Diabetic Hamsters Research Articles

Transcriptome changes of liver fluke Opisthorchis viverrini in diabetic hamsters.

A recent study in hamsters showed that infection with the liver fluke Opisthorchis viverrini in diabetic hosts worsens the severity of hepatobiliary disease. However, the effects of diabetes on the worm's phenotype and gene expression pattern remain unknown. This study investigated the impact of diabetes on the global gene expression and development of O. viverrini in diabetic hamsters. Parasitological parameters were assessed, and mRNA sequencing with bioinformatic analysis was performed. The study revealed that worm establishment rates in diabetic hamsters were directly correlated with fasting plasma glucose levels. Interestingly, worms collected from diabetic hosts exhibited stunted growth and reduced egg production. Transcriptomic analysis revealed significant alterations in gene expression, with 4314 and 567 differentially expressed genes at 21- and 35-days post-infection, respectively. Gene ontology enrichment analysis highlighted changes in biological processes related to stress response, metabolism, and cellular organization. Notably, genes associated with parasite virulence, including granulin, tetraspanins, and thioredoxins, showed significant upregulation in diabetic hosts. These findings demonstrate the profound impact of host diabetic status on O. viverrini development and gene expression, providing insights into the complex interplay between host metabolism and parasite biology, including molecular adaptations of O. viverrini in hosts. This study contributes to our understanding of opisthorchiasis in the context of metabolic disorders and may inform future strategies for disease management in diabetic human populations.

1595-P: Empagliflozin Improves Nephropathy and Heart Failure with Preserved Ejection Fraction Despite Limited Effects on NASH in a Novel Obese Diabetic Hamster Model

Introduction: Sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) has shown significant benefits for patients with diabetic nephropathy and heart failure with preserved ejection fraction (HFpEF), but the effects on nonalcoholic steatohepatitis (NASH) and liver fibrosis remain unclear. To further investigate the benefits of EMPA on these comorbidities, we established a novel diet-induced obese diabetic hamster model with human-like NASH and lipoprotein cholesterol metabolism, that also develops nephropathy and HFpEF. Methods: Obesity, NASH, and HFpEF were induced with a 20-week free choice diet, which presents hamsters with a choice between control chow or high fat/cholesterol diet, and normal water or 10% fructose water. After 20 weeks of diet, obese hamsters were intraperitoneally injected with streptozotocin (STZ) to induce diabetes and were then treated orally once daily for 5 weeks with vehicle or EMPA 30mg/kg. Results: Compared with vehicle, EMPA reduced hyperglycemia (vehicle: 373 +/- 43 mg/dL; EMPA: 182 +/- 30 mg/dL, p<0.01), increased pancreatic insulin content (+146%, p<0.05), significantly reduced plasma triglycerides and moderately raised LDL-cholesterol levels, as expected. However, EMPA did not improve NASH (including hepatocyte ballooning score) and liver fibrosis. EMPA reduced glomerular filtration rate and proteinuria (p=0.06 for both vs. vehicle), and significantly reduced urine albumin-to-creatinine ratio (-35%, p<0.01). In addition, EMPA showed significant improvement in HFpEF with reduced E/A and E’/E ratios with no alteration in ejection fraction, as measured by echocardiography. Conclusion: EMPA improves kidney parameters and HFpEF despite limited effects on NASH in obese diabetic hamsters. This preclinical model with multiple comorbidities will be useful to evaluate the combination of EMPA or other antidiabetic therapies with drugs targeting NASH. Disclosure F. Briand: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. C. Dubroca: Employee; CARDIOMEDEX. T. Sulpice: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. Employee; CARDIOMEDEX. Stock/Shareholder; CARDIOMEDEX.

