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Efficacy of Berberine in Patients with Type 2 Diabetes
Abstract
Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo. This pilot study was to determine the efficacy and safety of berberine in the treatment of type 2 diabetes mellitus patients. In study A, 36 adults with newly diagnosed type 2 diabetes mellitus were randomly assigned to treatment with berberine or metformin (0.5 g 3 times a day) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (from 9.5%+/-0.5% to 7.5%+/-0.4%, P<.01), fasting blood glucose (from 10.6+/-0.9 mmol/L to 6.9+/-0.5 mmol/L, P<.01), postprandial blood glucose (from 19.8+/-1.7 to 11.1+/-0.9 mmol/L, P<.01), and plasma triglycerides (from 1.13+/-0.13 to 0.89+/-0.03 mmol/L, P<.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes mellitus were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering fasting blood glucose and postprandial blood glucose from 1 week to the end of the trial. Hemoglobin A1c decreased from 8.1%+/-0.2% to 7.3%+/-0.3% (P<.001). Fasting plasma insulin and homeostasis model assessment of insulin resistance index were reduced by 28.1% and 44.7% (P<.001), respectively. Total cholesterol and low-density lipoprotein cholesterol were decreased significantly as well. During the trial, 20 (34.5%) patients experienced transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.
... inaccessible, leaving 141 articles. Following full-text review, 91 articles were then excluded, resulting in the inclusion of 50 articles (Rong et al., 1997;Zhang et al., 2000;Gao et al., 2002;Liu, 2004;Guo and Zhao, 2006;Li and Liu, 2007;Li et al., 2008;Li, 2008;Yin et al., 2008;Zhu et al., 2009;Sheng and Xie, 2010;Zhang et al., 2010;Meng et al., 2011;Xiang et al., 2011;Yin et al., 2011;Zhang et al., 2011;Liu, 2012;Wang et al., 2012;Xue et al., 2012;Zhang and Yuan, 2012;Zhou and Huang, 2012;Shu, 2014;Yu, 2015;Zhu et al., 2015;Du, 2016;Meng, 2016;Sun, 2016;Li, 2017;Sun, 2017;Wu, 2017;Xing, 2017;Zhang, 2017;Fan et al., 2018;Huang et al., 2018;Rashidi et al., 2018;Yao et al., 2018;Jiang and Wang, 2019;Yang et al., 2020;Zhang et al., 2020;Zhu et al., 2020;Chen C. et al., 2021;Chen, 2021). The flowchart of literature screening is plotted in Figure 1. ...
... All studies included subjects with uncomplicated T2DM. Four of the articles were published in English (Yin et al., 2008;Zhang et al., 2010;Rashidi et al., 2018;Zhang et al., 2020), while the remaining studies appeared in Chinese, all of which were RCTs. Among these studies, one was conducted in Iran (Rashidi et al., 2018), whereas the others were conducted in China. ...
... In 50 studies, 17 reported on the use of BBR alone, including 4 studies (Xiang et al., 2011;Rashidi et al., 2018;Zhang et al., 2020;Zhu et al., 2020) that compared BBR to a placebo and 13 studies that conducted head-to-head trials of BBR with other medications. Among these, 3 studies (Rong et al., 1997;Guo and Zhao, 2006;Liu, 2012) compared BBR to SU (including glyburide, gliclazide, and glipizide), 6 studies Yin et al., 2008;Wang et al., 2012;Du, 2016;Xing, 2017;Chen et al., 2023) compared to Met, 2 studies (Zhang et al., 2010;Zhang et al., 2011) contrasted with TZDs (rosiglitazone), and 2 studies (Zhang et al., 2000;Gao et al., 2002) compared to traditional Chinese medicine. Additionally, 33 studies compared BBR with one or two conventional medications used in combination, with the same conventional medication serving as the control. ...
Background
Despite the availability of multiple therapies for Type 2 diabetes mellitus (T2DM), challenges remain due to side effects and efficacy limitations. Berberine (BBR) has shown broad anti-diabetic effects, prompting a systematic assessment of its efficacy and safety through a meta-analysis.
Methods
A comprehensive search was conducted across eight database and search engines from inception until 06/09/2024. Only randomized controlled trials (RCTs) meeting inclusion criteria were analyzed. The Cochrane risk of bias assessment tool and Jadad scale were used to evaluate study quality. Meta-analysis was performed using RevMan v5.3 and Stata/SE v15.1.
