Streptozotocin Mice Research Articles

IL-27 Inhibits Hyperglycemia and Pancreatic Islet Inflammation Induced by Streptozotocin in Mice

Inflammation driven by immune cells and pro-inflammatory cytokines is implicated in pancreatic β-cell injury, leading to the development of diabetes mellitus. IL-27, a cytokine consisting of IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), binds a membrane-bound heterodimeric receptor consisting of the IL-27 receptor α chain (WSX-1) and gp130. IL-27 has anti-inflammatory properties that regulate T-cell polarization and cytokine production. We evaluated blood glucose and islet proinsulin concentrations, inflammatory cell infiltration in islets, and expression of IL-1β mRNA in pancreas in wild-type (WT), EBI3(-/-), and WSX-1(-/-) mice treated with streptozotocin (STZ). Hyperglycemia was augmented in EBI3(-/-) and WSX-1(-/-) mice compared with WT mice. Islet proinsulin levels after STZ treatment were lower in EBI3(-/-) and WSX-1(-/-) mice than in WT mice. The infiltration of islets by F4/80(+)CD11c(-)7/4(-) macrophages, CD4(+) T cells, and CD8(+) T cells was increased in EBI3(-/-) and WSX-1(-/-) mice compared with WT mice. The administration of recombinant IL-27, compared with control, decreased the blood glucose level, immune cell infiltration into islets, and IL-1β mRNA expression in the pancreas and increased islet proinsulin levels in WT and EBI3(-/-) mice. Thus, IL-27 inhibits STZ-induced hyperglycemia and pancreatic islet inflammation in mice and represents a potential novel therapeutic approach for β-cell protection in diabetes.

Tat-enhanced delivery of metallothionein can partially prevent the development of diabetes

Metallothioneins (MTs) are intracellular low-molecular-weight, cysteine-rich proteins with potent metal-binding and redox functions, but with limited membrane permeativity. The aim of this study was to investigate whether we could enhance delivery of MT-1 to pancreatic islets or β cells in vitro and in vivo. The second goal was to determine whether increased MT-1 could prevent cellular toxicity induced by high glucose and free fatty acids in vitro (glucolipotoxicity) and ameliorate the development of diabetes induced by streptozotocin in mice or delay the development of diabetes by improving insulin secretion and resistance in the OLETF rat model of type 2 diabetes. Expression of HIV-1 Tat–MT-1 enabled efficient delivery of MT into both INS-1 cells and rat islets. Intracellular MT activity increased in parallel with the amount of protein delivered to cells. The formation of reactive oxygen species, glucolipotoxicity, and DNA fragmentation due to streptozotocin decreased after treating pancreatic β cells with Tat–MT in vitro. Importantly, in vivo, intraperitoneal injection resulted in delivery of the Tat–MT protein to the pancreas as well as liver, muscle, and white adipose tissues. Multiple injections increased radical-scavenging activity, decreased apoptosis, and reduced endoplasmic reticulum stress in the pancreas. Treatment with Tat–MT fusion protein delayed the development of diabetes in streptozotocin-induced mice and improved insulin secretion and resistance in OLETF rats. These results suggest that in vivo transduction of Tat–MT may offer a new strategy to protect pancreatic β cells from glucolipotoxicity, may improve insulin resistance in type 2 diabetes, and may have a protective effect in preventing islet destruction in type 1 diabetes.

Morphological remodeling of nucleus ambiguus (NA) projections to cardiac ganglia in streptozotocin (STZ)-induced diabetic mice

Background: The baroreflex control of heart rate is reduced in diabetic mice (Lin et al. 2009, 2010). However, diabetes-induced anatomical changes of neural components within the baroreflex arc are not well defined. Since the NA plays a key role in baroreflex bradycardia, our goal was to examine NA projections to cardiac ganglia in STZ mice.