Effect of NMDA-receptors antagonist on serum lipid level under experimental hyperhomocysteinemia in diabetic hamsters

Background and Aims: Hyperhomocysteinemia is a common condition in a course of diabetes, obesity, metabolic syndrome and atherosclerosis. It is observed hyperstimulation of pancreatic NMDA-receptors by endogenous glutamate under metabolic disorders which intensified by another NMDA-agonist homocysteine, that impairs β-cell glucose-dependent insulin secretion. Insulin signal disorders and chronical hyperglycemia provoke atherogenic dyslipidemia. In current study, we have investigated the effect of NMDA-receptor antagonist memantine on lipids level in diabetic hamsters under experimental hyperhomocysteinemia.

Comparative Study of Native or Nano Quercetin on Epigenetic Modification and Nephropathy Biomarkers Post Challenges in Diabetic Hamsters

Aims: The aim of this study is to examine the regulatory effects of quercetin nanoparticles (QNPs) compared with native quercetin either with or without metformin against the abnormal molecular and biochemical pathways that eventually culminate in the pathologic condition clinically known as diabetic nephropathy (DN) in hamsters
 Methodology: After synthesis and characterization of the QNPs, seventy male adult hamsters are divided as following; G1:healthy control, G2:untreated DN hamsters, G3:DN+metformin G4:DN+native quercetin, G5:DN+QNPs, G6:DN+native quercetin+ metformin and G7: DN + QNPs + metformin.
 Results: Our results illustrated that the effect of QNPs + metformin is the most effective in IRS-1 and GLUT-4 gene expression that correlated with inhibition of HDACs which in turn improved diabetic and nephropathy biomarkers, this effectiveness followed by G6 then G3 and finally G4 after G5. These results were confirmed by immunohistochemical examinations. Levels of antioxidant and inflammatory biomarkers also reflected the protective effect of our treatments.
 Conclusion: All tested treatments significantly exhibit renal improvement.

Liver proteomics analysis reveals abnormal metabolism of bile acid and arachidonic acid in Chinese hamsters with type 2 diabetes mellitus

Non-obese, spontaneous, and genetically predisposed type 2 diabetic Chinese hamsters exhibit metabolic abnormalities similar to those observed in human T2DM. Here, tandem mass tag (TMT)-based quantitative proteomics technology was used to screen and identify differentially abundant proteins in the liver that are associated with diabetes in Chinese hamsters. GO and KEGG pathway enrichment analysis were conducted to validate the findings, as well as qRT-PCR and western blotting. In total, 103 proteins were identified in the livers of diabetic hamsters, of which 48 were up-regulated and 55 were down-regulated. KEGG pathway enrichment analysis further demonstrated that linoleic acid metabolism, arachidonic acid metabolism, bile secretion, and other pathways were affected. Moreover, AQP9 and EPHX1 were significantly down-regulated in the bile secretion pathway, whereas PTGES2, Cyp2c27, and Cyp2c70 were associated with the arachidonic acid metabolic pathway. Serum levels of bile acid (BA) and arachidonic acid (AA) in diabetic Chinese hamsters were significantly higher than those in control hamsters. Cumulatively, our findings indicate that the five candidate proteins may be associated with abnormal BA and AA metabolism, suggesting their involvement in pathological changes in the livers of Chinese hamsters with T2DM. SignificanceThe liver proteomics of Chinese hamsters describes differentially abundant proteins associated with T2DM, while promoting this animal model as an appropriate and ideal platform for investigating underlying molecular mechanisms of T2DM. This study reveals abnormal bile acid and arachidonic acid metabolism in T2DM hamsters, which may provide insights for studying the relationship between candidate proteins and KEGG pathways to elucidate the underlying molecular mechanism associated with T2DM.

