The study of renin–angiotensin–aldosterone in experimental diabetes mellitus

It is generally accepted that hypertension and other vascular pathologies increase in diabetes mellitus (DM) patients as a result of the renin–angiotensin–aldosterone (RAA) system. In this study, changes in the renin‐angiotensin‐aldosterone (RAA) system level was determined in Streptozotocin (STZ)‐injected rats. A total of 46 female Wistar albino rats (180–220 g body weight) was utilized in these experiments. STZ was given intraperitoneally to induce diabetes in rats. Streptozotocin (60 mg kg⁻¹ body weight) was dissolved in 0·1 m citrate–‐phosphate buffer (pH 4–5). The non‐diabetic rats were injected with sterilized buffer alone to act as a control group. Blood glucose levels were 398±8·2 mg dl⁻¹, 488±11·75 mg dl⁻¹ and 658±29·6 mg dl⁻¹ at days 3, 12 and 30 respectively. The level of plasma renin activity (PRA) was measured as 7·69±1·07 ng ml⁻¹ h⁻¹; 1·82±0·22 ng ml⁻¹ h⁻¹ and 0·67±0·12 ng ml⁻¹ h⁻¹ at days 3, 12 and 30, respectively. These values showed that the PRA levels are decreased with increased time period. Serum angiotensin converting enzyme (ACE, E.C. 3.4.15.1) levels were increased at days 12 and 30 (p<0·05 and p<0·005), whereas serum aldosterone levels were increased at days 3 and 12 (p<0·05). The level of urea and creatinine increased at days 12 and 30 (p<0·05 and p<0·005, respectively) when compared to the control group. The data from these experiments indicate that the PRA level decreased whereas ACE activity level increased in diabetic rats compared with the control. Aldosterone levels increased at the first stage of the experiment, but then decreased by the end of the experiment as a result of changes in renin and ACE levels. Copyright © 1999 John Wiley & Sons, Ltd.     

实验恒河猴糖尿病动物模型建立及视网膜并发症的研究

[目的]糖尿病是由于多种因素和遗传因素导致体内胰岛素相对或绝对分泌不足,而引起的代谢性内分泌疾病,它以血糖、尿糖升高为特点,起病隐蔽,通过并发症使人致残致死,是继心血管、癌症之后的第三大致死性疾病,很可能成为21世纪人类的“第一杀手”(1,2)。本文采用人工诱导的方法,建立恒河猴糖尿病动物模型,研究糖尿病疾病的发展和及其并发症的发生、发展规律和防治措施,同时对于治疗糖尿病新药的安全性评价和药物疗效的观察具有广阔的运用前景。[方法]选用成熟的、健康的、雄性恒河猴9只,随机分成三个组,其中高剂量组(60mg/kg)1只,中剂量组(45m…     

The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus

A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.     

Angiotensin II receptor binding in the locus ceruleus of spontaneously hypertensive rats and Wistar-Kyoto rats: A quantitative autoradiographic study with references to hypertension and cardiac/testicular hypertrophy

The locus ceruleus (LC) contains a high density of angiotensin II (All) receptors. The role of All receptors at the LC in genetic hypertension and organ function is unclear. Spontaneously hypertensive (SHR) rats and Wistar-Kyoto (WKY) rats were studied, and blood pressure of animals was measured using the tail-cuff method. Animals were decapitated and the heart weight (HW) and testicular weight (TW) of animals measured. All receptor binding was carried out by incubating the LC tissue sections with 200 pM [¹²⁵I]-All receptor ligand, and measured using quantitative autoradiography. Results showed that the HW/BW ratio was significantly higher in SHR rats than WKY rats. However, the TW/BW ratio was higher in SHR rats than WKY rats only at two hypertensive stages, whereas All receptor binding capacity in the LC was also statistically higher in SHR rats than WKY rats. Results indicated that cardiac and testicular hypertrophies were related to higher All receptor binding in the LC of SHR rats, when compared with WKY rats. Interestingly, the literature shows that there is an LC-testes axis. In conclusion, this study indicated that All receptors in the LC are associated with genetic hypertension, and testicular weight could be a reasonable index for essential hypertension.     

