that NO may be involved. Key words: sex differences, endothelial function, nitric oxide, streptozotocin (STZ), diabetes, rat aorta. On sait que l'hyperglycemie n'affecte pas le lit vasculaire de la meme maniere chez les hommes que chez les femmes. De fait, nous avons montre precedemment qu'une semaine apres l'induction du diabete par l'administration de streptozotocine (STZ), la fonction endotheliale de l'aorte de rats males est differente de celle des rats femelles. En vue d'examiner ce phenomene plus en detail, nous avons etudie les reponses aortiques chez des rats males et femelles 8 semaines apres l'induction du diabete (stade intermediaire). A cet effet, nous avons mesure la vasodilation dependante de l'endothelium (VDE) induite par l'acetylcholine (ACh) dans un modele d'anneaux aortiques contractes en reponse a la phenylephrine (PE). Les courbes de la reponse a la PE en fonction de la concentration etaient obtenues avant et apres l'administration de L-NAME, un inhibiteur de l'oxyde nitrique synthase (NOS). Par la suite, nous avons mesure l'expression de l'ARNm de l'oxyde nitrique synthase endotheliale (NOSe) et de la sous-unite NADPH oxydase (Nox1). Huit semaines apres l'induction du diabete, nous avons observe que la VDE etait plus marquee chez les femelles que chez les males et que la susceptibilite aux effets de la PE n'augmentait de facon importante que chez les rates diabetiques. En revanche, comme en temoignait la potentialisation de la reponse a la PE induite par l'administration de L-NAME, l'effet initial du NO etait attenue a des degres similaires dans les aortes de rats diabetiques males et femelles. Enfin, nous avons observe une diminution de l'expression de l'ARNm de la NOSe et une augmentation marquee de l'expression de la Nox1 chez les rats diabetiques femelles. Ces resultats laissent entendre qu'apres 8 semaines, le diabete aurait un effet plus deletere sur le fonctionnement de l'aorte chez les rats femelles, et que ce phenomene serait lie au NO. [Traduit par la Redaction] Mots-cles: differences entre les sexes, fonction endotheliale, oxyde nitrique, streptozotocine (STZ), diabete, aorte de rat., Introduction Cardiovascular diseases (CVD) are main causes of morbidity and mortality in diabetes. Both micro- and macro-vascular complications play a major role in the development of CVD in diabetic patients. [...]

Hypoglycemia-associated autonomic failure (HAAF) is a serious complication of diabetes which is associated with the absence of physiological homeostatic counter-regulatory mechanisms that are controlled by the hypothalamus and sympathetic nervous system. Identification of biomarkers for early detection of HAAF requires an advanced understanding of molecular signature of hypoglycemia which is yet to be identified. The outcomes of the present study have shown that the viability and the apoptotic rate of the hypothalamic neurons (mHypoE-N39) were decreased significantly due to hypoglycemia in a dose-dependent fashion (p < 0.05). Although there are more than 1000 miRNAs differentially expressed in hypothalamus, only twelve miRNAs (miR-7a, miR-7b, miR-9, miR-29b, miR-29c, miR-30a, miR-30b, miR-30c, miR-101b-3p, miR-181a-5p, miR-378-3p and miR-873-5p) were correlated to two main hypothalamic regulatory proteins, FOS and FTO. Expression of these proteins was very sensitive to hypoglycemia. We demonstrated that hypoglycemia modulates the expression of hypothalamic miRNAs that are related to FOS and FTO. Keywords: FOS, FTO, microRNAs, Diabetes mellitus, Hypoglycemia-associated autonomic failure, Author(s): Bashair M. Mussa[sup.1], Jalal Taneera[sup.2], Abdul Khader Mohammed[sup.3], Ankita Srivastava[sup.3], Debasmita Mukhopadhyay[sup.3] and Nabil Sulaiman[sup.4] Introduction Hypothalamus is composed of multiple clusters of neurons which express different hormones, neurotransmitters [...]