In vitro dual-target activities and in vivo antidiabetic effect of 3-hydroxy-N-(p-hydroxy-phenethyl) phthalimide in high-fat diet and streptozotocin-induced diabetic golden hamsters

The 3-hydroxy-N-(p-hydroxy-phenethyl) phthalimide (HNHP), which showed in vitro peroxisome proliferator-activated receptor-γ (PPAR-γ) activation and in vivo anti-inflammatory effect in our previous study, was speculated to be a dual-target lead compound because similar structures exhibited α-glucosidase inhibitory activities. To investigate the dual targeting potential, molecular docking of HNHP was performed targeting on PPAR-γ and α-glucosidase, and HNHP was found to bind with dual targets in the known active sites with relatively high affinities. The in vitro α-glucosidase inhibitory evaluation showed that HNHP inhibited the enzyme (IC50 = 0.669 µM) better than acarbose (IC50 = 49.133 µM). For in vivo antidiabetic activity study, type 2 diabetes mellitus was induced by high-fat diet (20%) and streptozotocin (30 mg/kg) in golden hamsters. The diabetic hamsters were administered with different doses (1, 2, 4 mg/kg/day) of HNHP and rosiglitazone (1 mg/kg/day, positive control) for consecutive 14 days, respectively. Compared with rosiglitazone, HNHP significantly increased the insulin sensitivity, while the fasting blood glucose, glycated hemoglobin Alc, urine sugar, body weight, food/water intake, and lipid profile of media-dose (2 mg/kg/day) group golden hamsters were significantly normalized. Furthermore, pathological investigation found that the media-dose of HNHP showed the best protection on pancreatic tissue. These findings indicated that the PPAR-γ activator HNHP possessed in vitro α-glucosidase inhibitory and in vivo antidiabetic activities. Thereby, HNHP would serve as a new dual-target optimization lead.

Combination of metformin and berberine represses the apoptosis of sebocytes in high-fat diet-induced diabetic hamsters and an insulin-treated human cell line.

Obesity and insulin resistance affect metabolic reactions, but their ensuing contributions to macrophage metabolism remain insufficiently understood. We investigated the contributions of berberine and metformin combination to the inhibition of sebocyte apoptosis in high-fat diet-induced diabetic hamsters and an insulin-treated human cell line. Golden hamsters were fed a high-glucose high-fat diet and administered a 6-week treatment with a combination of metformin and two concentrations of berberine (100 or 50 mg·kg-1 ). Body weights of treated hamsters were remarkably reduced compared with those of controls. Histological examination indicated that berberine repressed liver fat accumulation. Moreover, insulin and glucose concentrations were noticeably decreased by the combination treatments. In glucose tolerance tests, hamsters receiving berberine displayed higher tolerance to glucose, compared with the control group. Sebocytes isolated from high-fat diet-induced diabetic hamsters and insulin-treated human sebocytes displayed elevated cell death rates, which were attenuated by berberine and metformin treatments. Further studies showed that the effects of metformin and berberine on cellular apoptosis were mediated via the Bik pathway. Thus, berberine may effectively decrease circulating glucose levels, ameliorate insulin resistance, reduce body weight, and attenuate sebocyte apoptosis in diabetic hamsters, potentially decreasing vulnerability to the cardiovascular complications of diabetes. SIGNIFICANCE OF THE STUDY: The present data indicate that insulin stimulates changes in the expression levels of cell death-associated proteins, which participate in sebaceous gland diseases during obesity or diabetes. The anti-apoptotic effects of BBR and MET in sebaceous gland cells are regulated partially by Bik expression. To the best of our knowledge, this study is the first to suggest cell death counteracting effects of BBR in hamster and human sebocytes as well as to propose BBR as an innovative therapeutic agent for insulin-related sebaceous gland diseases, including acne.

Phenotypic characterization of a novel type 2 diabetes animal model in a SHANXI MU colony of Chinese hamsters.

