Berberine and Ginsenoside Rb1 Ameliorate Depression-Like Behavior in Diabetic Rats

Rhizoma coptidis(Huang-lian) and Asian ginseng have been widely used in the treatment of diabetes and other concurrent diseases with apparent effects. This study investigated the effects of the active ingredients of R. coptidis and ginseng, berberine and ginsenoside Rb1, on depression-like behavior in a rat diabetes model. The animal model was established via a high-fat diet and intraperitoneal injection of streptozotocin, while the animal’s depression-like behavior was induced via chronic unpredictable mild stress. These experimental rats were divided into four groups: control, depression-like behavior (DLB), metformin plus fluoxetine hydrochloride (M+FH), and berberine plus ginsenoside Rb1 (B+GRb1) groups. Glucose metabolism and insulin resistance were evaluated by oral glucose test and glucose clamp study. Depression-like behavior was evaluated via behavioral analyses, including forced swim, sucrose preference, elevated plus maze, and open-field tests. HE and Nissl staining, plasma cortisol expression of adrenocorticotropic hormone, and brain-derived neurotrophic factor (BDNF) levels were assayed to explore the mechanisms of action. Compared with the control, rats in the DLB group had a significant increase in the levels of blood glucose and depression-like behavior. The B+GRb1 group significantly improved glucose metabolism and insulin resistance, reduced depression-like behavior, downregulated levels of plasma cortisol and adrenocorticotropic hormone under stress, and upregulated BDNF protein expression compared to the DLB rats. HE and Nissl staining data revealed that B+GRb1 protected neurons from pathological and morphological changes. Thus, berberine and ginsenoside Rb1 not only improved glucose metabolism in diabetic rats but also ameliorated their depression-like behavior under chronic unpredictable stress. Mechanistically, studied data with plasma hormonal levels and brain neuronal pathological/morphological changes supported the observed effects. The combination of berberine and ginsenoside Rb1 may have a clinical value in the management of diabetic patients with depression.

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Alteration of the intestinal barrier and GLP2 secretion in Berberine-treated type 2 diabetic rats

Journal of Endocrinology ◽

10.1530/joe-13-0184 ◽

2013 ◽

Vol 218 (3) ◽

pp. 255-262 ◽

Cited By ~ 27

Author(s):

C Y Shan ◽

J H Yang ◽

Y Kong ◽

X Y Wang ◽

M Y Zheng ◽

...

Keyword(s):

Insulin Resistance ◽

Intestinal Barrier ◽

Resistance Index ◽

Diabetic Rats ◽

Diabetic Patients ◽

Sprague Dawley ◽

Type 2 Diabetic Patients ◽

Junction Protein ◽

Type 2 Diabetic

For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.

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L-cysteine Supplementation Increases Blood Levels of Hydrogen Sulfide and Nitrite, and Decreases Insulin Resistance and Vascular Inflammation in Zucker Diabetic Rats

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_038 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 405-405

Author(s):

Sushil Jain

Keyword(s):

Insulin Resistance ◽

Hydrogen Sulfide ◽

Animal Studies ◽

Vascular Inflammation ◽

Diabetic Animal ◽

Diabetic Rats ◽

Blood Levels ◽

Diabetic Patients ◽

Zdf Rats

Abstract Objectives Diabetic patients have lower blood levels of hydrogen sulfide (H2S). H2S has potent antioxidant, anti-inflammatory and anti-atherosclerotic effects in vitro and in animal studies. This study examined the hypothesis that supplementation with L-cysteine, an endogenous precursor of H2S increases blood levels of H2S and lowers insulin resistance and vascular inflammation biomarkers in type 2 diabetes using Zucker diabetic (ZDF) rats as a model. Methods Starting at age of 6 weeks, ZDF rats were supplemented orally, daily gavages for 8 weeks with saline-placebo (D, n = 8) or L-cysteine (LC, n = 12, 1 mg/kg BW) and fed a high calorie diet. 6 weeks age rats without any supplementation were considered baseline (BL) rats. Results Fasting blood levels of D rats showed lower H2S and elevated HGb, MCP-1 and insulin resistance when compared with baseline in which there was no onset of diabetes. LC supplementation significantly (P < 0.05) increased blood levels of H2S (37%), and NO2 (30%) and lowered levels of GHb (9%), MCP-1 (31%), TNF (31%) and HOMA insulin resistance (25%) compared with levels seen in saline supplemented D. The blood levels of GHb and IR showed a significant correlation (P < 0.05) with concentrations of H2S and nitrite in LC-supplemented ZDF rats. Conclusions This shows that L-cysteine supplementation can increase levels of H2S and NO2 in diabetic animal model, and needs to be validated as an adjuvant therapy for the reduction of vascular inflammation and insulin resistance in the diabetic patient population. Funding Sources This study was supported by the NCCIH.