Diabetes mellitus (DM) is widely recognized as the most severe metabolic disease associated with increased cardiovascular morbidity and mortality. The generation of reactive oxygen species (ROS) is a major event causally linked to the development of cardiovascular complications throughout the evolution of DM. Recently, monoamine oxidases (MAOs) at the outer mitochondrial membrane, with 2 isoforms, MAO-A and MAO-B, have emerged as novel sources of constant hydrogen peroxide ([H.sub.2][O.sub.2]) production in the cardiovascular system via the oxidative deamination of biogenic amines and neurotransmitters. Whether MAOs are mediators of endothelial dysfunction in DM is unknown, and so we studied this in a streptozotocin-induced rat model of diabetes. MAO expression (mRNA and protein) was increased in both arterial samples and hearts isolated from the diabetic animals. Also, [H.sub.2][O.sub.2] production (ferrous oxidation--xylenol orange assay) in aortic samples was significantly increased, together with an impairment of endothelium-dependent relaxation (organ-bath studies). MAO inhibitors (clorgyline and selegiline) attenuated ROS production by 50% and partially normalized the endothelium-dependent relaxation in diseased vessels. In conclusion, MAOs, in particular the MAO-B isoform, are induced in aortas and hearts in the streptozotocin-induced diabetic rat model and contribute, via the generation of [H.sub.2][O.sub.2], to the endothelial dysfunction associated with experimental diabetes. Key words: monoamine oxidases, experimental diabetes mellitus, oxidative stress, endothelial dysfunction, clorgyline, selegiline. Il est largement accepte que le diabete sucre est la maladie metabolique la plus grave, associee a une morbidite et une mortalite cardiovasculares. La production de derives reactifs de l'oxygene (DRO) est une manifestation majeure entrainant des complications cardiovasculaires tout au long de la progression du diabete sucre. Recemment, les monoamine oxydases (MAO) de la membrane mitochondriale externe sous deux isoformes (MAO-A et MAO-B) se sont demarquees comme de nouvelles sources de production constante de peroxyde d'hydrogene ([H.sub.2][O.sub.2]) dans le systeme cardiovasculaire par l'intermediaire de la desamination oxydative des amines biogenes et des neurotransmetteurs. On ne sait pas si les MAO sont des mediateurs de la dysfonction endotheliale dans le diabete sucre, et c'est ce que nous avons etudie avec ce modele de diabete induit par la streptozotocine chez le rat. L'expression des MAO (ARNm et proteines) augmentait dans les echantillons arteriels comme dans les creurs isoles d'animaux diabetiques. De plus, la production de [H.sub.2][O.sub.2] (test de l'oxydation des ions ferreux revelee par le xylenol orange) dans des echantillons d'aorte etait nettement accrue et associee a un deficit de la relaxation dependante de l'endothelium (etudes en bain d'organe). L'administration des inhibiteurs des MAO (clorgyline et selegiline) a permis de diminuer la production de DRO de 50% et est parvenue en partie a retablir la relaxation dependante de l'endothelium a une valeur normale dans les vaisseaux atteints. En conclusion, dans le modele de diabete induit par la streptozotocine chez le rat, les MAO, en particulier l'isoforme MAO-B, sont induites dans les aortes et les creurs des animaux et contribuent par la production de [H.sub.2][O.sub.2] a la dysfonction endotheliale observee dans un modele experimental du diabete. [Traduit par la Redaction] Mots-cles: monoamine oxydases, diabete sucre experimental, stress oxydatif, dysfonction endotheliale, clorgyline, selegiline., Introduction Diabetes mellitus (DM), the most severe metabolic disease associated with increased cardiovascular morbidity and mortality, is widely recognized nowadays as a serious threat to global health, owing to its [...]