Developing animal models for human diseases is critical for studying complex diseases such as type 2 diabetes mellitus (T2DM). Since inbred colonies of Chinese hamsters tend toward spontaneous development of diabetes, we investigated them as a possible model. We regarded individuals with fasting blood glucose (FBG) higher than 6.0 mmol/L and post-prandial blood glucose (PBG) higher than 7.0 mmol/L as diabetic based on the mean and 95% frequency distribution values of FBG and PBG. Diabetic hamsters were characterized based on metabolic profiles, histopathological features, and changes in the expression of genes involved in glucose and lipid metabolism. Metabolic analyses showed that diabetic hamsters exhibited mild hyperglycemia, hypertriglyceridemia, glucose intolerance, and insulin resistance. Histopathological analysis revealed that cell nuclei migrated inward in skeletal muscle and obvious partial liver lipid deposition and focal necrosis was found. We additionally observed mild injury, atrophy, and occasional vacuolization in islet cells. Changes in the expression of several genes related to glucose and lipid metabolism were observed. Decreased expression of adiponectin and GLUT4 and increased expression of PPARγ, Akt, and leptin was observed in skeletal muscle. Decreased expression of adiponectin with increased expression of PPARγ and leptin was observed in the liver. These results indicate that we have established a spontaneous diabetic hamster line that closely mimics human T2DM, which may hold potential for further research on the pathogenesis and treatment of this disease.

Effect of Butyric Acid Bacteria on a Spontaneous Diabetic Hamster

Effect of Butyric Acid Bacteria on a Spontaneous Diabetic Hamster

Flaxseed and Vitamin E Exert Synergic Antioxidant Action on Diabetic Nephropathy in Experimental Diabetes

This study investigated the effects of flaxseed and vitamin E on diabetic nephropathy lesions in an experimental-induced model of diabetes in hamsters. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) in male Golden Syrian hamsters, and diabetic animals were fed either standard diet, or standard diet supplemented with flaxseed (150 g/kg diet), vitamin E (400 mg a-tocopherol/kg diet) or combination of flaxseed and vitamin E in the same dosages, for 20 weeks. Kidney histological evaluation of the diabetic hamsters revealed histological lesions characteristic for diabetic nephropathy, while supplementation of the diet with flaxseed and/or vitamin E improved histological aspects of diabetic nephropathy.

Skeletal muscle insulin resistance in hamsters with diabetes developed from obesity is involved in abnormal skeletal muscle LXR, PPAR and SREBP expression.

Diabetic ‘lipotoxicity’ theory suggests that fat-induced skeletal muscle insulin resistance (FISMIR) in obesity induced by a high-fat diet (HFD), which leads to ectopic lipid accumulation in insulin-sensitive tissues, may play a pivotal role in the pathogenesis of type 2 diabetes. However, the changes in gene expression and the molecular mechanisms associated with the pathogenesis of FISMIR have not yet been fully elucidated. In the present study the changes in skeletal muscle gene expression were examined in FISMIR in obese insulin-resistant and diabetic hamster models induced by HFD with or without low-dose streptozotocin-treatment. Microarray technology and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to explore the potential underlying molecular mechanisms. The pathophysiological and metabolic features of obesity and type 2 diabetes in humans are closely resembled by these hamster models. The results of microarray analysis showed that the differentially expressed genes associated with metabolism were mostly related to the abnormal regulation and changes in the gene expression of liver X receptor (LXR), peroxisome proliferator-activated receptor (PPAR) and sterol regulatory element-binding protein (SREBP) transcriptional programs in the skeletal muscle from insulin-resistant and diabetic hamsters. The microarray findings confirmed by RT-qPCR indicated that the increased expression of SREBPs and LXRβ and the decreased expression of LXRα and PPARs were involved in the molecular mechanisms of FISMIR pathogenesis in insulin-resistant and diabetic hamsters. A significant difference in the abnormal expression of skeletal muscle LXRs, PPARs and SREBPs was found between insulin-resistant and diabetic hamsters. It may be concluded that the combined abnormal expression of LXR, PPAR and SREBP transcriptional programs may contribute to the development of FISMIR mediated by skeletal muscle lipid accumulation resulting from abnormal skeletal muscle glucose and lipid metabolism in these HFD- and streptozotocin injection-induced insulin-resistant and diabetic hamsters.