Role of the Na/Ca exchanger on the development of diabetes mellitus and its chronic complications

Diabetes mellitus (DM) is a serious metabolic disorder with micro- and macrovascular complications that results in significant morbidity and mortality. It is well established that cytosolic Ca²⁺ play an important role in controlling insulin secretion in pancreatic β-cells. The Na⁺/Ca²⁺ exchanger (NCX), an ion transport protein, is expressed in the plasma membrane of virtually all animal cells. NCX is a reversible carrier that can mediate the transport of Ca²⁺ across the plasma membrane in both directions. Therefore, great efforts have been made to identify NCX associated with DM. NCX is expressed in several tissues, and acts in the protection against intracellular calcium overload; in the regulation of insulin secretion by beta cells, and in improving vascular endothelium-dependent relaxation. All these mechanisms are associated with DM pathogenesis and its chronic complications. Therefore, NCX is a candidate protein for the development of these disorders. Only a few studies investigated NCX in relation to chronic complications of diabetes, with inconclusive results.     

Hypertension aggravates glomerular dysfunction with oxidative stress in a rat model of diabetic nephropathy

Oxidative stress may contribute to the pathogenesis of diabetic nephropathy (DN), although the detailed mechanism of reactive oxygen species (ROS) regulation is still unclear. This study examined the effect of high-salt diet on ROS production and expression of antioxidant enzymes in control and experimentally diabetic rats. Wistar fatty rats (WFR) as a type 2 diabetes mellitus model and Wistar lean rats (WLR) as a control were fed a normal-salt diet (NS) and high-salt diet (HS) from the age of 6 to 14 weeks. We then examined the blood pressure, urinary albumin excretion (UAE), and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. The expression of antioxidant enzymes including α-catalase (CAT), Cu-Zn superoxide dismutase (SOD), Mn SOD, and glutathione peroxidase (GPx) were analyzed in the glomeruli of the rats using Western blotting. The expression of NAD(P)H oxidase p47^phox and NFκB p65 was evaluated using immunohistochemical staining. By 14 weeks of age, the WFR-HS group exhibited hypertension and markedly increased UAE. The level of 8-OHdG, a marker of oxidative damage, in the WFR-HS group was also higher than that in the WLR groups or WFR-NS group. The expression of α-CAT and Mn SOD proteins was significantly decreased in isolated glomeruli in the WFR-HS group. GPx and Cu-Zn SOD expression did not differ between the WFR and WLR groups. High expression of ROS and decreases in antioxidants were seen in the glomeruli of diabetic rats with hypertension, suggesting that oxidative stress may be involved in the development of DN.     

The Effects of stingless bee (Tetragonula biroi) honey on streptozotocin-induced diabetes mellitus in rats

Diabetes mellitus (DM) is a metabolic disease characterised by chronic hyperglycaemia with impaired carbohydrate, fat and protein metabolism caused by defects in insulin secretion or action. Based on our previous research, stingless bee honey (SLBH) from Tetragonula biroi and T. laeviceps can inhibit alpha-glucosidase activities. Therefore, the aim of the present study was to determine the effects of daily oral administration of SLBH on body weight (BW) and fasting blood glucose (FBG) levels of male rats with streptozotocin (STZ)-induced DM. Thirty-six male Sprague Dawley rats were divided into six groups of six rats each. One group of normal non-diabetic rats served as a positive control. The diabetic groups were intraperitoneally (i.p.) injected with STZ (50 mg/kg BW) for induction of DM and divided into five equal subgroups of six animals each: an untreated group as a negative control; a group treated with 0.6 mg/kg BW of glibenclamide as a positive control and three SLBN treatment groups that had daily oral administration of 0.5, 1.0 or 2.0 g/kg BW, respectively, for 35 days. The results showed that SLBH significantly reduced loss of BW in diabetic rats. FBG levels in diabetic rat blood, collected from the tail, were measured using Accu-Chek test strips. The FBG levels in diabetic rats that have oral administered intake with glibenclamide and SLBH were stable. There were no changes in serum FBG levels in SLBH-treated diabetic rats for 35 days. Pancreatic histopathology results from all groups showed no abnormalities or tissue damage in either diabetic or non-diabetic rats. The results of this study show that administration of SLBH reduced BW loss or improved BW of rats with STZ-induced DM. Meanwhile, the reduction in loss of BW that occurred in diabetic rats after 35 days of SLBH administration was the result of reduced formation of fats and proteins, which are broken down into energy. Further research is needed to determine the antidiabetic effects of honey from other stingless honeybee species.     