Luminal appearance of 4-nitrophenol (PNP) metabolites (4-nitrophenol-β-glucuronide (PNP-G) and 4-nitrophenol-sulfate (PNP-S)) and activity of the related metabolic enzymes have been investigated in control and experimental diabetic rats. Experimental diabetes was induced by administration of streptozotocin (65 mg/kg i.v.). PNP (500 µmol/L) was luminally perfused in the small intestine and the metabolites were determined in the perfusion solution. Effect of insulin replacement was also investigated in the diabetic rats. It was found that experimental diabetes increased the luminal appearance of PNP-G, which could be completely compensated by rapid-acting insulin administration (1 U/kg i.v.). Activities of the enzymes involved in PNP-G production (UDP-glucuronyltransferase and β-glucuronidase) were also elevated; however, these changes were only partially compensated by insulin. Luminal appearance of PNP-S was not significantly changed by administration of streptozotocin and insulin. Activities of the enzymes of PNP-S production (sulfotransferases and arylsulfatases) did not change in the diabetic rats. The results indicate that experimental diabetes can provoke changes in intestinal drug metabolism. It increased intestinal glucuronidation of PNP but did not influence sulfate conjugation. No direct correlation was found between the changes of metabolic enzyme activities and the luminal appearance of the metabolites. Key words: experimental diabetes, insulin, intestinal drug metabolism, glucuronidation, sulfation, 4-nitrophenol. L'apparition dans le lumen des metabolites du 4-nitrophenol (PNP) (4-nitrophenol-β-glucuronide (PNP-G) et le 4-nitrophenolsulfate (PNP-S)) et l'activite des enzymes metaboliques reliees ont ete examinees chez des rats controles et des rats rendus diabetiques de maniere experimentale. Le diabete experimental a ete induit par l'administration de streptozotocine (65 mg/kg i.v.). PNP (500 µmol/L) a ete perfuse dans le lumen du petit intestin et la presence des metabolites a ete determinee dans la solution de perfusion. L'effet d'un supplement d'insuline a aussi ete etudie chez les rats diabetiques. Les auteurs ont trouve que le diabete experimental accroissait l'apparition du PNP-G dans le lumen, ce qui pouvait etre completement contrecarre par l'administration d'insuline a action rapide (1 U/kg i.v.). L'activite des enzymes impliquees dans la production de PNP-G (UDP-glucuronyl transferase et β-glucuronidase) etait aussi elevee; cependant, ces changements n'etaient que partiellement contrecarres par l'insuline. L'apparition de PNP-S dans le lumen ne changeait pas significativement a la suite de l'administration de streptozotocine et d'insuline. L'activite des enzymes impliquees dans la production de PNP-S (sulfotransferases et arylsulfatases) ne changeait pas chez les rats diabetiques. Les resultats indiquent que le diabete experimental peut provoquer des changements du metabolisme intestinal des medicaments. Il accroissait la glucuronidation intestinale du PNP mais n'influencait par la conjugaison de sulfate. Aucune correlation directe n'a ete trouvee entre les changements d'activite enzymatique et l'apparition des metabolites dans le lumen. [Traduit par la Redaction] Mots-cles : diabete experimental, insuline, metabolisme intestinal des medicaments, glucuronidation, sulfation, 4-nitrophenol., Introduction After oral drug administration following intestinal absorption, the molecules first reach the portal vein and the liver, then the systemic blood circulation. During these processes, the drug molecules can [...]