Regulations of berberine on gene expression of BMP4 transcriptional pathways to improve visceral white adipose tissues insulin resistance in type 2 diabetic hamsters

To study the effects of berberine on the gene mRNA expressions of BMP4 transcriptional pathways and brown/white adipose tissue conversion transcriptional pathways in visceral white adipose tissues(VWAT) in type 2 diabetic hamsters and explore the relevant mechanisms. The obese insulin-resistant hamster model were induced by using high-fat diet, and then the type 2 diabetic hamster model was created through injection with low-dose streptozotocin in the obese insulin-resistant hamster model. After the modeling, the hamsters were randomly divided into normal control, obese insulin-resistant, type 2 diabetic and berberine-treated diabetic groups. After the nine-week treatment, real-time quantitative PCR was used to measure the changes in gene mRNA expressions of VWAT BMP4 transcriptional pathways, brown/white adipose tissue conversion transcriptional pathways and their target genes in different groups. The results showed that the gene mRNA expressions of BMP4, BMPRⅡ, BMPRlA, Smad1, Smad5, Smad8, p38/MAPK, ATF2, PRDM16, C/EBPβ, PGC1α, PPARγ and brown adipose tissue-specific genes was decreased and that of Smad6, Smurf1 and white adipose tissue-specific genes was increased in VWAT of model hamsters. Treatment with berberine regulated BMP4 transcriptional pathways and brown adipose tissue transcriptional pathways and induced the gene mRNA expression of brown adipose tissue-specific genes in VWAT to develop browning gene phenotype of white adipose tissues, and then improved fat-induced insulin resistance. These findings indicated that BMP4 transcriptional pathways involved in the formation of fat-induced visceral white adipose tissues insulin resistance (FIVWATIR) and the browning molecular mechanism of white adipose tissues induced by berberine.

Severe hypertriglyceridemia and hypercholesterolemia accelerating renal injury: a novel model of type 1 diabetic hamsters induced by short-term high-fat / high-cholesterol diet and low-dose streptozotocin.

BackgroundHyperlipidemia is thought to be a major risk factor for the progression of renal diseases in diabetes. Recent studies have shown that lipid profiles are commonly abnormal early on type 2 diabetes mellitus (T2DM) with diabetic nephropathy. However, the early effects of triglyceride and cholesterol abnormalities on renal injury in type 1 diabetes mellitus (T1DM) are not fully understood and require reliable animal models for exploration of the underlying mechanisms. Hamster models are important tools for studying lipid metabolism because of their similarity to humans in terms of lipid utilization and high susceptibility to dietary cholesterol and fat.MethodsTwenty-four male Golden Syrian hamsters (100–110 g) were rendered diabetes by intraperitoneal injections of streptozotocin (STZ) on consecutive 3 days at dose of 30 mg/kg, Ten days after STZ injections, hamsters with a plasma Glu concentration more than 12 mmol/L were selected as insulin deficient ones and divided into four groups (D-C, D-HF, D-HC, and D-HFHC), and fed with commercially available standard rodent chow, high-fat diet, high-cholesterol diet, high-fat and cholesterol diet respectively, for a period of four weeks.ResultsAfter an induction phase, a stable model of renal injury was established with the aspects of early T1DM kidney disease, These aspects were severe hypertriglyceridemia, hypercholesterolemia, proteinuria with mesangial matrix accumulation, upgraded creatinine clearance, significant cholesterol and triglyceride deposition, and increasing glomerular surface area, thickness of basement membrane and mesangial expansion. The mRNA levels of sterol regulatory element binding protein-1c, transforming growth factors-β, plasminogen activator inhibitor-1, tumor necrosis factor-α and interleukin-6 in the D-HFHC group were significantly up-regulated compared with control groups.ConclusionsThis study presents a novel, non-transgenic, non-surgical method for induction of renal injury in hamsters, which is an important complement to existing diabetic models for pathophysiological studies in early acute and chronic kidney disease, especially hyperlipidemia. These data suggest that both severe hypertriglyceridemia and hypercholesterolemia can accelerate renal injury in the early development of T1DM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0041-5) contains supplementary material, which is available to authorized users.