Results
Fifty studies involving 4,150 participants were included. BBR alone significantly reduced fasting plasma glucose (FPG) (MD = −0.59 mmol/L, p = 0.048), 2-h postprandial blood glucose (2hPBG) (MD = −1.57 mmol/L, p < 0.01), low-density lipoprotein cholesterol (LDL-C) (MD = −0.30 mmol/L, p < 0.01), total cholesterol (TC) (MD = −0.30 mmol/L, p = 0.034), and triglycerides (TG) (MD = −0.35 mmol/L, p < 0.01). When combined with hypoglycemic drugs, BBR significantly improved FPG (MD = −0.99 mmol/L, p < 0.01), 2hPBG (MD = −1.07 mmol/L, p < 0.01), glycated hemoglobin (HbA1c) (MD = −0.69%, p < 0.01), and other metabolic markers, including fasting insulin (Fins), homeostasis model assessment index for assessing insulin resistance (HOMA-IR), lipid profiles and inflammatory markers. The most common BBR dosage was 0.9–1.5 g/d, with treatment cycles typically lasting 1–3 months.
Conclusion
Current evidence suggests that BBR alone or in combination has significant potential for treating type 2 diabetes mellitus (T2DM). Future research should encompass a broader scope, including not just the beneficial effects of BBR in head-to-head studies, but more crucially, delving into its mechanisms of action with hypoglycemic drugs to optimize T2DM treatment strategies.
... Our study found that BBR significantly reduced body weight, BMI, body fat percentage, visceral fat percentage, and diastolic blood pressure compared to baseline, though these reductions were not significant for glucose regulation parameters (Table S3). These results are consistent with clinical trials showing that BBR effectively lowers lipid levels (plasma triglycerides, total cholesterol, and LDL) [83][84][85] but has a limited effect on glucose metabolism. BBR does not have an insulin secretagogue effect on β-TC3 cells in vitro but may have a glucose-lowering effect on hepatocytes (HepG2 cell line) [86]. ...
... BBR does not have an insulin secretagogue effect on β-TC3 cells in vitro but may have a glucose-lowering effect on hepatocytes (HepG2 cell line) [86]. However, another study in poorly controlled diabetic patients receiving insulin injections showed that BBR increased fasting and postprandial C-peptide levels (a marker of pancreatic β-cell function) [83]. This suggests that BBR may not directly stimulate insulin secretion but may improve islet function in patients who do not respond to oral hypoglycemic agents [87]. ...
... This suggests that BBR may not directly stimulate insulin secretion but may improve islet function in patients who do not respond to oral hypoglycemic agents [87]. However, its hypoglycemic effect is still controversial, since other studies have shown that the administration of BBR (0.5 g t.i.d.) at the beginning of each meal reduces fasting and postprandial blood glucose in patients with newly diagnosed T2DM [83]. Another study reported that glycosylated hemoglobin decreased after BBR treatment (0.5 g b.i.d.), and there were significant improvements in blood glucose and lipid levels [88]. ...
Gymnema sylvestre (GS) and berberine (BBR) are natural products that have demonstrated therapeutic potential for the management of obesity and its comorbidities, as effective and safe alternatives to synthetic drugs. Although their anti-obesogenic and antidiabetic properties have been widely studied, comparative research on their impact on the gene expression of adipokines, such as resistin (Res), omentin (Ome), visfatin (Vis) and apelin (Ap), has not been reported. Methodology: We performed a comparative study in 50 adult Mexican patients with obesity treated with GS or BBR for 3 months. The baseline and final biochemical parameters, body composition, blood pressure, gene expression of Res, Ome, Vis, and Ap, and safety parameters were evaluated. Results: BBR significantly decreased (p < 0.05) body weight, blood pressure and Vis and Ap gene expression and increased Ome, while GS decreased fasting glucose and Res gene expression (p < 0.05). A comparative analysis of the final measurements revealed a lower gene expression of Ap and Vis (p < 0.05) in patients treated with BBR than in those treated with GS. The most frequent adverse effects in both groups were gastrointestinal symptoms, which attenuated during the first month of treatment. Conclusion: In patients with obesity, BBR has a better effect on body composition, blood pressure, and the gene expression of adipokines related to metabolic risk, while GS has a better effect on fasting glucose and adipokines related to insulin resistance, with minimal side effects.
... In another group of 48 patients with poorly controlled diabetes mellitus, blood glucose, total cholesterol and LDL-c were significantly reduced when berberine was combined with their still inadequate treatment. 18 A meta-analysis of 11 randomized controlled trials on the effect of the berberine molecule on blood lipids concluded that this substance reduced significantly total cholesterol, triglycerides and LDL-c while it increased HDL-c, but also that it should be further evaluated in a larger population. 19 Besides somatic effects, berberine is reported to have beneficial effects on various neurodegenerative and neuropsychiatric disorders such as having a stunt action in Alzheimer disease progression, and protective effects on forebrain ischemia, mental depression, schizophrenia and anxiety. ...
... Although high doses of berberine can result in severe adverse effects such as a lowered blood pressure, dyspnea, flu-like symptoms, and cardiac damage, 28 only mild to moderate gastrointestinal discomfort was reported at doses used in clinical treatments against hyperglycemia or hyperlipidemia albeit in one study, some 35% of 66 patients under berberine medication suffered from it. 18 Reported discomfort events were diarrhea, 18,19 constipation, 18,19,29 flatulence, 18,19 heartburn 16 and 'abdominal pain'. 18,30 Other somatic impairments such as allergic skin reaction and arrhythmia (Ding 2002 in 31 ) were also reported. ...