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Effects of Berberine on Diabetes and Cognitive Impairment in an Animal Model: The Mechanisms of Action

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500658 ◽

2021 ◽

pp. 1-17

Author(s):

Jing-Hua Zhang ◽

Jin-Feng Zhang ◽

Jun Song ◽

Yu Bai ◽

Lan Deng ◽

...

Keyword(s):

Insulin Resistance ◽

Cognitive Impairment ◽

Cognitive Function ◽

Glucose Metabolism ◽

Tau Protein ◽

Neuronal Apoptosis ◽

Mechanisms Of Action ◽

Diabetic Rats ◽

Tunel Assay ◽

Phosphorylated Tau

Diabetes is a group of metabolic disorders with an increased risk of developing cognitive impairment and dementia. The hippocampus in the forebrain contains an abundance of insulin receptors related to cognitive function and plays an important role in the pathophysiology of neurodegenerative disorders. Berberine from traditional Chinese medicine has been used to treat diabetes and diabetic cognitive impairment, although its related mechanisms are largely unknown. In this study, a STZ diabetes rat model feeding with a high-fat diet was used to test the effects of berberine compared with metformin. Oral glucose tolerance and hyperinsulinemic-euglycemic clamp were used for glucose metabolism and insulin resistance. The Morris water maze was used to observe the compound effects on cognitive impairment. Serum and hippocampal [Formula: see text]-amyloid peptide (A[Formula: see text], Tau and phosphorylated Tau protein deposition in the hippocampi were measured. The TUNEL assay was used to detect the neuronal apoptosis, supported by histomorphological changes and transmissional electron microscopy (TEM) image. Our data showed that the diabetic rats had a significantly cognitive impairment. In addition to improving glucose metabolism and reducing insulin resistance, berberine significantly improved the cognitive function in the rat. Berberine also effectively decreased the expression of hippocampal tau protein, phosphorylated Tau, and increased insulin receptor antibodies. Moreover, berberine downregulated the abnormal phosphorylation of A[Formula: see text] and Tau protein and improved hippocampal insulin signaling. The TUNEL assay confirmed that berberine reduced hippocampal neuronal apoptosis supported by TEM. Thus, berberine significantly improved the cognitive function in diabetic rats by changing the peripheral and central insulin resistance. The reduction of neuronal injury, A[Formula: see text] deposition, abnormal phosphorylation of Tau protein, and neuronal apoptosis in the hippocampus were observed as the related mechanisms of action.

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Hawthorn Leaf Flavonoids Protect against Diabetes-Induced Cardiomyopathy in Rats via PKC-α Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/2071952 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Qing Min ◽

Yuting Bai ◽

Yuchen Zhang ◽

Wei Yu ◽

Minli Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Blood Glucose ◽

Protective Effect ◽

Signaling Pathway ◽

Morphological Changes ◽

Cardiac Injury ◽

Diabetic Rats ◽

Diabetic Patients ◽

Underlying Mechanisms

Objectives. DCM has become one of the main reasons of death in diabetic patients. In this study, we aimed to explore the hawthorn leaf flavonoids (HLF) protective effect against diabetes-induced cardiac injury and the underlying mechanisms in experimental rats. Methods. Experimental diabetic model was induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg) in rats after feeding with high-fat diet for 8 weeks. The diabetic rats received a 16-week treatment of different doses of HLF (50, 100, and 200). The morphological changes of myocardial cells were observed by light microscope; the concentration of antioxidant indicator and TNF-α and the expression of PKC-α mRNA, PKC-α, and NF-κB proteins were assessed as well. Results. STZ-induced diabetes mellitus prompted blood glucose, cardiac injury, oxidative stress, and inflammation, accompanied with suppressed body weight. On the contrary, HLF administration improved body weight and blood glucose and attenuated myocardial structural abnormalities in diabetic rats. In addition, HLF decreased MDA level and enhanced SOD activities, inhibited TNF-α expression, and downregulated PKC-α mRNA, PKC-α, and NF-κB which were induced by diabetes. Conclusions. HLF has a protective effect against diabetic cardiomyopathy in rats. The mechanism may be involved in reducing oxidative stress and inflammation via inactivation of the PKC-α signaling pathway.