Effects of berberine on amelioration of hyperglycemia and oxidative stress in high glucose and high fat diet-induced diabetic hamsters in vivo.

This study investigated the effects of berberine on amelioration of hyperglycemia and hyperlipidemia and the mechanism involved in high glucose and high fat diet-induced diabetic hamsters. Golden hamsters fed with high glucose and high fat diet were medicated with metformin, simvastatin, and low or high dose of berberine (50 and 100 mg·kg−1) for 6 weeks. The results showed that the body weights were significantly lower in berberine-treated groups than control group. Histological analyses revealed that the treatment of berberine inhibited hepatic fat accumulation. Berberine significantly reduced plasma total cholesterol, triglyceride, free fatty acid, low density lipoprotein cholesterol, malondialdehyde, thiobarbituric acid-reactive substance, and 8-isoprostane level but significantly increased plasma superoxide dismutase activity. Glucose and insulin levels were significantly reduced in metformin and berberine-treated groups. Glucose tolerance tests documented that berberine-treated mice were more glucose tolerant. Berberine treatment increased expression of skeletal muscle glucose transporter 4 mRNA and significantly decreased liver low density lipoprotein receptor mRNA expression. The study suggested that berberine was effective in lowering blood glucose and lipids levels, reducing the body weight, and alleviating the oxidative stress in diabetic hamsters, which might be beneficial in reducing the cardiovascular risk factors in diabetes.

Antioxidative and antiatherogenic effects of flaxseed, α-tocopherol and their combination in diabetic hamsters fed with a high-fat diet.

Oxidative stress has previously been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications. In the present study, the effects of supplementation with dietary antioxidants, flaxseed and α-tocopherol were investigated in diabetic golden Syrian hamsters fed with a high-fat diet. Thirty-five golden Syrian hamsters were randomly divided into a control group (C) and four diabetic groups (DM, DM + flax, DM + E and DM + Flax + E). The hamsters received four different diets for a 20-week period, as follows: i) Groups C and DM received a high-fat diet (40% energy as fat), deficient in α-linolenic acid (ALA); ii) the DM + Flax group received a high-fat diet enriched with ground flaxseed 15 g/100 g of food, rich in ALA; iii) the DM + E group received a high-fat diet enriched with vitamin E, 40 mg α-tocopherol/100 g of food; and iv) the DM + Flax + E group received a high-fat diet enriched with flaxseed and vitamin E. The results of serum lipid and oxidative stress analysis suggested that the antiatherogenic effect of flaxseed, α-tocopherol and their combination added to a high-fat diet in diabetic hamsters was based primarily on their antioxidative role, demonstrated by decreased serum lipid peroxidation and increased liver glutathione content. Improvements of serum glucose and non-high-density lipoprotein cholesterol (HDL-C) levels were observed and may have contributed to the prevention of diabetic macroangiopathy evidenced in the histopathological examination. The antioxidant effect of flaxseed was similar to that of α-tocopherol in diabetic hamsters fed a high-fat diet and combined supplementation did not appear to bring more benefits than flaxseed alone. Moreover, the high dose of ground flaxseed alone may have a better cardioprotective effect than α-tocopherol in diabetic hamsters by reducing total cholesterol and non-HDL-C levels and increasing HDL-C levels.