... Although high doses of berberine can result in severe adverse effects such as a lowered blood pressure, dyspnea, flu-like symptoms, and cardiac damage, 28 only mild to moderate gastrointestinal discomfort was reported at doses used in clinical treatments against hyperglycemia or hyperlipidemia albeit in one study, some 35% of 66 patients under berberine medication suffered from it. 18 Reported discomfort events were diarrhea, 18,19 constipation, 18,19,29 flatulence, 18,19 heartburn 16 and 'abdominal pain'. 18,30 Other somatic impairments such as allergic skin reaction and arrhythmia (Ding 2002 in 31 ) were also reported. ...
An extract of Berberis plants is nowadays used as a dietary supplement as well as for treating several medical symptoms, e.g., mostly for regulating glycemia, lipid metabolism and central nervous system disorders. Few or no information has so far been reported about side effects of berberine on behavioral and physiological-linked traits. We thus investigated on the potential adverse effects of the alkaloid berberine by using the ant Myrmica sabuleti as a model. We found that berberine decreased the ant’s food intake, activity, locomotion, and sensory perception, but did not impact their social interactions, cognition, learning and memorization. The ants did not adapt themselves to the side effect of berberine on their locomotion. They did not develop strong dependence on berberine consumption. After weaning, the behavioral effect of a diet with berberine linearly decreased until it vanished in 15 – 18 hours. Researches to assess the effect of berberine on various associated behavioral and physiological traits in mammals and in humans are still needed in order to draw a complete safety profile of this substance.
... For example, berberine, a compound found in several plants including Berberis vulgaris and Coptis chinensis, has been shown to possess anti-obesity and anti-diabetic properties (Liu et al., 2011). Inn a randomized double-blind placebo-controlled study of berberine supplementation improved glucose metabolism and insulin sensitivity in patients with Type 2 diabetes (Yin et al., 2008). ...
... Another study showed that berberine treatment improved glycaemia control and lipid metabolism in diabetic mice fed an HFD (Zhang et al., 2010). In a randomized controlled trial, berberine treatment significantly improved glycaemia control and lipid metabolism in patients with Type 2 diabetes (Yin et al., 2008). ...
Obesity and Type 2 diabetes are prevalent metabolic dysfunctions that present significant health challenges worldwide. Available cures for these ailments have constraints with accompanying unwanted effects that persistently exist. Compounds
originated from plants have recently been introduced as hopeful remedies to treat metabolic disorders because of their diverse pharmacological activities. This detailed observation gives an introduction into the treatment capacity of plant-derived compounds regarding metabolic syndromes while analyzing various groups alongside their performance in this field despite unique mechanisms designed by nature itself. Interestingly, this study provides some examples including curcumin, resveratrol, quercetin, berberine, epigallocatechin gallate (EGCG), and capsaicin, which highlights potential therapeutic impacts for future testing. However, current clinical trials inspecting human studies investigating efficacies concerning metabolism challenge present limitations. Finally, the review weighs up bad reactions possibly inflicted after administering plant-originated materials though suggestive insights will be provided later. Above all, it outlines the chance to identify novel therapies encapsulated within natural substances based upon recent developments could hold significant promise toward managing misplaced metabolisms globally.
... The entire efficacy rate reached up to 90%, with no major negative effects. 53 Yin et al. 54 evaluated the efficacy of berberine in patients with type-2 diabetes mellitus. They found that berberine was as effective as metformin in modulating glucose metabolism parameters, such as HbA1c (glycated haemoglobin), fasting blood glucose, post 2-h blood glucose, fasting insulin, and postprandial insulin. ...
... In addition, berberine can significantly reduce the HbA1c levels in diabetics. 54 Shah et al. 55 investigated the therapeutic potential of ethanolic extract derived from C. teeta roots in a rat model of diabetes induced by alloxan. Their findings revealed significant ameliorative effects in rats treated with the extract, demonstrating a halt in body weight loss, and notable reductions in food and fluid intake, serum glucose, serum urea, and serum creatinine levels. ...
Coptis teeta Wall. (C. teeta) is a herb that goes by the name “Mishmi Tita”, and holds significant value as a medicinal plant for treat
ing various health conditions. This endangered plant, listed in the Red Data Book, is commonly found in India, Nepal, Bhutan
and China. The present review aims to comprehensively summarize the traditional, pharmaceutical, and phytochemical aspects
of C. teeta, providing a foundation for researchers to explore this endangered plant, and take bold steps to conserve, cultivate, and
promote awareness among local people.
... metformin and buformin. Finally, berberine is a natural bioactive molecule with a variety of therapeutic effects, including anti-diabetic activity comparable to biguanide drugs [69]. ...