Effects of diabetes type and treatment on zinc status in diabetes mellitus

Zinc status was assessed in 53 diabetic patients: 18 insulin-dependent diabetic patients (IDDM), 22 noninsulin-dependent diabetic patients (NIDDM) treated with oral antidiabetic agents, and 13 insulin-treated, noninsulin-dependent diabetic patients (IRDM). Plasma zinc concentrations were in the usual range for healthy subjects in these three groups (15.3±0.9 μmol/L). Urinary zinc excretions were elevated in the IDDM group (18.3±4.1 μmol/24 h;p<0.01 vs normal) and in the NIDDM group (17.5±3.5 μmol/24 h;p<0.01 vs normal), but normal in the IRDM group (11.3±2.4 μmol/24 h). In 14 NIDDM patients treated with transient continuous sc insulin injections, urinary zinc decreased from 16.5±2.2 μmol/24 h before insulin treatment to 11.5±0.3 μmol/24 h after insulin treatment without any modification in plasma zinc concentrations.     

Effects of Cudrania tricuspidata water extract on blood pressure and renal functions in NO-dependent hypertension

A pharmacological inhibition of nitric oxide synthase (NOS) in rats for 4-6 weeks produces renal vasoconstriction, renal dysfunction, and severe hypertension. The present study was aimed at investigating whether Cudrania tricuspidata (C. tricuspidata) water extract ameliorates N(G)-Nitro-L-arginine methylester (L-NAME)-induced hypertension. Treatment of L-NAME (60 mg/L drinking water, 4 weeks) causes a sustained increase in systolic blood pressure (SBP). The concentration of plasma NO metabolites and NO/cGMP productions in the vascular tissues of the L-NAME-treated group were significantly reduced as compared with those in the control. C. tricuspidata water extract blocked increase of SBP in the L-NAME-treated group and restored SBP to normal level. Futhermore, C. tricuspidata water extract was able to preserve the vascular NO/cGMP production and plasma NO metabolites concentration. However, there are no changes in the expression of ecNOS and iNOS of thoracic aorta among the rats of control, L-NAME-treated group, and L-NAME and C. tricuspidata water extract co-treated group. The urinary sodium level, urine volume, and creatinine clearance were significantly higher in rats co-treated with C. tricuspidata water extract and L-NAME than in L-NAME-treated group. Taken together, these results suggest that C tricuspidata water extract prevents the increase of SBP in the L-NAME-induced hypertension that may have been caused by enhanced generation of vascular NO/cGMP.     

Effects of angiotensin II on the spontaneous activity of rostral ventrolateral medullary cardiovascular neurons and blood pressure in spontaneously hypertensive rats

The interactive role of rostral ventrolateral medulla (RVL) cardiovascular neurons and brain angiotensin II (Ang II) in regulating the arterial blood pressure was examined by recording simultaneously the spontaneous activity of these spinal projecting neurons and the arterial blood pressure in the pentobarbital-anesthetized spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar Kyoto rat (WKY). It was found that Ang II elicited dose-dependent excitatory responses in a subpopulation of RVL cardiovascular neurons, followed by a subsequent increase in blood pressure. These effects of Ang II were significantly greater in SHR than in WKY. The effects were attenuated or abolished by co-administration of Ang II antagonist, [Sar¹, Ile⁸]-Ang II. Pre-administration of [Sar¹, Ile⁸]-Ang II to RVL using bilateral microinjection attenuated the blood pressure effects of intracerebroventricularly administered Ang II by as much as 70%. These results indicated that spinal projecting RVL cardiovascular neurons are important in mediating the pressor action of Ang II. The enhanced sensitivity and responsiveness of RVL cardiovascular neurons to Ang II may be pertinent to the genesis of hypertension in adult SHR.     

Angiotensin II,as well as 5-hydroxytriptamine,is a potent vasospasm inducer of saphenous vein graft for coronary artery bypass grafting in patients with diabetes mellitus