Knockout of Toll-Like Receptor-2 Attenuates Both the Proinflammatory State of Diabetes and Incipient Diabetic Nephropathy

Type 1 diabetes (T1DM) is a proinflammatory state and confers an increased risk for vascular complications. Toll-like receptors (TLR) could participate in diabetic vasculopathies. Whether TLR activation contributes to the proinflammatory state of T1DM and the pathogenesis of diabetic nephropathy remains unknown. We induced T1DM in TLR2 knockout mice (TLR2-/-) and wild-type littermates (C57BL/6J-WT) using streptozotocin (STZ). Fasting blood, peritoneal macrophages, and kidneys were obtained for flow cytometry, Western blot, microscopy, and cytokine assays at 6 and 14 weeks after induction of diabetes. Macrophage TLR2 expression and MyD88-dependent signaling were increased in diabetic mice (WT+STZ) compared with nondiabetic WT mice. These biomarkers were attenuated in diabetic TLR2-/- macrophages. WT+STZ mice showed increased kidney:body weight ratio due to cell hypertrophy, increased albuminuria, decreased kidney nephrin, podocin, and podocyte number and increased transforming growth factor-β and laminin compared with WT mice. Nephrin, podocin, and podocyte number and effacement were restored, and transforming growth factor-β and laminin levels were decreased in TLR2-/-+ STZ mice kidneys versus WT+STZ. Peritoneal and kidney macrophages were predominantly M1 phenotype in WT+STZ mice; this was attenuated in TLR2-/-+STZ mice. These data support a role for TLR2 in promoting inflammation and early changes of incipient diabetic nephropathy, in addition to albuminuria and podocyte loss.

Effect of Tempol on Diabetes-Induced Decreases in Retinal Blood Flow in the Mouse

Purpose: The purpose was to investigate the effect of the superoxide dismutase mimetic tempol on decreases in retinal blood flow that are found in diabetic mice.Materials and Methods: Streptozotocin (STZ) was injected into male C57BL/6 mice to induce hyperglycemia. One week following the STZ injection, subsets of the mice were given drinking water with or without 1 mM tempol for an additional three weeks. At the end of the four-week protocol, microvascular parameters were quantified via intravital microscopy, and included measurements of retinal diameters, red blood cell (RBC) velocities, blood flow rates, and wall shear rates.Results: Diabetes induced ~40–45% decreases in retinal blood flow rate (p < 0.001) four weeks following injection of STZ. The decrease in blood flow rate occurred with decreases in microvascular diameters (D) and RBC velocities (V). The average percentage decrease in velocity was greater than the percentage decrease in diameter and, therefore, wall shear rates (= 8 V/D) were ~25% lower in the diabetics than in the non-diabetics (p < 0.05). A three-week administration of tempol in the STZ mice allowed significantly higher blood flow rates than in the untreated STZ mice, with RBC velocities improved by the antioxidant (p < 0.05 on the venular side). However, tempol provided only moderate (and not statistically significant) improvements in wall shear rates.Conclusions: The antioxidant tempol provides partial improvements in retinal microvascular hemodynamics early in the progression of STZ-induced diabetes in mice.

Sporadic dementia of Alzheimer's type induced by streptozotocin promotes anxiogenic behavior in mice

Alzheimer disease, a form of dementia in which loss of memory is the first and the most characteristic symptom, is frequently accompanied by affective symptoms. Intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) to rodents has been reported as an appropriate model for sporadic dementia of Alzheimer's type (SDAT), characterized by a progressive impairment of memory. However, very little or nothing is known about non-cognitive behavioral effects (e.g. anxiety-like behavior) in the STZ model. In this context, the hypothesis to be tested in this study is if i.c.v. injection of STZ (0.1 mg/site, 4 μl) induces anxiety-like behavior in mice. The findings of the present study indicate that i.c.v. injection of STZ in mice resulted in an anxiogenic behavior. Mice spent less time and decreased the number of entries in the open arms in the elevated plus-maze task. The latency to the first entry in the dark side in the light–dark box task was reduced by STZ. No difference was found in anxiety-like behavior between early and late time (i.e., at 7 and 21 days after infusion, respectively). These results indicate that i.c.v. STZ injection caused an anxiogenic behavior in mice.

Neuroprotector effect of p,p'‐methoxyl‐diphenyl diselenide in a model of sporadic dementia of Alzheimer's type in mice: contribution of antioxidant mechanism

The present study investigated whether the antioxidant activity of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)] is involved in its protective effect against cognitive impairment induced by streptozotocin (STZ) in a model of sporadic dementia of Alzheimer's type (SDAT). Swiss mice were treated with STZ or vehicle [2 µl of 2·5 mg ml(-1) solution; intracerebroventricularly (i.c.v.)] twice, 48 h apart. (MeOPhSe)(2) (25 mg kg(-1)) or vehicle was orally administered 30 min prior to each STZ treatment. Neuroprotector effect of (MeOPhSe)(2) on the behavioral performance of mice on spatial recognition memory consolidation was investigated in the Y-maze test. After that, mouse brains were removed for measuring antioxidant parameters. (MeOPhSe)(2) protected against the impairment in learning and memory caused by i.c.v. administration of STZ in mice. (MeOPhSe)(2) protected against the increase in reactive species and the reduction of glutathione levels, as well as, the increase in superoxide dismutase and glutathione S-transferase activities caused by STZ in whole brain. These results suggest that antioxidant property is involved, at least in part, in the neuroprotective effect of (MeOPhSe)(2) on SDAT induced by STZ in mice.