The objective of the study was to investigate the role of electrical remodeling of the ventricular myocardium in hemodynamic impairment and the development of arrhythmogenic substrate. Experiments were conducted with 11 healthy and 12 diabetic (alloxan model, 4 weeks) rabbits. Left ventricular pressure was monitored and unipolar electrograms were recorded from 64 epicardial leads. Aortic banding was used to provoke arrhythmia. The diabetic rabbits had prolonged QTc, with activation-recovery intervals (surrogates for repolarization durations) being relatively short on the left ventricular base and long on the anterior apical portions of both ventricles (P < 0.05). In the diabetic rabbits, a negative correlation (-0.726 to -0.817) was observed between dP/[dt.sub.max], dP/[dt.sub.min], and repolarization dispersions. Under conditions of systolic overload (5 min), tachyarrhythmias were equally rare and the QTc and activation-recovery intervals were shortened in both groups (P < 0.05), whereas QRS was prolonged in the diabetic rabbits only. The repolarization shortening was more pronounced on the apex, which led to the development of apicobasal and interventricular end of repolarization gradients in the healthy animals, and to the flattening of the repolarization profile in the diabetic group. Thus, the diabetes-related pattern of ventricular repolarization was associated with inotropic and lusitropic impairment of the cardiac pump function. Key words: activation-recovery intervals, arrhythmias, inotropy, lusitropy, repolarization. L'objectif de cette etude etait d'estimer le role que le remodelage myocardique electrique pourrait jouer dans les deficiences hemodynamiques et le developpement d'un substrat arythmogene ventriculaire. Des experiences ont ete realisees sur 11 lapins sains et 12 lapins diabetiques (modele induit par l'alloxane, 4 semaines). La pression ventriculaire gauche a ete suivie et des electrocardiogrammes unipolaires ont ete enregistres de 64 sondes epicardiques. Le cerclage aortique a ete utilise comme manoeuvre pro-arythmique provocatrice. Les lapins diabetiques presentaient un QTc prolonge, avec des intervalles d'activationrecuperation (substitut des durees de repolarisation) relativement courts a la base ventriculaire gauche et longue dans les portions apicales anterieures des deux ventricules (P < 0,05). Chez les animaux diabetiques, une correlation negative (-0,726 a -0,817) a ete observee entre le dP/[dt.sub.max], le dP/[dt.sub.min] et les dispersions de repolarisation. Lors d'une surcharge systolique (5 min), les tachyarythmies etaient rares chez les deux groupes, le QRS etait prolonge chez les diabetiques, alors que le QTc et les intervalles d'activation-recuperation etaient raccourcis chez les deux groupes (P < 0,05). Le raccourcissement de la repolarisation etait plus prononce a l'apex, ce qui menait au developpement de gradients de repolarisation des extremites apico-basale et inter-ventriculaire chez les animaux sains, et a l'aplatissement du profile de repolarisation chez les diabetiques. Ainsi, le patron de repolarisation ventriculaire lie au diabete etait associe a des deficiences inotropes et lusitropes de la fonction de la pompe cardiaque. [Traduit par la Redaction] Mots-cles : intervalles d'activation-recuperation, arythmie, inotropie, lusitropie, repolarisation., Introduction Diabetes mellitus (DM) leads to electrical myocardial remodeling, which manifests as prolonged action potential duration due to the down-regulation of potassium currents (Magyar et al. 1992; Zhang et al. [...]

The peptide hormone glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion and inhibits both gastric emptying and glucagon secretion. GLP-1 receptor (GLP-1R) agonists control glycemia via glucose-dependent mechanisms of action and promote weight loss in obese and diabetic individuals. Nevertheless, the mechanisms and cellular targets transducing the weight loss effects remain unclear. Two recent studies in the JCI provide insight into the neurons responsible for this effect. Sisley et al. reveal that GLP-1R agonist-induced weight loss requires GLP-1Rs in the CNS, while Secher et al. reveal that a small peptide GLP-1R agonist penetrates the brain and activates a subset of GLP-IR-expressing neurons in the arcuate nucleus to produce weight loss. Together, these two studies elucidate pathways that inform strategies coupling GLP-1R signaling to control of body weight in patients with diabetes or obesity., The metabolic effects of GLP-1 Glucagon-like peptide-1 (GLP-1) is a small peptide hormone that is continuously secreted from enteroendocrine cells at a low level in the fasting or interprandial state. [...]