... metformin and buformin. Finally, berberine is a natural bioactive molecule with a variety of therapeutic effects, including anti-diabetic activity comparable to biguanide drugs [69]. Figure 6. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.
... The entire efficacy rate reached up to 90%, with no major negative effects. 53 Yin et al. 54 evaluated the efficacy of berberine in patients with type-2 diabetes mellitus. They found that berberine was as effective as metformin in modulating glucose metabolism parameters, such as HbA1c (glycated haemoglobin), fasting blood glucose, post 2-h blood glucose, fasting insulin, and postprandial insulin. ...
... In addition, berberine can significantly reduce the HbA1c levels in diabetics. 54 Shah et al. 55 investigated the therapeutic potential of ethanolic extract derived from C. teeta roots in a rat model of diabetes induced by alloxan. Their findings revealed significant ameliorative effects in rats treated with the extract, demonstrating a halt in body weight loss, and notable reductions in food and fluid intake, serum glucose, serum urea, and serum creatinine levels. ...
Coptis teeta Wall. (C. teeta) is a herb that goes by the name “Mishmi Tita”, and holds significant value as a medicinal plant for treating various health conditions. This endangered plant, listed in the Red Data Book, is commonly found in India, Nepal, Bhutan and China. The present review aims to comprehensively summarize the traditional, pharmaceutical, and phytochemical aspects of C. teeta, providing a foundation for researchers to explore this endangered plant, and take bold steps to conserve, cultivate, and promote awareness among local people. A thorough literature search was conducted on PubMed, Google Scholar, Research Gate, SciFinder, and the ISI Web of Knowledge, using the following terms: “Coptis teeta”, “Coptis teeta Wall.”, “Mishmi tita”, “Rhizoma coptidis”, “Chinese medicine from Coptis teeta”, and “Traditional uses of Coptis teeta”. A comprehensive examination of 69 articles published between 1982 and 2023 was conducted to explore the properties and traditional applications of C. teeta. It was found that this plant and its active compounds exhibit a range of effects, such as fighting against microbes, alleviating diarrhoea, lowering blood pressure, regulating heart rhythm, reducing inflammation, improving mood, treating trachoma, managing diabetes, providing pain relief, and countering reactions. A total of 27 compounds were identified in different parts of this plant, according to the surveyed literature. These have been traditionally utilized to address ailments, including conditions, eye disorders, skin issues, gastrointestinal troubles like constipation and jaundice, and urinary disorders. Furthermore, these have shown potential in cancer treatment and mitigating inflammation. C. teeta boasts diverse traditional uses and promising pharmacological activities due to its rich chemical composition. Berberine is the main constituent, and various communities utilize it for various ailments. While endangered, C. teeta offers exciting medicinal potential, warranting further research and sustainable conservation efforts. Cultivating the plant and raising public awareness are crucial steps towards its preservation.
... Anti-trachoma action for eliminating Chlamydia trachomatis from the eye, and preventing symptom recurrence in the treatment of trachoma (58,91). Significant increase the glucose uptake in 3T3-L1 adipocytes in animals and humans (92,93), significantly reduce the HbA1c levels in diabetes (94). ...
Coptis teeta Wall., commonly known as Mishmi teeta, is a perennial herbaceous plant belonging to the Ranunculaceae family and is rich in various bioactive compounds. It is classified as endangered on the Red List and is endemic to the Eastern Himalayas in Northeast India, representing a valuable repository of traditional wisdom and ethno medicinal practices. This article compiles available data on C. teeta for the first time, drawing from classical Ayurveda texts, botanical floras and research databases. Since 3000 B.C., this "Goldthread" has been an integral part of Traditional Chinese Medicine (TCM) as Rhizoma coptidis. Through an extensive literature search, including online published reviews, research articles, and ethnomedicinal survey reports, it has been found that various tribes in Arunachal Pradesh, India, have utilized its potent therapeutic benefits for centuries to treat ailments such as gastrointestinal disorders, malaria, diabetes, eye disorders, infectious diseases, and more. The vivid pharmacological activities of C. teeta are primarily attributed to its alkaloids and other non-alkaloidal components, although limited preclinical work has been reported to date. The roots and rhizomes of C. teeta are rich in alkaloids such as berberine, jatrorrhizine, columbamine, epiberberine, coptisine and palmatine. These compounds play a significant therapeutic role in managing various ailments, including diabetes and cardiovascular diseases. They possess anti- inflammatory and analgesic properties, offer neuroprotective effects, aid in metabolic regulation and exhibit antimicrobial activity. Additionally, this review discusses the extensive trade benefits of C. teeta, the reasons for its threatened status, and various practical approaches for its conservation and cultivation. By bridging ethnomedicinal knowledge with scientific modernization through a multidisciplinary research approach, this review aims to unlock the hidden treasures of C. teeta and encourage further pharmacological research and standardization.
