Emotional stress and diabetic control: A postulated model for the effect of emotional distress upon intermediary metabolism in the diabetic

The findings of a number of clinical investigators across a wide variety of situations and using a wide variety of observational procedures agree on the disruptive effects of emotional distress upon diabetic control. An integrative model of coordinated neural and hormonal reactions to emotional stress and their additive and potentiating effects on intermediary metabolism in proposed. The end result of these effects, as part of a general fight/flight or defense-alarm reaction, is a strong energy mobilization response (namely, a sharp rise in blood glucose and free fatty acid levels resulting in increased levels of serum cholesterol, triglycerides, and ketone bodies), which the diabetic cannot readily counterregulate. It is further proposed that increased diabetic control, together with lower insulin requirements, may result from the inclusion of stress management procedures as an adjunct to traditional medical treatment. The findings of a large number of investigators supporting these propositions are presented and discussed.I am indebted to the following people for their extensive editorial comments and suggestions; G. Blakemore Evans, William Hay, and Theodore J. Lavaque. I am thankful to Roger Hatcher for his support and extensive input as well as his editorial comments.     

The effect of ascorbate supplementation on oxidative stress in the streptozotocin diabetic rat.

An increase in oxidative stress may contribute to the development of diabetic complications. The key aqueous-phase chain-breaking antioxidant ascorbate is known to be deficient in diabetes, and we have therefore investigated the effects of ascorbate supplementation on oxidative stress in the streptozotocin diabetic rat. Markers of lipid peroxidation (malondialdehyde [MDA] and diene conjugates) were increased in plasma and erythrocytes of untreated diabetic animals, and levels of the antioxidants ascorbate and retinol were reduced. Plasma tocopherol was unchanged. Insulin treatment normalized MDA and ascorbate levels, although ascorbate metabolism remained disturbed, as indicated by increased levels of dehydroascorbate. High-dose ascorbate supplementation in the absence of insulin treatment restored plasma ascorbate to normal and increased plasma retinol and tocopherol levels. However, MDA and diene conjugate levels remained unchanged, possibly as a result of increased iron availability. High-dose ascorbate supplementation should be approached with caution in diabetes, as ascorbate may exert both antioxidant and prooxidant effects in vivo.     

Effect of restraint stress on prolactin and corticosterone levels in streptozotocin-induced diabetic rats

Changes in neuroendocrine function have been shown to occur in diabetic animals. The aim of the present study was to examine both the prolactin (PRL) and corticosterone (CORT) responses to a short period of restraint stress after the animals had been made diabetic for six weeks. The streptozotocin - induced diabetic rats had resting CORT levels which were significantly higher than the control animals. Acute restraint significantly increased CORT levels in both the control and diabetic rats. The CORT levels after stress were higher in the diabetic rats. However, the magnitude of the response (percent increase) was less in these animals. The resting PRL levels were not significantly different in the diabetic and control animals. The PRL levels significantly increased in both the control and diabetic rats when they were exposed to the restraint stress. The PRL levels after stress were significantly less in the diabetic rats, indicating a blunted PRL stress response. These results indicate that the diabetic state can affect an animals PRL and CORT response to a new acute stress.     

Downregulation of prolactin-releasing peptide gene expression in the hypothalamus and brainstem of diabetic rats

We investigated the prolactin-releasing peptide (PrRP) mRNA levels in the hypothalamus and brainstem of streptozotocin (STZ)-induced diabetic rats and fa/fa Zucker diabetic rats, using in situ hybridization histochemistry. PrRP mRNA levels in the hypothalamus and brainstem of STZ-induced diabetic rats were significantly reduced in comparison with those of control rats. PrRP mRNA levels in the diabetic rats were reversed by both insulin and leptin. PrRP mRNA levels in the fa/fa diabetic rats were significantly reduced in comparison with those of Fa/? rats. PrRP mRNA levels in the fa/fa diabetic rats were significantly increased by insulin-treatment, but did not reach control levels in the Fa/? rats. We also investigated the effect of restraint stress on PrRP mRNA levels in STZ-induced diabetic rats. The PrRP mRNA levels in the control and the STZ-induced diabetic rats increased significantly after restraint stress. The diabetic condition and insulin-treatment may affect the regulation of PrRP gene expression via leptin and other factors, such as plasma glucose level. The diabetic condition may not impair the role of PrRP as a stress mediator.     