This study evaluates the influence of streptozotocin-induced diabetes on the kinetic disposition and metabolism of mexiletine (MEX) enantiomers in rats. Animals in the control (n = 6 for each blood collection time), diabetic (single intravenous dosage of 45 mg x [(kg body mass).sup.-1] of streptozotocin), and insulin-treated groups (diabetic rats treated daily with 2 IU insulin) received by gavage a single dose of 10 mg x [(kg body mass).sup.-1] racemic MEX. MEX enantiomers and the metabolites hydroxymethylmexiletine (HMM) and p-hydroxymexiletine PHM) were analyzed by LC-MS/MS. Statistical analysis was based on a serial sacrifice design, and parameter estimation was performed using a Bayesian modeling procedure. Area under the curve (AUC) for the (-)-(R) enantiomers of MEX, HMM, and PHM did not differ between the control and diabetic groups. However, AUC for (+)-(S)-MEX and (+)-(S)-HMM were lower in the diabetic than in the control group. Insulin treatment recovered glucose levels to normal and the (+)-(S)-MEX AUC and (+)-(S)-HMM AUC became similar to the AUCs observed in the nondiabetic animals. Key words: mexiletine, enantiomers, metabolites, pharmacokinetics, diabetes, insulin, rats. Cette etude evalue l'influence du diabete induit par la streptozotocine sur la disposition cinetique et le metabolisme des enantiomeres de la mexiletine (MEX) chez le rat. Les animaux des groupes controle (n = 6a chaque prelevement sanguin), diabetique (une seule dose i.v. de 45 mg x [(kg de masse corporelle).sup.-1] de streptozotocine) et traite a l'insuline (diabetique traite quotidiennement avec 2 UI d'insuline) ont recu par gavage une seule dose de 10 mg x [(kg de masse corporelle).sup.-1] d'un melange racemique de MEX. Les enantiomeres de MEX et leurs metabolites, la hydroxymethylmexiletine (HMM) et la p-hydroxymexiletine (PHM), ont ete analyses par LC-MS/MS. L'analyse statistique a ete basee sur des donnees issues d'un protocole de sacrifice seriel et l'estimation parametrique a ete realisee par une modelisation Bayesienne. Les aires sous la courbe (ASC) des enantiomeres (-)-(R) de MEX, de HMM et de PHM ne differaient pas significativement entre les groupes controle et diabetique. Toutefois les ASC de (+)-(S)-MEX et (+)-(S)-HMM etaient plus faibles chez le groupe diabetique comparativement au groupe controle. Le traitement a l'insuline permettait de retablir les niveaux normaux de glucose et les ASC de (+)-(S)-MEX et de (+)-(S)-HMM similaires a ceux des animaux non diabetiques. [Traduit par la Redaction] Mots-cles: mexiletine, enantiomeres, metabolites, pharmacocinetique, diabete, insuline, rats., Introduction Mexiletine (MEX; 1-(2,6-dimethylfenoxi)-2-aminopropane), a drug available as a racemic mixture of (-)-R and (+)-(S) enantiomers, is used clinically for alleviating neuropathic pain in diabetes (Andriaensen et al. 2005). The [...]