Changes in the pharmacokinetics of digoxin in polyuria in streptozotocin-induced diabetic mice and lithium carbonate-treated mice

In humans, digoxin is mainly eliminated through the kidneys unchanged, and renal clearance represents approximately 70% of the total clearance. In this study, we used the mouse models to examine digoxin pharmacokinetics in polyuria induced by diabetes mellitus and lithium carbonate (Li2CO3) administration, including mechanistic evaluation of the contribution of glomerular filtration, tubular secretion, and tubular reabsorption.After digoxin administration to streptozotocin (STZ)-induced diabetic mice, digoxin CL/F increased to approximately 2.2 times that in normal mice. After treatment with Li2CO3 (0.2%) for 10 days, the CL/F increased approximately 1.1 times for normal mice and 1.6 times for STZ mice.Creatinine clearance (CLcr) and the renal mRNA expression levels of mdr1a did not differ significantly between the normal, STZ, and Li2CO3-treated mice.The urine volume of STZ mice was approximately 26 mL/day, 22 times that of normal mice. The urine volume of Li2CO3-treated mice increased approximately 7.3 times for normal mice and 2.3 times for STZ mice.These results suggest that the therapeutic effect of digoxin may be significantly reduced in the presence of polyuria either induced by diabetes mellitus or manifested as an adverse effect of Li2CO3 in diabetic patients, along with increased urine volume.

Diminished glucagon suppression after β-cell reduction is due to impaired α-cell function rather than an expansion of α-cell mass

Impaired suppression of glucagon levels after oral glucose or meal ingestion is a hallmark of type 2 diabetes. Whether hyperglucagonemia after a β-cell loss results from a functional upregulation of glucagon secretion or an increase in α-cell mass is yet unclear. CD-1 mice were treated with streptozotocin (STZ) or saline. Pancreatic tissue was collected after 14, 21, and 28 days and examined for α- and β-cell mass and turnover. Intraperitoneal (ip) glucose tolerance tests were performed at day 28 as well as after 12 days of subcutaneous insulin treatment, and glucose, insulin, and glucagon levels were determined. STZ treatment led to fasting and post-challenge hyperglycemia (P < 0.001 vs. controls). Insulin levels increased after glucose injection in controls (P < 0.001) but were unchanged in STZ mice (P = 0.36). Intraperitoneal glucose elicited a 63.1 ± 4.1% glucagon suppression in control mice (P < 0.001), whereas the glucagon suppression was absent in STZ mice (P = 0.47). Insulin treatment failed to normalize glucagon levels. There was a significant inverse association between insulin and glucagon levels after ip glucose ingestion (r(2) = 0.99). β-Cell mass was reduced by ∼75% in STZ mice compared with controls (P < 0.001), whereas α-cell mass remained unchanged (P > 0.05). α-Cell apoptosis (TUNEL) and replication (Ki67) were rather infrequently noticed, with no significant differences between the groups. These studies underline the importance of endogenous insulin for the glucose-induced suppression of glucagon secretion and suggest that the insufficient decline in glucagon levels after glucose administration in diabetes is primarily due to a functional loss of intraislet inhibition of α-cell function rather than an expansion of α-cell mass.

Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

Reactive oxygen species (ROS) have been widely implicated in the pathogenesis of diabetes and more recently in mitochondrial alterations in skeletal muscle of diabetic mice. However, so far the exact sources of ROS in skeletal muscle have remained elusive. Aiming at better understanding the causes of mitochondrial alterations in diabetic muscle, we designed this study to characterize the sites of ROS production in skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Hyperglycemic STZ mice showed increased markers of systemic and muscular oxidative stress, as evidenced by increased circulating H(2)O(2) and muscle carbonylated protein levels. Interestingly, insulin treatment reduced hyperglycemia and improved systemic and muscular oxidative stress in STZ mice. We demonstrated that increased oxidative stress in muscle of STZ mice is associated with an increase of xanthine oxidase (XO) expression and activity and is mediated by an induction of H(2)O(2) production by both mitochondria and XO. Finally, treatment of STZ mice, as well as high-fat and high-sucrose diet-fed mice, with oxypurinol reduced markers of systemic and muscular oxidative stress and prevented structural and functional mitochondrial alterations, confirming the in vivo relevance of XO in ROS production in diabetic mice. These data indicate that mitochondria and XO are the major sources of hyperglycemia-induced ROS production in skeletal muscle and that the inhibition of XO reduces oxidative stress and improves mitochondrial alterations in diabetic muscle.