Improvement of myocardial glycolipid metabolic disorder in diabetic hamster with Astragalus polysaccharides treatment

The objective of the present study is to observe the effect of Astragalus polysaccharide (APS) on myocardial glucose and lipid metabolism in diabetes (DM) hamster and to explore its mechanism in intervention of DM cardiomyopathy. Low-dose- streptozotocin-induced hamsters (STZ, 40 mg/kg × 3 days, i.p.) with blood glucose >13.9 mmo/L were considered as type 2 diabetic models. We measure blood glucose, serum lipid, insulin, C-peptide, myocardial enzyme levels, myocardial glycogen staining, myocardial ultrastructure, fluorescence quantitative RT-PCR detection of myocardial PPAR-α and the target genes (FATP, ACS) and GLUT4 mRNA expression in normal control group, DM group and APS treatment group hamsters. There was significant glycolipid metabolic disorders in DM group compared with normal group. Glucose, glycosylated serum protein, myocardial enzymes and lipid levels in APS treatment group decreased significantly than DM group, but insulin and C-peptide levels was no difference. Myocardial glycogen staining and abnormal myocardial ultrastructure in APS treatment group were significantly improved than in DM group. Gene expression of myocardial PPAR-α and its target genes (FATP, ACS) in APS group were significantly lower than in DM group, while gene expression of GLUT4 in APS group was higher than DM group. APS can partially improve myocardial glucose and lipid metabolism disorders in diabetic hamsters and protect myocardium in some extent.

Chymase inhibition prevents myocardial fibrosis through the attenuation of NOX4-associated oxidative stress in diabetic hamsters.

Aims/Introduction: Diabetic cardiomyopathy entails the cardiac injury induced by diabetes, independent of vascular disease or hypertension. Despite numerous experimental studies and clinical trials, the pathogenesis of diabetic cardiomyopathy remains elusive. Here, we report that chymase, an immediate angiotensin II (AngII)-forming enzyme in humans and hamsters, and NOX4-induced oxidative stress have pathogenic roles in myocardial fibrosis in diabetic hamsters. Expression of chymase was evaluated in the hearts of streptozotocin (STZ)-induced diabetic hamsters. The impact of chymase-specific inhibitors, TEI-E00548 and TEI-F00806, on myocardial fibrosis, and increased levels of intracardiac AngII, accumulation of 8-hydroxy-2'-deoxyguanosine (an oxidative stress marker in urine and heart tissue) and expression of heart NOX4 in diabetic hamsters were investigated. Myocardial chymase expression was markedly upregulated in STZ hamsters in a glucose-dependent manner. A total of 8 weeks after STZ administration, the diabetic hamsters showed enhanced oxidative stress and NOX4 expression in the heart, in parallel with increased myocardial AngII production. Oral administration of chymase-specific inhibitors, TEI-F00806 and TEI-E00548, normalized heart AngII levels, and completely reversed NOX4-induced oxidative stress and myocardial fibrosis in STZ-induced diabetic hamsters, although they did not affect the activity of the systemic renin-angiotensin system or systolic blood pressure. Chymase inhibition might prevent oxidative stress and diabetic cardiomyopathy at an early stage by reducing local AngII production. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00202.x, 2012).

Vimentin and laminin are altered on cheek pouch microvessels of streptozotocin-induced diabetic hamsters

OBJECTIVES:Normal endothelial cells respond to shear stress by elongating and aligning in the direction of fluid flow. Hyperglycemia impairs this response and contributes to microvascular complications, which result in deleterious effects to the endothelium. This work aimed to evaluate cheek pouch microvessel morphological characteristics, reactivity, permeability, and expression of cytoskeleton and extracellular matrix components in hamsters after the induction of diabetes with streptozotocin.METHODS:Syrian golden hamsters (90–130 g) were injected with streptozotocin (50 mg/kg, i.p.) or vehicle either 6 (the diabetes mellitus 6 group) or 15 (the diabetes mellitus 15 group) days before the experiment. Vascular dimensions and density per area of vessels were determined by morphometric and stereological measurements. Changes in blood flow were measured in response to acetylcholine, and plasma extravasation was measured by the number of leakage sites. Actin, talin, α-smooth muscle actin, vimentin, type IV collagen, and laminin were detected by immunohistochemistry and assessed through a semiquantitative scoring system.RESULTS:There were no major alterations in the lumen, wall diameters, or densities of the examined vessels. Likewise, vascular reactivity and permeability were not altered by diabetes. The arterioles demonstrated increased immunoreactivity to vimentin and laminin in the diabetes mellitus 6 and diabetes mellitus 15 groups.DISCUSSION:Antibodies against laminin and vimentin inhibit branching morphogenesis in vitro. Therefore, laminin and vimentin participating in the structure of the focal adhesion may play a role in angiogenesis.CONCLUSIONS:Our results indicated the existence of changes related to cell–matrix interactions, which may contribute to the pathological remodeling that was already underway one week after induction of experimental diabetes.