... Extracted from the roots, stems, and bark of certain plants, berberine has received a lot of attention in recent years for its health benefits and extensive research. In this article, we explore the sources of berberine in various herbs and explore the evidencebased health benefits of this potent ingredient, backed by scientific research [65][66][67][68][69][70] . ...
Polycystic Ovarian Disorder is among the most well-known hormonal diseases influencing many women overall prompting the development of cysts on the ovaries. Albeit, the specific ground for its improvement isn’t very much revealed till now, however a mix of hereditary, ecological and way of life factors were considered as noticeable contributing variables for its development and advancement. The ongoing treatments for polycystic ovarian disorder incorporate a way of life alteration, utilization of oral contraceptives, anti-androgen therapy and insulin-sensitizing agents, ovulation induction and assisted reproductive technologies. Even though these ongoing treatments are well dependent to some degree in females enduring polycystic ovarian issues, various secondary effects are being accounted for to be related to these treatments. Herbal treatment could be an option for polycystic ovarian problems as it offers compelling recuperation with immaterial aftereffects. Herbal treatment frequently focuses on the main driver of the sickness instead of alleviating symptoms, expecting to re-establish general well-being and prosperity. In this ongoing review, we have compiled the purposes of specific spices for the treatment of polycystic ovarian disorders including cinnamon, fenugreek, gymnema, saw palmetto, spearmint, liquorice, turmeric and berberine - containing plants. These plants were accounted for too effective against polycystic ovarian disorder with their system of activity as portrayed. Escalated research on these plants will clear many new courses towards the advancement of medication disclosure and medication plans for the powerful treatment of polycystic ovarian issues.
... The pharmacological agent used was BBR, a natural cytoprotective phyto-compound that has been safely used in clinical studies of other disease conditions. 44 Although beneficial effects of BBR in animal models of MI were described previously, 34,36 the reported mechanism of benefit involved cytoprotection and immune modulation, and miR-24-3p expression was not measured. In a different biological setting, BBR was shown to stimulate miR-24-3p expression in lymphoblastic leukaemia cells. ...
Background and Aims
Cardiac fibrosis in response to injury leads to myocardial stiffness and heart failure. At the cellular level, fibrosis is triggered by the conversion of cardiac fibroblasts (CF) into extracellular matrix–producing myofibroblasts. miR-24-3p regulates this process in animal models. Here, we investigated whether miR-24-3p plays similar roles in human models.
Methods and Results
Gain– and loss–of–function experiments were performed using human induced pluripotent stem cell–derived cardiomyocytes (hCM) and primary hCF under normoxic or ischaemia–simulating conditions. hCM–derived extracellular vesicles (EVs) were added to hCF. Similar experiments were performed using three-dimensional human cardiac microtissues and ex vivo–cultured human cardiac slices.
hCF transfection with miR-24-3p mimic prevented TGFβ1–mediated induction of FURIN, CCND1 and SMAD4—miR-24-3p target genes participating in TGFβ1–dependent fibrinogenesis —, regulating hCF–to–myofibroblast conversion. hCM secreted miR-24-3p as EV cargo. hCM–derived EVs modulated hCF activation. Ischaemia–simulating conditions induced miR-24-3p depletion in hCM-EVs and microtissues. Similarly, hypoxia downregulated miR-24-3p in cardiac slices. Analyses of clinical samples revealed decreased miR-24-3p levels in circulating EVs in acute myocardial infarction (AMI) patients, compared with healthy subjects. Post-mortem RNAScope analysis showed miR-24-3p downregulation in myocardium from AMI patients, compared with patients who died from noncardiac diseases. Berberin, a plant–derived agent with miR-24-3p–stimulatory activity, increased miR-24-3p contents in hCM-EVs, downregulated FURIN, CCND1 and SMAD4, and inhibited fibrosis in cardiac microtissues.
Conclusions
These findings suggest that hCM may control hCF activation through miR-24-3p secreted as EV cargo. Ischaemia impairs this mechanism, favouring fibrosis.
... Berberine is an alkaloid with a variety of pharmacological effects, including anti-inflammatory, antioxidant, and insulin sensitivity-improving actions (41,42). This study identified that the elevated expression of the berberine target gene BIRC5 across various tissues is associated with an increased risk of PCOS. ...
Background
Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder in women of reproductive age, is mainly ameliorated through drugs or lifestyle changes, with limited treatment options. To date, numerous researchers have found that fertility nutrient supplements may benefit female reproductive health, but their direct impact on polycystic ovary syndrome risk remains unclear.
Methods
Our research employs Mendelian Randomization to assess how fertility nutrients affect PCOS risk. Initially, we reviewed 49 nutrients and focused on 10: omega-3 fatty acids, calcium, dehydroepiandrosterone, vitamin D, betaine, D-Inositol, berberine, curcumin, epigallocatechin gallate, and metformin. Using methodologies of Inverse Variance Weighting and Mendelian Randomization-Egger regression, we examined their potential causal relationships with PCOS risk.