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Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer’s subjects?

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00784-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Grazia Daniela Femminella ◽

Nicholas R. Livingston ◽

Sanara Raza ◽

Thalia van der Doef ◽

Eleni Frangou ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Metabolism ◽

Grey Matter ◽

Insulin Signalling ◽

Diabetic Patients ◽

Grey Matter Volume ◽

Model Assessment ◽

Matter Volume ◽

Peripheral Insulin Resistance ◽

18F Fdg

Abstract Background Type 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. Methods In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. Results In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. Conclusions In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

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Anethum graveolens L‎. Alleviates Sperm ‎Damage by Limiting Oxidative Stress ‎and Insulin ‎Resistance ‎in ‎Diabetic Rats ‎

The Open Medicinal Chemistry Journal ◽

10.2174/1874104502014010035 ◽

2020 ◽

Vol 14 (1) ◽

pp. 35-44

Author(s):

Ebrahim Abbasi-Oshaghi ◽

Iraj Khodadadi ◽

Fatemeh Mirzaei ◽

Mehrdad Ahmadi ◽

Heidar Tayebinia ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Morphological Changes ◽

Diabetic Rats ◽

Male Rats ◽

Diabetic Rat ◽

Anethum Graveolens ◽

Sod Activity ◽

Histological Changes ◽

Anti Oxidant

Background: It has been reported that diabetes is associated with sperm ‎damage and infertility. Objective: The purpose of this experiment was to survey the effect of Anethum graveolens L. (Dill) powder on sperm profiles, oxidative stress, insulin resistance, and histological changes in male diabetic rats. Methods: Male rats were randomly divided into 6 groups (n=7); group 1: normal rats, 2: normal rats + 100mg/kg Dill, 3: normal rats + 300mg/kg Dill, 4: diabetic rats, 5: diabetic rats + 100mg/kg Dill, and 6: diabetic rats + 300mg/kg Dill. After 2 months of treatments, the sperm profile, anti-oxidant activity, superoxide dismutase (SOD) activity, and malondialdehyde were measured. The histopathology of testis was evaluated. Hormonal changes and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Results: Total anti-oxidant and SOD activity in diabetic rats significantly decreased, while MDA concentration was significantly increased in the testis and pancreas of diabetic rats compared with control. However, the use of Dill significantly normalized these profiles. The treatment of diabetic rats with Dill changed the sperm parameters. The levels of testosterone, FSH, and LH in diabetic rats were significantly reduced, but the treatment with Dill did not alter the level of these hormones. Dill also significantly normalized testis morphological changes, insulin resistance, and inflammation. Conclusion: The use of Dill normalized oxidative stress, inflammation, and insulin resistance in diabetic rats that correlated with sperm profile and testis histological changes. The treatment of diabetic rat models with Dill did not show harmful effects on sperm profiles.

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Morphological Changes of Gingiva in Streptozotocin Diabetic Rats

International Journal of Dentistry ◽

10.1155/2009/725628 ◽

2009 ◽

Vol 2009 ◽

pp. 1-4 ◽

Cited By ~ 12

Author(s):

C. Tesseromatis ◽

A. Kotsiou ◽

H. Parara ◽

E. Vairaktaris ◽

M. Tsamouri

Keyword(s):