Meal-induced insulin sensitization (MIS) describes the augmented postprandial response to insulin through action of the hepatic insulin sensitizing substance (HISS). HISS-action is impaired in insulin resistance associated with aging and type 2 diabetes, but could be preserved by the antioxidant cocktail SAMEC, along with voluntary exercise. In this study, we tested whether antioxidant supplementation during voluntary training would interact with the effects of exercise on HISS-mediated glucose uptake in healthy and prediabetic rats. The 7-day voluntary running-wheel training was used as an exercise intervention. SAMEC supplementation was provided only during the 7-day training session. The rapid insulin sensitivity test (RIST) was conducted to determine insulin- and HISS-dependent glucose uptake in 14-week-old healthy rats, and sucrose-induced insulinresistant rats, with or without exercise in the presence or absence of SAMEC supplementation. The postprandial insulin sensitivity was increased by exercise, primarily through enhancement of the HISS-dependent glucose uptake, which remained unaffected by SAMEC. SAMEC supplementation did not either harm or add benefit to the positive effects of exercise on insulin sensitivity in healthy or prediabetic rats. While SAMEC alone was a demonstrated preventive against the progressive loss of HISS action in previous studies, short-term supplementation in this study did not reverse the established disease state. Key words: insulin, hepatic insulin sensitizing substance (HISS), meal-induced insulin sensitization, age, diet, exercise, antioxidant. La sensibilisation a l'insuline (SI) induite par la prise alimentaire decrit l'accroissement de la reponse postprandiale a l'insuline a la suite de l'action de la substance hepatique sensibilisant a l'insuline (HISS, acronyme de Hepatic Insulin Sensitizing Substance). L'action de la HISS est reduite en situation de resistance a l'insuline associee au vieillissement et au diabete de type 2, mais elle pourrait etre preservee par un melange antioxydant, le SAMEC, et l'exercice volontaire. Dans cette etude, nous avons verifie si une supplementation en antioxydants lors d'un entrainement volontaire pourrait interagir avec les effets de l'exercice sur la captation de glucose stimulee par la HISS chez des rats sains et pre-diabetiques. L'exercice a consiste en un entrainement volontaire sur roue pendant 7 jours. La supplementation en SAMEC a ete fournie uniquement pendant la session d'entrainement de 7 jours. Le test rapide de sensibilite a l'insuline a ete realise afin de mesurer la captation de glucose dependante de l'insuline et de la HISS chez des rats de 14 semaines sains ou qui presentaient une resistance a l'insuline induite par le sucrose, entraines ou non, en presence ou en absence d'une supplementation en SAMEC. La sensibilite postprandiale a l'insuline etait accrue par l'exercice, essentiellement par l'intermediaire de l'augmentation de la captation du glucose dependante de la HISS, laquelle n'etait pas affectee par le SAMEC. La supplementation en SAMEC n'etait ni nuisible ni n'ajoutait de benefices aux effets positifs de l'exercice sur la sensibilite a l'insuline chez les rats sains ou pre-diabetiques. Alors que le SAMEC seul prevenait la perte d'action progressive de la HISS selon des etudes precedents, la supplementation a court terme utilisee l'etude actuelle ne pouvait renverser l'etat pathologique etabli. [Traduit par la Redaction] Mots-cles : insuline, substance hepatique sensibilisant a l'insuline (HISS), sensibilisation a l'insuline induite par la prise alimentaire, age, diete, exercice, antioxydant., Introduction The storage and partitioning of nutrient energy are dominantly regulated by insulin, which is lipogenic, and HISS (hepatic insulin sensitizing substance) (Lautt et al. 2010), which selectively stimulates glucose [...]

ARTICLE INFO Keywords: Tinospora crispa Borapetoside A Antihyperglycemia Mice with diabetes mellitus ABSTRACT Aim: This study explores the hypoglycemic effects of borapetoside A. the most active principle among three major [...]

ARTICLE INFO Keywords: Kudzu Pueraria lobara Puerarin Glucose metabolism Lipicls ABSTRACT The incidence of type 2 diabetes and metabolic disease is rapidly increasing, but effective therapies for their prevention and [...]

Abstract Aim This study explores the expectation that diabetes self-management is adversely affected by individuals' economic problems. Method A convenience sample of ten individuals, aged between 41 and 64 with [...]

Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound [...]