Results
Our findings indicate omega-3 fatty acids reduced PCOS risk (OR=0.73, 95% CI: 0.57-0.94, P=0.016), whereas betaine increased it (OR=2.60, 95% CI: 1.09-6.17, P=0.031). No definitive causal relations were observed for calcium, dehydroepiandrosterone, vitamin D, D-Inositol, and metformin (P>0.05). Drug target Mendelian Randomization analysis suggested that increased expression of the berberine target gene BIRC5 in various tissues may raise PCOS risk (OR: 3.00-4.88; P: 0.014-0.018), while elevated expressions of curcumin target gene CBR1 in Stomach and epigallocatechin gallate target gene AHR in Adrenal Gland were associated with reduced PCOS risk (OR=0.48, P=0.048; OR=0.02, P=0.018, respectively).
Conclusions
Our research reveals that specific fertility nutrients supplementation, such as omega-3 fatty acids, berberine, and curcumin, may reduce the risk of PCOS by improving metabolic and reproductive abnormalities associated with it.
... In a 12-week trial of adults with obesity, Hu et al. (2012) found that taking 500 mg of berberine three times a day reduced their body weight by an average of 5 kg (2.3 kg). It was reported that individuals lowered their body fat levels by up to 3.6% [8,9] . Meanwhile, the side effects of berberine assessed in a short-term clinical trial revealed that berberine produced relatively modest digestive symptoms, such as constipation, indigestion, and diarrhea [10] . ...
Diabetes mellitus is one of the most common disorders among all ages. There are two types of diabetes: type 1 and type 2. In type 1 diabetes there will be no insulin secretion therefore, the glucose molecules cannot be metabolized into energy and remain in the blood circulation, resulting in elevated blood glucose levels and a diabetic condition. In type 2 diabetes (T2D) the insulin receptors fail to respond to insulin production and metabolizing the intake of glucose molecules, which leads to diabetic conditions. Diabetes affects an extensive range of physiological and metabolic activities. Triglyceride levels in the blood are a significant indication of the occurrence of diabetes mellitus 2. Diabetes-2 is caused by an unhealthy dietary habit in day-today life. Drosophila, known as the Cinderella of genetics due to its genetic resemblance to humans, can be utilized as a model organism to construct the T2D prototype by feeding it with a high-sugar diet for a period. Because of its shorter life cycle and genetic similarities with humans, we can identify and test for physiological and biochemical alterations caused by the high sugar diet that is relative to humans. Berberine chloride, a bioactive molecule found in many edible plant materials, could regulate blood glucose levels and normalize physiological and biochemical abnormalities. It can be used as a medication to treat type 2 diabetes. As this molecule is not hazardous to insects, it can be used to treat HSD-induced flies and examine its potentiality for diabetic conditions. In this study, we investigate the anti-diabetic potential of berberine chloride on the HSD-induced Drosophila melanogaster. To check the protein-ligand interaction in the insulin signaling pathway bioinformatic tools (In-silico) were incorporated to predict the drug binding capacity in a specific site of the targeted protein. The significance of all the test data was verified by using statistical tools.
... As a traditional herbal medicine with antiinflammatory effects and the ability to improve insulin resistance, BBR has attracted significant attention for treating T2D (Guo et al., 2021). Additionally, compared to the popular diabetic drug metformin, BBR is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism (Yin, Xing, & Ye, 2008). For instance, Paul et al. (2019) reported that consuming BBR had a protective effect against platelet aggregation, apoptosis, and superoxide production by attenuating oxidative stress (Paul et al., 2019). ...
This study compared the capacity of two different models of HIIT [high‐(HC) and low‐(LC) compression], with or without the use of berberine (BBR), on NOD‐like receptor pyrin domain‐containing protein‐3 (NLRP3), H19, interleukin (IL)‐1β, high‐sensitivity C‐reactive protein (hs‐CRP), and insulin resistance markers. Fifty‐four middle‐aged men with overweight or obesity and prediabetes [fasting blood glucose (FBG) 110–180 mg/dL] were randomly and equally assigned to the HC, LC, HC + BBR, LC + BBR, BBR, and non‐exercising control (CON) groups. The HC (2:1 work‐to‐rest) and LC (1:1 work‐to‐rest) home‐based training programs included 2–4 sets of 8 exercises at 80%–95% HRmax, twice a week for 8 weeks. Participants in the berberine groups received approximately 1000 mg daily. All exercise interventions led to a significant reduction in hs‐CRP, IL‐1β, insulin, FBG, and insulin resistance index (HOMA‐IR) versus CON. Notably, there was a significant reduction in FBG and HOMA‐IR with the BBR group compared to the baseline. Both NLRP3 and H19 experienced a significant drop only with LC in comparison to the baseline. While both exercise protocols were beneficial overall, LC uniquely exhibited more anti‐inflammatory effects, as indicated by reductions in H19 and NLRP3. However, the addition of berberine to the exercise programs did not demonstrate additional benefits.