Diabetes Mellitus ◽

Morphological Changes ◽

Diabetic Rats ◽

Control Group ◽

Diabetic Patients ◽

Histological Investigation ◽

Bacterial Diseases ◽

Male Wistar Rats ◽

Streptozotocin Induced Diabetes ◽

Routine Assay

Gingivitis and periodontitis are chronic bacterial diseases of the underlying and surrounding tooth tissues. Diabetes mellitus is responsible for tooth deprivation both by decay and periodontal disease. The streptozotocin-induced diabetes results in a diabetic status in experimental animals similar to that observed in diabetes patients. The aim of the study was to investigate the relationship between the gingival lesions and the microangiopathy changes in streptozotocin-induced diabetes mellitus. Forty male Wistar rats were divided into two groups (control and experimental). Diabetes mellitus was induced by 45 mg/kg IV streptozotocin. The histological investigation of the marginal gingival and the relevant gingival papilla showed inflammation of the lamina propria and the squamous epithelium as well as marked thickness of the arteriole in the diabetic group, but no changes were observed in the control group. The results suggested a probable application of a routine gingival histological investigation in diabetic patients in order to control the progress of disease complications. It may be concluded that histological gingival investigation can be used as a routine assay for the control of the diabetic disease and prevention of its complications.

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Chronic Unpredictable Mild Stress Aggravates Mood Disorder, Cognitive Impairment, and Brain Insulin Resistance in Diabetic Rat

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/2901863 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Hui Yang ◽

Wei Li ◽

Pan Meng ◽

Zhuo Liu ◽

Jian Liu ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Diabetic Rats ◽

Control Group ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Diabetes Group ◽

Brain Insulin ◽

Immobility Time ◽

Brain Insulin Resistance

Diabetes-induced brain insulin resistance is associated with many mental diseases, including depression. Epidemiological evidences demonstrate the pathophysiologic link between stress, depression, and diabetes. This study was designed to determine whether chronic unpredictable mild stress- (CUMS-) induced changes in brain insulin resistance could contribute to deterioration in mood and cognitive functions in diabetic rats. Male SD rats were randomly assigned to three groups, including standard control group, the diabetes group, and the diabetes with CUMS group. After 7 weeks, emotional behaviors and memory performances as well as metabolic phenotypes were measured. In addition, we examined the changes in protein expression related to brain insulin signaling. Our results show that rats in diabetes with CUMS group displayed a decreased locomotor behavior in open-field test, an increased immobility time in forced swim test, and tail suspension test, and an impaired learning and memory in the Morris water maze when compared to animals in diabetes group. Further, diabetes with CUMS exhibited a significant decrease in phosphorylation of insulin receptor and an increase phosphorylation of IRS-1 in brain. These results suggest that the depression-like behaviors and cognitive function impairments in diabetic rats with CUMS were related to the changes of brain insulin signaling.

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Intensive insulin treatment induces insulin resistance in diabetic rats by impairing glucose metabolism-related mechanisms in muscle and liver

Journal of Endocrinology ◽

10.1530/joe-11-0105 ◽

2011 ◽

Vol 211 (1) ◽

pp. 55-64 ◽

Cited By ~ 37

Author(s):

Maristela Mitiko Okamoto ◽

Gabriel Forato Anhê ◽

Robinson Sabino-Silva ◽

Milano Felipe dos Santos Ferreira Marques ◽

Helayne Soares Freitas ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Phosphoenolpyruvate Carboxykinase ◽

Glucose Transporter ◽

Glycogen Storage ◽

Diabetic Rats ◽

Diabetic Patients ◽

Good Glycemic Control ◽

Insulin Sensitizer ◽

Neutral Protamine Hagedorn

Insulin replacement is the only effective therapy to manage hyperglycemia in type 1 diabetes mellitus (T1DM). Nevertheless, intensive insulin therapy has inadvertently led to insulin resistance. This study investigates mechanisms involved in the insulin resistance induced by hyperinsulinization. Wistar rats were rendered diabetic by alloxan injection, and 2 weeks later received saline or different doses of neutral protamine Hagedorn insulin (1.5, 3, 6, and 9 U/day) over 7 days. Insulinopenic-untreated rats and 6U- and 9U-treated rats developed insulin resistance, whereas 3U-treated rats revealed the highest grade of insulin sensitivity, but did not achieve good glycemic control as 6U- and 9U-treated rats did. This insulin sensitivity profile was in agreement with glucose transporter 4 expression and translocation in skeletal muscle, and insulin signaling, phosphoenolpyruvate carboxykinase/glucose-6-phosphatase expression and glycogen storage in the liver. Under the expectation that insulin resistance develops in hyperinsulinized diabetic patients, we believe insulin sensitizer approaches should be considered in treating T1DM.

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