Early oxidative stress in the diabetic kidney: effect of DL-alpha-lipoic acid

Oxidative stress is implicated in the pathogenesis of diabetic nephropathy. The attempts to identify early markers of diabetes-induced renal oxidative injury resulted in contradictory findings. We characterized early oxidative stress in renal cortex of diabetic rats, and evaluated whether it can be prevented by the potent antioxidant, DL-alpha-lipoic acid. The experiments were performed on control rats and streptozotocin-diabetic rats treated with/without DL-alpha-lipoic acid (100 mg/kg i.p., for 3 weeks from induction of diabetes). Malondialdehyde plus 4-hydroxyalkenal concentration was increased in diabetic rats vs. controls (p <.01) and this increase was partially prevented by DL-alpha-lipoic acid. F(2) isoprostane concentrations (measured by GCMS) expressed per either mg protein or arachidonic acid content were not different in control and diabetic rats but were decreased several-fold with DL-alpha-lipoic acid treatment. Both GSH and ascorbate (AA) levels were decreased and GSSG/GSH and dehydroascorbate/AA ratios increased in diabetic rats vs. controls (p <.01 for all comparisons), and these changes were completely or partially (AA) prevented by DL-alpha-lipoic acid. Superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione transferase, and NADH oxidase, but not catalase, were upregulated in diabetic rats vs. controls, and these activities, except glutathione peroxidase, were decreased by DL-alpha-lipoic acid. In conclusion, enhanced oxidative stress is present in rat renal cortex in early diabetes, and is prevented by DL-alpha-lipoic acid.     

Effects of selenium on endothelial dysfunction and metabolic profile in low dose streptozotocin induced diabetic rats fed a high fat diet

Endothelial dysfunction develops as a result of oxidative stress and is responsible for diabetic vascular complications. We investigated the effects of selenium on endothelial dysfunction and oxidative stress in type 2 diabetic rats. Male Wistar rats were divided into five groups: controls, untreated diabetics, and diabetics treated with 180, 300, 500 mcg/kg selenium each day. Diabetes was induced by a single intraperitoneal injection of low dose streptozotocin to rats fed a high fat diet. Endothelium-dependent and -independent relaxations were measured in the thoracic aorta. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and endothelial nitric oxide synthase (eNOS) mRNA expressions were analyzed using real-time polymerase chain reaction (RT-PCR). Fasting blood glucose, lipid profile, lipid oxidation, insulin and nitric oxide were measured in blood samples. Malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase levels were measured in liver samples. RT-PCR showed that selenium reversed increased NADPH oxidase expression and decreased eNOS expression to control levels. Selenium also improved the impairment of endothelium-dependent vasorelaxation in the diabetic aorta. Selenium treatment significantly decreased blood glucose, cholesterol and triglyceride levels, and enhanced the antioxidant status in diabetic rats. Our findings suggest that selenium restores a normal metabolic profile and ameliorates vascular responses and endothelial dysfunction in diabetes by regulating antioxidant enzyme and nitric oxide release.     

Effect of zinc on the lipid peroxidation and the antioxidant defense systems of the alloxan-induced diabetic rabbits

The effects of oral zinc supplementation on lipid peroxidation and the antioxidant defense system of alloxan (80-90 mg/kg)-induced diabetic rabbits were examined. Forty-five New Zealand male rabbits, 1 year old, weighing approximately 2.5 kg, were allocated randomly and equally as control, diabetic, and zinc-supplemented diabetic groups. After diabetes was induced, zinc-supplemented diabetic rabbits had 150 mg/L of zinc as zinc sulfate (ZnSO(4)) in their drinking tap water for 3 months. The feed and water consumption was higher in diabetic groups than (P<0.01) healthy rabbits. The body weight was lower in diabetic rabbits compared to control. The blood glucose levels were higher in diabetic groups than controls. The elevated plasma malondialdehyde (MDA) levels were determined in the diabetic group (P<0.01). The glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and ceruloplasmin levels in the diabetic group were decreased by the effect of diabetes but there was no difference between zinc-supplemented diabetic and control rabbits. Serum zinc concentrations were lower in diabetic rabbits but iron (Fe) and copper (Cu) levels in sera were not different among the groups. As a result, it was concluded that daily zinc supplementation could reduce the harmful effects of oxidative stress in diabetics.     

Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin-induced diabetic rats

The present study investigated the effects of resveratrol (RV), a polyphenol with potent antioxidant properties, on oxidative stress parameters in liver and kidney, as well as on serum biochemical parameters of streptozotocin (STZ)-induced diabetic rats. Animals were divided into six groups (n = 8): control/saline; control/RV 10 mg/kg; control/RV 20 mg/kg; diabetic/saline; diabetic/RV10 mg/kg; diabetic/RV 20 mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the liver, kidney and serum were used for experimental determinations. Results showed that TBARS levels were significantly increased in the diabetic/saline group and the administration of resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups (P < 0.05). The activities of catalase (CAT), superoxide dismutase (SOD) and aminolevulinic acid dehydratase (δ-ALA-D) and the levels of non protein thiols (NPSH) and vitamin C presented a significant decrease in the diabetic/saline group when compared with the control/saline group (P < 0.05). The treatment with resveratrol was able to prevent these decrease improving the antioxidant defense of the diabetic/RV10 and diabetic/RV20 groups (P < 0.05). In addition, the elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamiltransferase (γ-GT) activities as well as in levels of urea, creatinine, cholesterol and triglycerides observed in the diabetic/saline group were reverted to levels close to normal by the administration of resveratrol in the diabetic/RV10 and diabetic/RV20 groups (P < 0.05). These findings suggest that resveratrol could have a protector effect against hepatic and renal damage induced by oxidative stress in the diabetic state, which was evidenced by the capacity of this polyphenol to modulate the antioxidant defense and to decrease the lipid peroxidation in these tissues.     

Lutein effect on retina and hippocampus of diabetic mice

Oxidative stress markers and functional tests were studied to confirm early biochemical and functional changes in retina and hippocampus of diabetic mice. The effects of lutein treatment were also tested. Mice were induced diabetic by alloxan injection and divided into subgroups: control, control+lutein, diabetic, diabetic+lutein, diabetic+insulin, and diabetic+insulin+lutein. Treatments started on Day 4 after alloxan injection and animals were sacrificed on Day 14. Malondialdehyde and glutathione concentrations and glutathione peroxidase activity were measured as oxidative stress markers. The following functional tests for retina and hippocampus were performed: electroretinogram and Morris water maze test. NFkappaB activity was also measured. Oxidative stress and NFkappaB activity increase in the retina and hippocampus after 15 days of diabetes. Impairment of the electroretinogram and a correlation between latencies of the water maze test and glycated hemoglobin (HbA1c) levels were observed. Lutein prevented all these changes even under hyperglycemic conditions. Retina appears to be affected earlier than hippocampus by diabetes-induced oxidative stress. Although a proper glycemic control is desirable in preventing the development of diabetic complications, it is not sufficient to prevent them completely. Lutein could be an appropriate coadjuvant treatment for the changes observed in this study.     

Protective effect of esculetin on hyperglycemia-mediated oxidative damage in the hepatic and renal tissues of experimental diabetic rats

Diabetes mellitus is the most common serious metabolic disorder and it is considered to be one of the five leading causes of death in the world. Hyperglycemia-mediated oxidative stress plays a crucial role in diabetic complications. Hence, this study was undertaken to evaluate the protective effect of esculetin on the plasma glucose, insulin levels, tissue antioxidant defense system and lipid peroxidative status in streptozotocin-induced diabetic rats. Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. Extent of oxidative stress was assessed by the elevation in the levels of lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD); reduction in the enzymic antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST); nonenzymic antioxidants Vitamin C, E and reduced glutathione (GSH) were observed in the liver and kidney tissues of diabetic control rats as compared to control rats. Oral supplementation of esculetin to diabetic rats for 45 days significantly brought back lipid peroxidation markers, enzymic and nonenzymic antioxidants to near normalcy. Moreover, the histological observations evidenced that esculetin effectively rescues the hepatocytes and kidney from hyperglycemia mediated oxidative damage without affecting its cellular function and structural integrity. These findings suggest that esculetin (40 mg/kg BW) treatment exerts a protective effect in diabetes by attenuating hyperglycemia-mediated oxidative stress and antioxidant competence in hepatic and renal tissues. Further, detailed studies are in progress to elucidate the molecular mechanism by which esculetin elicits its modulatory effects in insulin signaling pathway.     

Ameliorative potential of S-allyl cysteine on oxidative stress in STZ induced diabetic rats

Increased oxidative stress and impaired antioxidant defense mechanism are important factors in the pathogenesis and progression of diabetes mellitus and other oxidant-related diseases. The present study was undertaken to evaluate the possible protective effects of S-allyl cysteine (SAC) against oxidative stress in streptozotocin (STZ) induced diabetic rats. SAC was administered orally for 45 days to control and STZ induced diabetic rats. The effects of SAC on glucose, plasma insulin, thiobarbituric acid reactive substances (TBARS), hydroperoxide, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG ratio were studied. The levels of glucose, TBARS, hydroperoxide, and GSSG were increased significantly whereas the levels of plasma insulin, reduced glutathione, GSH/GSSG ratio, superoxide dismutase, catalase and GPx were decreased in STZ induced diabetic rats. Administration of SAC to diabetic rats showed a decrease in plasma glucose, TBARS, hydroperoxide and GSSG. In addition, the levels of plasma insulin, superoxide dismutase, catalase, GPx and reduced glutathione (GSH) were increased in SAC treated diabetic rats. The above findings were supported by histological observations of the liver and kidney. The antioxidant effect of SAC was compared with glyclazide, a well-known antioxidant and antihyperglycemic drug. The present study indicates that the SAC possesses a significant favorable effect on antioxidant defense system in addition to its antidiabetic effect.     