Diabetes mellitus (DM) is an important risk factor for adverse outcomes of coronary artery bypass grafting. The bypass grafts harvested from patients with DM tend to go into spasm after their implantation into the coronary circulation. To clarify the contribution of 5-hydroxytriptamine (5-HT) and angiotensin II (AngII) in the bypass graft spasm, we examined the contractile reactivity to 5-HT or AngII of isolated human endothelium-denuded saphenous vein (SV) harvested from DM and non-DM patients. The 5-HT-induced constriction of the SV was significantly augmented in the DM group than in the non-DM group, which is similar to our previous report. AngII-induced constriction of the SV was also significantly augmented in the DM group than the non-DM group. Especially in the non-DM group, the AngII-induced maximal vasoconstriction was markedly lower than the 5-HT-induced one. Meanwhile, the increasing rates of AngII-induced vasoconstriction in the DM group to the non-DM group were significantly greater than those of 5-HT-induced vasoconstriction. These results indicate that 5-HT is a potent inducer of SV graft spasm in both DM and non-DM patients, while AngII is a potent inducer of SV graft spasm only in patients with DM. Furthermore, the protein level of AngII AT₁ receptor (AT₁R), but not the protein level of 5-HT_2A receptor, in the membrane fraction of the SV smooth muscle cells of DM patients was significantly increased as compared with that of the non-DM patients. These results suggest that the mechanism for hyperreactivity to AngII in the SV from DM patients is due to, at least in part, the increase in the amount of AT₁R on membrane of the SV smooth muscle cells.     

Effects of prostanoids on phenylephrine-induced contractions in the mesenteric vascular bed of rats with streptozotocin-induced diabetes mellitus

The main aim of this study was to compare the vascular reactivity of the perfused (Krebs, 4 ml/min) mesenteric vascular bed (MVB) isolated from rats with streptozotocin (STZ)-induced diabetes of 8 weeks duration to that of the MVB from non-diabetic (ND) Wistar rats. There were no differences in basal perfusion pressure between the MVB isolated from STZ and ND rats. The addition of indomethacin to the perfusate increased the basal perfusion pressure in both ND (18.8 +/- 0.7 vs 29.4 +/- 3.7 mmHg, p < 0.05) and STZ rats (18.3 +/- 0.9 vs 27.2 +/- 2.6 mmHg, p < 0.05), suggesting the release of a vasodilator prostaglandin. Remotion of the endothelium did not affect this response, indicating that prostaglandin was released from vascular smooth muscle. The response to phenylephrine was reduced in STZ rats compared to ND rats (2.3 [1.6-3.8] vs 8.3 [3.5-19.4], ED50. [IC 95%]) and was not modified by removal of the endothelium or by perfusion of L-nitro-arginine (50 microM). In contrast, indomethacin was able to reduce the response to phenylephrine in ND but not in STZ rats (2.3 [1.6-3.8] vs 4.7 [3.2-6.0], ED50. [IC 95%], p=0.02), suggesting that the blunted response to phenylephrine observed in STZ was due to the abolition of the release of prostaglandin by vascular smooth muscle. In conclusion, experimental diabetes induction in the rat is followed by a reduction of the contractile effect of phenylephrine due to the lack of release of a vasoconstrictor prostaglandin from vascular smooth muscle.     

Cardiovascular oxidative stress is reduced by an ACE inhibitor in a rat model of streptozotocin-induced diabetes

Blockade of the renin-angiotensin system (RAS) reduces cardiovascular morbidity and mortality in diabetic patients. Ang II-mediated generation of reactive oxygen species (ROS) has been suggested to be involved in several diabetic complications. We investigated whether the inhibition of Ang II production with an ACE inhibitor (ACEi) reduces oxidative stress and limits structural cardiovascular remodeling in a rat model of streptozotocin (STZ)-induced diabetes. Diabetic rats were treated for 7 weeks with an ACEi (lisinopril, 5 mg/kg/d), an antioxidant (N-acetyl-l-cysteine (NAC), 0.5 g/kg/d) and their combination. At sacrifice, ROS in the myocardium and thoracic aorta, LV myocyte number and size and aorta morphology were determined by quantitative histological methods. Superoxide and hydroxyl radical content, detected by dihydroethidium (DHE) and 8-hydroxydeoxyguanosine (8-OHdG), were 6.7 and 4.5-fold, respectively, higher in diabetic myocardium than in non-diabetic controls (p<0.001). The amount of superoxide was 5-fold higher in the thoracic aorta of diabetic rats compared to controls (p<0.001). Diabetes caused a modest increase in myocyte volume (+13%, p<0.01), a reduction of LV myocyte number (-43%, p<0.001), an accumulation of collagen around coronary arterioles (1.9-fold increase, p<0.01) and a decrease in arterial elastin/collagen ratio (-63%, p<0.001) compared to controls. Treatment with the ACEi attenuated ROS formation and prevented phenotypic changes in the heart (cardiomyocyte hypertrophy, perivascular fibrosis) and in the aorta of diabetic rats to the same extent as NAC. The absence of an additive effect, suggests a common mechanism of action, through the reduction of oxidative stress.     