Inhibitory Effect of Pomegranate on Intestinal Sodium Dependent Glucose Uptake

Intestinal glucose uptake is mainly performed by its specific transporters, SGLT1 and GLUTs expressed in the intestinal epithelial cells. By using Caco-2 cells and 2-NBDG, we observed that intestinal glucose uptake was markedly inhibited by pomegranate (Punica granatum L, PG) among 200 screened edible Korean plants. The effects of the PG extract on Na(+)-dependent glucose uptake were further evaluated using brush border membrane vesicles (BBMV) obtained from the mouse small intestine. PG inhibited Na(+)-dependent glucose uptake with the IC(50) value of 424 μg/ml. The SGLT1 protein expression was dose dependently down regulated with PG treatment in Caco-2 cells. We next assessed the antihyperglycemic effect of PG in streptozotocin (STZ)-induced diabetic mice. Administration of PG (800 mg/kg) to STZ mice for four weeks improved postprandial glucose regulation. Furthermore, elevated Na(+)-dependent glucose uptake by BBMV isolated from STZ mice was normalized by PG treratment. These results suggest that PG could play a role in controlling the dietary glucose absorption at the intestinal tract by decreasing SGLT1 expression, and may contribute to blood glucose homeostasis in the diabetic condition.

Midkine, a heparin-binding protein, is increased in the diabetic mouse kidney postmenopause.

Estrogen is thought to protect against the development of chronic kidney disease, and menopause increases the development and severity of diabetic kidney disease. In this study, we used streptozotocin (STZ) to induce diabetes in the 4-vinylcyclohexene diepoxide (VCD)-treated mouse model of menopause. DNA microarrays were used to identify gene expression changes in the diabetic kidney postmenopause. An ANOVA model, CARMA, was used to isolate the menopause effect between two groups of diabetic mice, diabetic menopausal (STZ/VCD) and diabetic cycling (STZ). In this diabetic study, 8,864 genes of the possible 15,600 genes on the array were included in the ANOVA; 99 genes were identified as demonstrating a >1.5-fold up- or downregulation between the STZ/VCD and STZ groups. We randomly selected genes for confirmation by real-time PCR; midkine (Mdk), immediate early response gene 3 (IEX-1), mitogen-inducible gene 6 (Mig6), and ubiquitin-specific protease 2 (USP2) were significantly increased in the kidneys of STZ/VCD compared with STZ mice. Western blot analysis confirmed that Mdk and IEX-1 protein abundance was significantly increased in the kidney cortex of STZ/VCD compared with STZ mice. In a separate study, DNA microarrays and CARMA analysis were used to identify the effect of menopause on the nondiabetic kidney; VCD-treated mice were compared with cycling mice. Of the possible 15,600 genes on the array, 9,142 genes were included in the ANOVA; 20 genes were identified as demonstrating a >1.5-fold up- or downregulation; histidine decarboxylase and vanin 1 were among the genes identified as differentially expressed in the postmenopausal nondiabetic kidney. These data expand our understanding of how hormone status correlates with the development of diabetic kidney disease and identify several target genes for further studies.

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

Toll-like receptor-2 (TLR2) is a pivotal pathogen recognition receptor that has a key role in inflammation, diabetes, and injury. Hyperglycemia, inflammation, and oxidative stress induce TLR2-myeloid differentiation factor-88 (MyD88) expression and signaling, and are major pathophysiological mechanisms in the impaired diabetic wound-healing process. The aim of the study was to examine the contribution of TLR2-MyD88 expression and signaling to the prolonged inflammation observed in diabetic wounds. Diabetes was induced in male C57BL/6J and TLR2−/− mice using streptozotocin (STZ) with matching nondiabetic mice as control. In addition, nonobese diabetic (NOD) mice were used to represent the spontaneous type 1 diabetes condition. After 2 weeks of persistent hyperglycemia in the mice, full-thickness excision wounds were made on the backs aseptically. Total RNA and protein were subjected to real-time PCR and western blot analyses. Wound sizes were measured using digital planimetry. TLR2 mRNA and protein expression increased significantly in wounds of C57BL/6J+STZ and NOD mice (P<0.05) compared with nondiabetic C57BL/6J mice. MyD88 expression, interleukin receptor-associated kinase-1 phosphorylation, and nuclear factor-κ B (NF-κB) activation were increased in diabetic wounds compared with nondiabetic wounds. Wounds of TLR2−/−+STZ mice showed less oxidative stress, decreased MyD88 signaling, NF-κB activation, and cytokine secretion. The wound closure was significant in TLR2−/−+ STZ mice compared with C57BL/6J+STZ mice. Collectively, our findings show that increased TLR2 mRNA and protein expression, signaling, and activation contribute to the prolonged inflammation in the diabetic wounds and that absence of TLR2 may result in decreased inflammation and improved wound healing.