... Rutaceae, Berberis sp. (Cheng et al. 2022;Rauf, et al. 2021;Shabani et al. 2021;Song et al. 2020;Yin et al. 2008) has been reported to possess multiple pharmacological effects such as antioxidant, anti-inflammatory, anti-nociceptive, anti-HIV antitumor, antimicrobial, hepatoprotective, neuroprotective, hypolipidemic and hypoglycemic memory enhancement, antidepressant, effects (Shabani et al. 2021;Imenshahidi and Hosseinzadeh 2020;Tian et al. 2023;Akbar et al. 2021;Warowicka et al. 2020;Singh et al. 2019;Wang et al. 2017). It is also among the active ingredients used in Ayurvedic and Chinese medicine (Vuddanda et al. 2010;Kumar et al. 2015). ...
Antioxidant-rich supplementation plays an essential role in the function of mammals’ central nervous system. However, no research has documented the effect of berberine (BER) supplementation on the cerebrocerebellar function of prepubertal rats. The present study was designed to investigate the impact of BER supplementation on neurochemical and behavioural changes in prepubertal male rats. Five groups (90 ± 5 g, n = 7 each) of experimental rats were orally treated with corn oil or different doses of BER (25, 50, 100, and 200 mg/kg bw) from the 28th at 68 post-natal days. On the 69 days of life, animals underwent behavioural assessment in the open field, hanging wire, and negative geotaxis tests. The result revealed that BER administration improved locomotive and motor behaviour by increasing distance travelled, line crossings, average speed, time mobile, and absolute turn angle in open field test and decrease in time to re-orient on an incline plane, a decrease in immobility time relative to the untreated control. Furthermore, BER supplementation increased (p < 0.05) antioxidant enzyme activities such as SOD, CAT, GPx, GSH, and TSH and prevented increases (p < 0.05) in oxidative and inflammatory levels as indicated by decreases in RONS, LPO, XO, carbonyl protein, NO, MPO, and TNF-α compared to the untreated control. BER-treated animals a lessened number of dark-stained Nissl cells compared to the untreated control rats. Our findings revealed that BER minimised neuronal degeneration and lesions, improved animal behaviour, and suppressed oxidative and inflammatory mediators, which may probably occur through its agonistic effect on PPAR-α, PPAR-δ, and PPAR-γ – essential proteins known to resolve inflammation and modulate redox signalling towards antioxidant function.
... Berberine, the main active component of Coptis chinensis Franch (Ranunculales), an ancient Chinese herbal medicine, has been used for millennia to treat diabetes. An RCT conducted by Yin et al. (2008) involving 36 T2DM patients compared the effects of berberine with those of metformin. The study found that the efficacy of berberine in regulating glucose metabolism, including HbA1C, FPG, postprandial blood glucose (PBG), fasting insulin, and postprandial insulin, was comparable to that of metformin (p < 0.01). ...
Context
The global prevalence of type 2 diabetes mellitus (T2DM) has increased significantly in recent decades. Despite numerous studies and systematic reviews, there is a gap in comprehensive and up-to-date evaluations in this rapidly evolving field.
Objective
This review provides a comprehensive and current overview of the efficacy of Traditional Chinese Medicine (TCM) in treating T2DM.
Methods
A systematic review was conducted using PubMed, Web of Science, Wanfang Data, CNKI, and Medline databases, with a search timeframe extending up to November 2023. The search strategy involved a combination of subject terms and free words in English, including ‘Diabetes,’ ‘Traditional Chinese Medicine,’ ‘TCM,’ ‘Hypoglycemic Effect,’ ‘Clinical Trial,’ and ‘Randomized Controlled Trial.’ The studies were rigorously screened by two investigators, with a third investigator reviewing and approving the final selection based on inclusion and exclusion criteria.
Results
A total of 108 relevant papers were systematically reviewed. The findings suggest that TCMs not only demonstrate clinical efficacy comparable to existing Western medications in managing hypoglycemia but also offer fewer adverse effects and a multitarget therapeutic approach. Five main biological mechanisms through which TCM treats diabetes were identified: improving glucose transport and utilization, improving glycogen metabolism, promoting GLP-1 release, protecting pancreatic islets from damage, and improving intestinal flora.
Conclusions
TCM has demonstrated significant protective effects against diabetes and presents a viable option for the prevention and treatment of T2DM. These findings support the further exploration and integration of TCM into broader diabetes management strategies.
... BR exists as a yellowish isoquinoline alkaloid in certain plants, including Berberis ( Fig. 1) [12], which contains a high potential for blocking the growth of cancer cells [13]. According to related studies, BR is effective against type 2 diabetes and hypercholesterolemia [14,15]. Despite the mentioned advantages, certain drawbacks limited the application of BR in treatments such as poor aqueous solubility, slight absorption, and low bioavailability [16,17]. ...