Lignin-derived lignophenols attenuate oxidative and inflammatory damage to the kidney in streptozotocin-induced diabetic rats

Abstract

This study investigated the effects of lignin-derived lignophenols (LPs) on the oxidative stress and infiltration of macrophages in the kidney of streptozotocin (STZ)-induced diabetic rats. The diabetic rats were divided into four groups with 0%, 0.11%, 0.33% and 1.0% LP diets. The vehicle-injected controls were given a commercial diet. At 5 weeks, superoxide (O₂^?) production, macrophage kinetics, the degree of fibrosis in glomeruli and mRNA expression for monocyte chemoattractant protein-1 (MCP-1) were examined. The NADPH-stimulated O₂^? levels in the kidney of the diabetic rats treated with 1.0% LP were significantly lower than those in untreated diabetic rats. The number of macrophages, levels of MCP-1 mRNA expression and degree of glomerular fibrosis increased in untreated LP and these levels were significantly lower in 1.0%LP-treated rats. The results suggested that LPs suppress the excess oxidative stress, the infiltration and activation of macrophages and the glomerular expansion in STZ-induced diabetic kidneys.     

Effect of S-allylcysteine,a sulphur containing amino acid on iron metabolism in streptozotocin induced diabetic rats

It is suggested that iron may play a role in the pathogenesis of diabetes. Iron is not only chaperoned through its essential functional pathways, but it also causes damage to biological systems by catalyzing the production of reactive oxygen species. So, the parenchymal tissues of several organs are subject to cell injury and functional insufficiency due to excess deposition of iron. The present study investigated the effects of S-allylcysteine (SAC), a sulphur containing amino acid derived from garlic on the changes in iron metabolism induced by oxidative stress in tissues, as well as on serum biochemical parameters of streptozotocin (STZ)-induced diabetic rats. SAC was administered orally for 45 days to control and experimental diabetic rats. The effects of SAC on glucose, insulin, serum iron, ferritin, transferrin, serum bilirubin, heart heme oxygenase activity (HO) and δ-aminolevulinicacid dehydratase activity (δ-ALA-D) in liver and kidneys were studied. The levels of glucose, iron, ferritin, bilirubin and HO in liver were increased significantly (p < 0.05) whereas the levels of insulin, transferrin and δ-ALA-D in tissues were decreased in diabetic rats. Administration of SAC to diabetic rats showed a decrease in blood glucose, iron, ferritin, bilirubin and HO. In addition, the levels of insulin, transferrin and δ-ALA-D activity in tissues were increased in SAC treated diabetic rats. These findings suggest that S-allylcysteine could have a protective effect against alterations in oxidative stress induced iron metabolism in the diabetic state which was evidenced by the capacity of this natural antioxidant to modulate parameters of iron metabolism.     

Effects of Aspirin and Nimesulide on tissue damage in diabetic rats

This study was designed to compare the effect of Aspirin (AS) and Nimesulide (NM) on renal failure and vascular disorder in streptozotocin (STZ)-induced diabetic rats. Rats were divided into four groups; control, diabetic rats, diabetic rats plus AS and diabetic rats plus NM, which are COX inhibitors. The renal and aorta tissues morphology were investigated by light microscopy. Trunk blood was also obtained to determine plasma lipid peroxidation product malondialdehyde (MDA) and plasma activity of antioxidant enzymes. MDA levels were increased in the diabetic rats when compared to the control group. AS and NM administration caused a significant decrease in MDA production. Morphological damage in diabetic rats was severe in the kidney and in the aorta tissue. Treatment of AS reduced these damages, but NM did not exert positive effect on these damages in diabetic rats. As a result, although both AS and NM corrected lipid peroxidation parameters such as MDA via their antioxidant properties, only AS ameliorated pathological alteration in tissues. These findings indicate that there may be another mechanism in beneficial effect of AS in diabetic rats.     