PS1-29 Interleukin 27 inhibits hyperglycemia and pancreatic islet inflammation induced by streptozotocin in mice

PS1-29 Interleukin 27 inhibits hyperglycemia and pancreatic islet inflammation induced by streptozotocin in mice

Malfunction of bone marrow-derived osteoclasts and the delay of bone fracture healing in diabetic mice

It is well known that bone fracture healing is delayed in diabetes mellitus, but the mechanism remains to be elucidated. Since several studies have demonstrated that diabetes causes abnormalities in bone marrow-derived cells, we used the streptozotocin (STZ)-induced diabetic mouse model after bone marrow transfer from green fluorescent protein (GFP) transgenic mice, and examined fracture healing. Compared with nondiabetic mice, diabetic mice at 3 weeks after fracture showed a decrease in mineralized callus, with the remainder consisting of cartilage. Bone formation parameters and mineralization rate were not altered in the STZ mice, but bone resorption parameters were significantly decreased. Therefore, the delayed bone formation in the STZ mice may have resulted from an impairment of cartilage resorption. Interestingly, we found that 80% of the osteoclasts in the callus were derived from bone marrow and the sizes of the osteoclasts as well as the resorption pits formed were significantly smaller in the diabetic mice. Moreover, transcript analysis using RNA isolated by laser capture microdissection (LCM) showed that the expression of DC-STAMP, a putative pivotal gene for osteoclast fusion, was decreased in osteoclasts from diabetic mice. Since the sustainability of osteoclast function depends on the controlled renewal of multinuclear osteoclasts, impaired osteoclast function in diabetes may contribute to decreased cartilage resorption and delayed endochondral ossification.

Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes

OBJECTIVEOur recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes.RESEARCH DESIGN AND METHODSDiabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose.RESULTSIn diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose–induced ER stress was inhibited by blocking Rac1 or NADPH oxidase.CONCLUSIONSRac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy.

Inhibition or Deletion of Soluble Epoxide Hydrolase Prevents Hyperglycemia, Promotes Insulin Secretion, and Reduces Islet Apoptosis

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and antiapoptotic mediators. However, the roles of sEH in diabetes and the pancreas are unknown. Our aims were to determine whether sEH is involved in the regulation of hyperglycemia in diabetic mice and to investigate the reasons for the regulation of insulin secretion by sEH deletion or inhibition in islets. We used two separate approaches, targeted disruption of Ephx2 gene [sEH knockout (KO)] and a selective inhibitor of sEH [trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB)], to assess the role of sEH in glucose and insulin homeostasis in streptozotocin (STZ) mice. We also examined the effects of sEH KO or t-AUCB on glucose-stimulated insulin secretion (GSIS) and intracellular calcium levels in islets. Hyperglycemia in STZ mice was prevented by both sEH KO and t-AUCB. In addition, STZ mice with sEH KO had improved glucose tolerance. More important, when insulin levels were assessed by hyperglycemic clamp study, sEH KO was found to promote insulin secretion. In addition, sEH KO and t-AUCB treatment augmented islet GSIS. Islets with sEH KO had a greater intracellular calcium influx when challenged with high glucose or KCl in the presence of diazoxide. Moreover, sEH KO reduced islet cell apoptosis in STZ mice. These results show not only that sEH KO and its inhibition prevent hyperglycemia in diabetes, but also that sEH KO enhances islet GSIS through the amplifying pathway and decreases islet cell apoptosis in diabetes.