Influence of alloxan-induced diabetes and selenite treatment on blood glucose and glutathione levels in mice

Many clinical studies reported that diabetic patients had lower glutathione contents in erythrocytes or plasma. Recently, selenium, an essential trace element with well-known antioxidant characteristics, has been found to have insulin-mimetic properties. But seldom information is available about the influence of selenium on glutathione changes induced by diabetes mellitus in animals. Therefore, this study was designed to compare the impacts of selenite treatment on glutathione (GSH) levels of blood and tissues such as brain, kidney, liver, spleen and testis in mice. Four groups were used in this study: a control group, a diabetic group, a selenite-treated normal group and a selenite-treated diabetic group. Selenite was administered to the mice for 4 weeks with an oral dose of 2 mg kg(-1) day(-1) by gavage. The blood glucose level, and GSH level in blood and tissues were determined. The results show that the selenite-treated diabetic group had significantly lower blood glucose levels than the diabetic group. Moreover, alloxan-induced diabetes significantly decreased GSH levels in blood, kidney, liver and testis compared to the controls. Selenite treatment of the diabetic mice only improved the GSH levels in liver and brain. On the other hand, selenite administered to the normal mice reduced GSH levels in the liver compared to the controls. In conclusion, this study suggests that selenite treatment of diabetic mice with an effective dose would be beneficial for the antioxidant system of liver and brain although it exerts a toxic effect on the liver of normal mice.     

Vitamin E supplementation in rats with experimental diabetes mellitus: analysis of myosin-V and nNOS immunoreactive myenteric neurons from terminal ileum

The effect of vitamin E (1 g/kg body weight) supplementation on myosin-V and neuronal nitric oxide synthase (nNOS) immunoreactive myenteric neurons from the ileum of diabetic rats was investigated in the present study. Forty animals were divided into the following groups: normoglycemics (N), normoglycemics treated with vitamin E (NE), diabetics (D), and diabetics treated with vitamin E (DE). Quantitative and morphometric analyses were performed. The area of the tertiary plexus was also determined. Diabetes produced a 24% reduction in the number of myosin-V neurons in group D compared with group N, an effect that was accompanied by an increase in the tertiary plexus area (P < 0.05). Neuronal density was 27% higher in group NE than group N (P < 0.05). Nitrergic neuronal density was not altered as a consequence of either diabetes or vitamin E treatment. Myosin-V and nNOS immunoreactive neuronal cell body area increased significantly in group NE. The area of myosin-V and nNOS myenteric neurons also increased in group D. Vitamin E treatment (group DE) increased only the size of nitrergic neurons. The present results suggest that vitamin E elicited a neuroprotective and neurotrophic effect on the natural aging process, but with regard to diabetes, vitamin E supplementation exerted a neurotrophic effect only on nitrergic neurons.     

Anti-lipid deposition effect of HMG-CoA reductase inhibitor, pitavastatin, in a rat model of hypertension and hypercholesterolemia

Since the rat is an atherosclerosis-resistant species, the study of atherosclerosis using rats is limited. The present study was undertaken to develop an atherosclerotic model in rats, to investigate the effect of nitric oxide (NO) inactivation and hyperlipidemia, and to evaluate the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, on NO inactivation and on hyperlipidemia-induced changes in the cardiovascular system. Four-month-old male spontaneously hypertensive hyperlipidemic rats (SHHR) and Sprague-Dawley (SD) rats were used to study 1) the effect of the period of treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L) on high fat diet (HFD)-treated SHHR and SD rats, and 2) the effect of pitavastatin (Pit, 0.3 mg/kg/day) on the changes in the aorta of L-NAME- and HFD-treated SHHR and SD rats. L-NAME administration for 1 month then HFD feeding for 2 months markedly increased the deposition of lipids and the thickness of the endothelium in SHHR. Continuous L-NAME treatment with HFD produced severe injury and stripped of endothelium in both strains. The plasma total cholesterol of L-NAME + HFD-treated and L-NAME + HFD + Pit-treated SHHR was significantly higher than that of control SHHR. Lipid deposition, however, was comparatively less in the aorta of L-NAME + HFD + Pit-treated SHHR. The concentration of cholesterol in the aorta of control SHHR was significantly lower than that in the aorta of L-NAME + HFD-treated SHHR, whereas that of L-NAME + HFD + Pit-treated SHHR was the same as that in control SHHR. These data indicated that Pit blocked lipid deposition in the aorta of L-NAME + HFD treated SHHR without changing plasma lipid profiles. In conclusion, NO inactivation and HFD induce lipid deposition in the endothelium, and the HMG-CoA reductase inhibitor blocks the deposition in SHHR.     