Anti-diabetic effects of electrolyzed reduced water in streptozotocin-induced and genetic diabetic mice

Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Both an increase in reactive oxygen free radical species (ROS) and a decrease in the antioxidant defense mechanism lead to the increase in oxidative stress in diabetes. Electrolyzed reduced water (ERW) with ROS scavenging ability may have a potential effect on diabetic animals, a model for high oxidative stress. Therefore, the present study examined the possible anti-diabetic effect of ERW in two different diabetic animal models. The genetically diabetic mouse strain C57BL/6J-db/db (db/db) and streptozotocin (STZ)-induced diabetic mouse were used as insulin deficient type 1 and insulin resistant type 2 animal model, respectively. ERW, provided as a drinking water, significantly reduced the blood glucose concentration and improved glucose tolerance in both animal models. However, ERW fail to affect blood insulin levels in STZ-diabetic mice whereas blood insulin level was markedly increased in genetically diabetic db/db mice. This improved blood glucose control could result from enhanced insulin sensitivity, as well as increased insulin release. The present data suggest that ERW may function as an orally effective anti-diabetic agent and merit further studies on its precise mechanism.     

The role of oxidative stress in diabetic vascular and neural disease

This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-induced vascular and neural dysfunction. Oxidative stress occurs when the balance between the production of oxidation products and the ability of antioxidant mechanisms to neutralize these products is tilted in the favor of the former. The production of reactive oxygen species has been shown to be increased in patients with diabetes. The possible sources for the overproduction of reactive oxygen species is widespread and include enzymatic pathways, autoxidation of glucose and the mitochondria. Increase in oxidative stress has clearly been shown to contribute to the pathology of vascular disease not only in diabetes but also in hypertension, stroke and ischemia. Since the etiology of diabetic neuropathy is considered to have a large vascular component, prevention of oxidative stress in diabetes is considered by many investigators to be a primary defense against the development of diabetic vascular disease. Potential therapies for preventing increased oxidative stress in diabetes and the neural vasculature will be discussed.     

Comparative investigation of kidney mesangial cells from increased oxidative stress-induced diabetic rats by using different microscopy techniques

High glucose and increased oxidative stress levels are the known important mediators of diabetic nephropathy. However, the effects of these mediators on tissue damage basically due to extracellular matrix expansion in mesangial cells have yet to be fully examined within the context of early stage diabetic nephropathy. In this study, we attempted to characterize changes in mesangial cells of streptozotocin-induced diabetic rats with a comparative investigation of kidney tissue by using different microscopy techniques. The serum levels of urea and creatinine of diabetic rats, as biomarkers of kidney degeneration, decreased significantly compared to those of age-matched controls. In diabetic rats, there are increased malondialdehyde and oxidized-glutathione levels as well as reduced-glutathione and glutathione-peroxidase activity levels in renal tissue compared to those of the controls. By using light and electron microscopies, we showed that there were marked thickening in Bowman’s membrane and glomerular capillary wall, increased amount of extracellular matrix often occupying Bowman’s space, degenerations in tubules, an increased number of mesangial cells in the network of glomerular capillary walls, and increased amount of lipid accumulation in proximal tubules in the renal tissue of diabetic rats. Our confocal microscopy data confirmed also the presence of irregularity and widened in glomerular capillaries, their attachment to the Bowman’s capsule, degenerated heterochromatin, thickening in foci of glomerular basement membrane, and marked increase in mesangial cells. These results suggest that a detailed structural investigation of kidney tissue provides further information on the important role of mesangial cells in pathogenesis of diabetic nephropathy.     

Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats

Oxidative stress has been suggested as a contributory factor in development and complication of diabetes. The aim of the study was to evaluate the effect of diosmin (DS) in oxidative stress in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats by measuring the lipid peroxidation (LPO) as well as the ameliorative properties. Experimental diabetes was induced by a single intraperitoneal (i.p) injection of STZ (45 mg/kg body weight (b.w.)) dissolved in 0.1 mol/L citrate buffer (pH 4.5), 15 min after the i.p administration of NA (110 mg/kg b.w.). Diabetic rats exhibited increased plasma glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and the levels of low-molecular weight antioxidants vitamin C, vitamin E and reduced glutathione (GSH) were decreased while increases in the levels of LPO markers were observed in liver and kidney tissues of diabetic control rats as compared to normal control rats. Oral treatment with DS (100mg/kg/day) for a period of 45 days showed significant ameliorative effects on all the biochemical parameters studied. Biochemical findings were supported by histological studies. These results indicated that DS has potential ameliorative effects in addition to its antidiabetic effect in type 2 diabetic rats.