Impairment of baroreflex control of heart rate and structural changes of cardiac ganglia in conscious streptozotocin (STZ)-induced diabetic mice

Baroreflex control of heart rate (HR) is impaired in human diabetes mellitus and in large experimental models. However, baroreflex impairment in diabetic mouse models and diabetes-induced remodeling of baroreflex circuitry are not well studied. We examined the impairment of baroreflex control of heart rate (HR) and assessed structural remodeling of cardiac ganglia in the streptozotocin (STZ)-induced diabetic mouse model. FVB mice were either injected with vehicle or STZ. Group 1: mice were anesthetized and the femoral artery and vein were catheterized at the 30th day after vehicle or STZ injection. On the second day after surgery, baroreflex-mediated HR responses to sodium nitroprusside (SNP) and phenylephrine (PE)-induced mean arterial blood pressure (MABP) changes were measured in conscious mice. Group 2: Fluoro-Gold was administered (i.p.) to label cardiac ganglia in each mouse at the 25th day after vehicle or STZ injection. After another five days, animals were perfused and cardiac ganglia were examined using confocal microscopy. Compared with control, we found in STZ mice: 1) the HR decreased, but MABP did not. 2) The PE-induced increases of MABP were decreased. 3) Baroreflex bradycardia was attenuated in the rapid MABP ascending phase but the steady-state ΔHR/ΔMABP was not different at all PE doses. 4) SNP-induced MABP decreases were not different. 5) Baroreflex tachycardia was attenuated. 6) The sizes of cardiac ganglia and ganglionic principal neurons were decreased. 7) The ratio of nucleus/cell body of cardiac ganglionic neurons was increased. We conclude that baroreflex control of HR is impaired in conscious STZ mice. In addition, diabetes may induce a significant structural remodeling of cardiac ganglia. Such an anatomical change of cardiac ganglia may provide new information for the understanding of diabetes-induced remodeling of the multiple components within the baroreflex circuitry.

Differences in the pharmacokinetics of Cyp3a substrates in TSOD and streptozotocin-induced diabetic mice

The pharmacokinetics of drugs can change in diabetes mellitus and even among diabetics. They may differ between type I diabetes (T1DM) and type 2 diabetes (T2DM).As triazolam was administered orally to Tsumura, Suzuki, obese, diabetes (TSOD) mice and streptozotocin (STZ) mice, clearance per body (CL/F) in TSOD mice did not differ compared with Tsumura, Suzuki, non-obesity (TSNO) mice. In STZ mice, CL/F was greater than in control mice. Small intestinal cytochrome P450 (Cyp) 3a expression in TSOD mice was significantly lower than in TSNO mice. No significant difference existed in small intestinal Cyp3a expression between STZ mice and control mice. In insulin-treated mice, small intestinal Cyp3a expression was significantly lower than in control mice.These results suggested that the differences in changes in small intestinal Cyp3a expression between T1DM and T2DM may be due to differences in plasma insulin concentrations. This may be a factor in the difference in the drug pharmacokinetics between T2DM and T1DM patients.

Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice

The aim of the present study is to investigate the effect of quercetin, a naturally occurring flavonoid, on cerebral blood flow (CBF), brain energy metabolism, memory impairment, oxidative stress and cholinergic dysfunction in brain following intracerebral (i.c.) streptozotocin (STZ) administration in mice. STZ (0.5 mg/kg, i.c.) was administered twice at an interval of 48 h. We found a significant reduction in CBF as measured by Laser Doppler Flowmetry (LDF). The brain energy metabolism was also altered as evidenced by significant reduction in brain ATP content. Daily treatment with quercetin (2.5, 5 and 10 mg/kg, p.o.) starting from the first dose of STZ showed a dose-dependent restoration of CBF and ATP content. Further, quercetin prevented STZ induced memory impairment as assessed by Morris water maze and passive avoidance tests. Biochemical analysis revealed that STZ significantly increased malondialdehyde (MDA), nitrite and depleted glutathione (GSH) levels in the mice brain. Quercetin decreased oxidative and nitrosative stress as evidenced by a significant decrease in MDA, nitrite and increase in GSH levels. Quercetin also attenuated elevated acetylcholinesterase activity in the STZ-treated mice. Neither STZ (i.c.) nor quercetin showed any change in locomotor activity and blood glucose level. The present study demonstrates the beneficial effects of quercetin in improving CBF along with preventing memory impairment, oxidative stress, altered brain energy metabolism and cholinergic dysfunction caused by STZ in mice. Therefore, consumption of dietary stuff rich in quercetin should be encouraged to ward off dementia associated with vascular and neurodegenerative disorders.