Berberine-Improved Visceral White Adipose Tissue Insulin Resistance Associated with Altered Sterol Regulatory Element-Binding Proteins, Liver X Receptors, and Peroxisome Proliferator-Activated Receptors Transcriptional Programs in Diabetic Hamsters

The diabetic "lipotoxicity" hypothesis presents that fat-induced visceral white adipose tissue insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Berberine, a hypolipidemic agent, has been reported to have antidiabetic activities. The molecular mechanisms for this property are, however, not well clarified. Therefore in this study type 2 diabetic hamsters were induced by high-fat diet with low-dose streptozotocin. Then, we investigated the gene expression alterations and explored the molecular mechanisms underlying the therapeutic effect of berberine on fat-induced visceral white adipose tissue insulin resistance in diabetic hamsters by microarray analysis followed by real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmation. Type 2 diabetic hamsters exhibited hyperglycemia and relative hyperinsulinemia, glucose intolerance, insulin resistance, intra-adipocyte lipid accumulation, significant increase in body weight and visceral white adipose tissue weight, abnormal serum adipokines levels, and deleterious dyslipidemia. Furthermore, they had increased sterol regulatory element-binding proteins (SREBPs) expression and decreased liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) expression in visceral white adipose tissue. After 9-week berberine treatment, fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters were significantly improved. Compared with diabetic hamsters, expression of LXRs and PPARs significantly increased and SREBPs significantly decreased in visceral white adipose tissue from berberine-treated diabetic hamsters. These results suggest that altered visceral white adipose tissue LXRs, PPARs, and SREBPs transcriptional programs are involved in the therapeutic mechanisms of berberine on fat-induced visceral white adipose tissue insulin resistance in type 2 diabetic hamsters.

Effects of the interaction of diabetes and iron supplementation on hepatic and pancreatic tissues, oxidative stress markers, and liver peroxisome proliferator-activated receptor-α expression

This study evaluated the effects of the interaction of diabetes and a carbonyl iron supplemented on hepatic and pancreatic tissues, oxidative stress markers and liver peroxisome proliferator-activated receptor-α expressions. Hamsters were divided: Control which received a standard AIN 93 diet; Control Iron, composed of control animals that received a diet with 0.83% carbonyl iron; Diabetic, composed of animals that received a injection of streptozotocin (50 mg/kg, intraperitoneal) on day 35; and Diabetic Iron composed of streptozotocin treated animals that received a diet supplemented with carbonyl iron. Diabetes increased the glucose level and reduced triglycerides. Diabetic Iron group showed higher levels of glucose and serum triglycerides as compared to the Diabetic group. Diabetes decreased mRNA levels of peroxisome proliferator-activated receptor-α. Iron attenuated the diabetes induced down regulation of peroxisome proliferator-activated receptor-α mRNA. Moreover, diabetes increased carbonyl protein and decreased glutathione levels and catalase activity, while iron attenuated the increase in levels of carbonyl protein and attenuated the decrease in those of glutathione level and catalase activity. Histological analysis shows that supplementation iron caused an increase in the size of the islets in Control Iron. The results show that iron does not aggravated liver oxidant/antioxidant status and peroxisome proliferator-activated receptor-α expression in diabetic hamsters.