The present study was designed to elucidate a possible mechanism of hyperglycemia-induced tubular injury and to examine a therapeutic potential of dietary eicosapentaenoic acid (EPA) for the prevention of diabetic kidney disease. Utilizing streptozotocin-induced diabetic mice, the extents of albuminuria and histological injuries were monitored at 2 wk after diabetic induction. Reactive oxygen species (ROS) production, apoptosis, and hypoxia in the kidney were evaluated by immunohistochemistry and Western blotting. An in vitro study was performed using rat proximal tubular cells (NRK-52E) to confirm the protective effect of EPA for methylglyoxal (MG)-induced ROS generation and staurosporine (STS)-induced mitochondrial apoptosis. The extents of albuminuria and histological tubular injuries were significantly lower in EPA-treated diabetic mice compared with untreated diabetic mice. The levels of lipid peroxidation product (4-hydroxy-2-nonenal), oxidative DNA damage (8-hydoxy-deoxyguanosine), and mitochondrial apoptosis (TUNEL, caspase-9, cleaved caspase-3, and cytochrome c release) in the tubular cells were also significantly lower in EPA-treated diabetic mice. Furthermore, hypoxia-inducible factor (HIF)-1[alpha] expression was significantly upregulated in the kidney tissues from EPA-treated mice compared with untreated diabetic mice. MG-induced ROS overproduction and STS-induced mitochondrial apoptosis in NRK-52E cells were significantly reduced by EPA treatment in vitro. These results indicated that the ROS generation and mitochondrial apoptosis were involved in hyperglycemia-induced tubular injury and EPA had a beneficial effect by suppressing ROS generation and mitochondrial apoptosis partly through augmentation of an HIF-1[alpha] response in diabetic kidney disease. streptozotocin; diabetic nephropathy; renal tubules; ROS; hypoxia; HIF-1[alpha] doi: 10.1152/ajprenal.00637.2009

The incidence of obesity is increasing worldwide and is hence considered a major public health concern. Obesity underlies the development of several metabolic complications including cardiovascular diseases, diabetes, and inflammation. Research on ways to slow the development of obesity have traditionally focused on dietary and lifestyle modifications such as restricting caloric intake and increasing physical activity. An area that has recently aroused considerable research interest is investigating the potential role of spices, particularly the Asian spice turmeric, for combating obesity. Curcumin is the active ingredient in turmeric. Evidence suggests curcumin may regulate lipid metabolism, which plays a central role in the development of obesity and its complications. The present review addresses the evidence and mechanisms by which curcumin may play a role in downregulating obesity and reducing the impact of associated problems. [c] 2010 International Life Sciences Institute doi: 10.1111/j.1753-4887.2010.00341.x

Increased intestinal bile acid absorption and expansion of the bile acid pool has been implicated in the hypercholesterolemia associated with diabetes mellitus. However, the molecular basis of the increase in bile acid absorption in diabetes mellitus is not fully understood. The ileal apical [Na.sup.+]-dependent bile acid transporter (ASBT) is primarily responsible for active reabsorption of the majority of bile acids. Current studies were designed to investigate the modulation of ASBT function and expression in streptozotocin (STZ)-induced diabetes mellitus in rats and to examine the effect of insulin on rat ASBT promoter by insulin. Diabetes mellitus was induced in Sprague-Dawley rats by intraperitoneal injection of low doses of STZ (20 mg/kg body wt) on five consecutive days. Human insulin (10 U/day) was given to a group of diabetic rats for 3 days before euthanasia. RNA and protein were extracted from mucosa isolated from the small intestine and ASBT expression was assessed by real-time quantitative RT-PCR and Western blotting. Our data showed that ASBT mRNA and protein expression were significantly elevated in diabetic rats. Insulin treatment of diabetic rats reversed the increase in ASBT protein expression to control levels. Consistently, ileal [Na.sup.+]-dependent [[sup.3]H]taurocholic uptake in isolated intestinal epithelial cells was significantly increased in diabetic rats. In vitro studies utilizing intestinal epithelial Caco-2 cells demonstrated that ASBT expression and promoter activity were significantly decreased by insulin. These studies demonstrated that insulin directly influences ASBT expression and promoter activity and that ASBT function and expression are increased in rats with STZ-induced diabetes mellitus. The increase in ASBT expression may contribute to disturbances in cholesterol homeostasis associated with diabetes mellitus. hypercholesterolemia; insulinopenia; enterohepatic circulation doi: 10.1152/ajpgi.00139.2010.