Occurrence of spontaneous diabetes mellitus in a cynomolgus monkey (Macaca fascicularis) and impaired glucose tolerance in its descendants

Spontaneous diabetes mellitus was diagnosed in a cynomolgus monkey. Clinical and pathological features, such as abnormal glucose tolerance, loss of insulin response, or degeneration of pancreatic beta-cells, resemble human noninsulin-dependent diabetes mellitus. Two descendants of the monkey have developed impaired glucose tolerance and insulin response. Genetic factors seem involved in the appearance of carbohydrate intolerance in this family group of monkeys.     

Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats

Renin angiotensin system (RAS) worsens diabetic nephropathy (DN) by increasing oxidative stress. We compared the effect of three different RAS inhibitors: the angiotensin converting enzyme inhibitor Ramipril, the vasopeptidase inhibitor AVE7688 and the angiotensin receptor (AT1) antagonist Losartan on the formation of oxidative and carbonyl stress derived protein modifications in kidney from Zucker obese hyperglycemic rats (ZDFn Gm-fa/fa). Gas chromatography-mass spectrometry was used to measure representative markers of several protein oxidative pathways: direct oxidation [dinitrophenylhydrazine reactive carbonyls (DNP), glutamic (GSA), and aminoadipic (AASA) semialdehydes], mixed glyco- and lipoxidation [N^ε-carboxyethyl-lysine (CEL) and N^ε-(carboxymethyl)-lysine (CML)] and lipoxidation-[N^ε-(malondialdehyde)-lysine-(MDAL)], as well as renal fatty acid composition. Urinary albumin (a marker of DN), DNP, GSA, and MDAL levels, were increased in all obese rats and were dose dependently decreased by AVE7688 whereas Ramipril and Losartan were less efficient. These results show that RAS inhibition improves DN at several levels, independently of its effects on blood pressure and glycemic control, via mechanisms depending of renal oxidative stress.     

Effects of rs769217 and rs1001179 polymorphisms of catalase gene on blood catalase,carbohydrate and lipid biomarkers in diabetes mellitus

Abstract

Oxidative stress and deficiency of the enzyme catalase, which is the primary scavenger of the oxidant H₂O₂, may contribute to diabetes. The current study examined two polymorphisms in the catalase gene, ?262C>nT in the promoter and 111C>T in exon 9, and their effects on blood catalase activity as well as on concentrations of blood glucose, haemoglobin A1c, triglyceride, cholesterol, HDL, LDL, ApoA-I and ApoB. Subjects were type-1 and type-2 diabetics. We evaluated PCR-single strand conformational polymorphism for 111C>T and PCR-restriction fragment length polymorphism for ??262C>T. TT genotype frequency of 111C>T polymorphism was increased in type-1 diabetes. Type-2 diabetics with the CC or CT genotypes had decreased catalase and increased glucose, hemoglobinA1c and ApoB. Type-2 diabetics who have TT genotype in ?262C>T may have elevated risk for diabetes complications; these patients had the lowest mean catalase and HDL, as well as the highest glucose, haemoglobin A1c, cholesterol and ApoB.     

Effect of C111T polymorphism in exon 9 of the catalase gene on blood catalase activity in different types of diabetes mellitus

Hydrogen peroxide plays a major role in the pathomechanism of diabetes mellitus and its main regulator is enzyme catalase.

The blood catalase and the C111T polymorphism in exon 9 was examined in type 1, type 2 and gestational diabetes mellitus.

Compared to the control group (104.7 ± 18.5 MU/l) significantly decreased (p < 0.001) blood catalase activities were detected in type 2 (71.2 ± 14.6 MU/l), gestational (68.5 ± 12.2 MU/l) diabetes mellitus and without change in type 1 (102.5 ± 26.9 MU/l). The blood catalase decreased (p = 0.043) with age for type 2 diabetics and did not change (p>0.063) for type 1, gestational diabetic patients and controls. Blood catalase showed a weak association with hemoglobin A1c for type 1 diabetic patients (r = 0.181, increasing).

The mutant T allele was increased in type 1 and gestational diabetes mellitus, and CT+TT genotypes showed decreased blood catalase activity for type 1 and increased activities for type 2 diabetic patients.

The C111T polymorphism may implicate a very weak effect on blood catalase activity in different types of diabetes mellitus.