As an antioxidative isoquinoline quaternary alkaloid, berberine (BR) is derived from certain types of plants, such as Berberis aristate, and despite its ability to inhibit cell proliferation, its poor aqueous solubility has limited its effectiveness in treatments. This study attempted to extract cellulose nanocrystals (CNCs) from ginger sticks to perform BR delivery and proceeded by characterizing the prepared CNCs and CNCs-BR by the results of DLS, TEM, FESEM, XRD, and FTIR. Moreover, various biophysical methods were used to investigate the interaction of BR-loaded CNCs with human serum holo-transferrin (HTF). The obtained outcomes confirmed the effectiveness of our spherical CNCs in reducing the size of the drug from 403.06 to 203.42 nm in CNCs-BR and consequently improving the solubility of BR. The XRD analysis approved the successful elimination of amorphous regions in cellulose, while the diminution of crystallinity index after the loading of BR indicated the occurrence of their interaction. The induced alterations in the functional groups and hydrophilicity enhancement of CNCs and CNCs-BR were displayed by FTIR. The fluorescence studies indicated the capability of CNCs-BR in interacting with HTF and quenching its fluorescence emission intensity through a static quenching process, which was revealed by the inverse correlation between Ksv values and temperature. In conformity to the results of synchronous fluorescence spectroscopy, CNCs-BR caused more changes in the vicinity of Trp residue in contrast to Tyr, while the FRET analysis determined the energy transfer between HTF and CNCs-BR to be 0.18, and their distance to be 2.41 nm. The drawn conclusion from these observations confirmed the suitability of CNCs as a carrier for BR along with their improved bioavailability caused by the effective interaction between HTF and BR-loaded CNCs. The results also showed that loading BR on CNCs not only improved its water solubility but also led to a sustained release behavior in a simulated gastrointestinal condition of the body.
Graphical abstract
... Despite these structural differences, both compounds are known to activate AMPK, a key regulator involved in various metabolic pathways related to diabetes [5]. Several studies have shown that berberine can act as a compound with good anti-hyperglycemic and antihyperlipidemic activities [15][16][17]. Pre-clinical tests and clinical trials on berberine compounds showed the good effects of berberine on cardiovascular, liver, and kidney diseases [5,18]. In addition to its antidiabetic properties, berberine also exhibits antioxidant and anti-inflammatory activities, distinguishing it from conventional antidiabetic medications [17,18]. ...
Diabetes mellitus (DM) is a metabolic disorder disease that causes hyperglycemia conditions and associated with various chronic complications leading to mortality. Due to high toxicity of conventional diabetic drugs, the exploration of natural compounds as alternative diabetes treatments has been widely carried out. Previous in silico studies have highlighted berberine, a natural compound, as a promising alternative in antidiabetic therapy, potentially acting through various pathways, including the inhibition of the FOXO1 transcription factor in the gluconeogenesis pathway. However, the specific mechanism by which berberine interacts with FOXO1 remains unclear, and research in this area is relatively limited. Therefore, this study aims to determine the stability of berberine structure with FOXO1 based on RMSD, RMSF, binding energy, and trajectory analysis to determine the potential of berberine to inhibit the gluconeogenesis pathway. This research was conducted by in silico method with molecular docking using AutoDock4.2 and molecular dynamics study using Amber20, then visualized by VMD.
Docking between ligand and FOXO1 receptor was carried out with Autodock4.2. For molecular dynamics simulations, the force fields of DNA.OL15, protein.ff14SB, gaff2, and tip3p were used.
... Shidfar et al. found that in diabetic patients, daily consumption of 3 g of barberry for 12 weeks led to signifcant reductions in FBS, insulin levels, HOMA-IR, TC, LDL-C, and TG levels while having no signifcant efect on HDL-C levels [22]. Te efcacy of berberine was evaluated in patients with T2D by Yin et al., who found signifcant reductions in FBS, HbA1c, and postprandial blood glucose (PBG) levels, suggesting that berberine has an efect similar to that of metformin [141]. In a study conducted by Di Pierro and colleagues, signifcant improvements in HOMA-IR and insulin levels were observed in patients who took berberine over a 90-day treatment period [142]. ...
Type 2 diabetes (T2D) is known as a major public health problem with a noticeable adverse impact on quality of life and health expenditures worldwide. Despite using routine multiple pharmacological and nonpharmacological interventions, including diet therapy and increasing physical activity, controlling this chronic disease remains a challenging issue, and therapeutic goals are often not achieved. Therefore, recently, other therapeutic procedures, such as using herbal products and functional foods as complementary or alternative medicine (CAM), have received great attention as a new approach to managing T2D complications, according to the literature. We reviewed the existing evidence that supports using various fundamental medicinal herbs, including cinnamon, saffron, ginger, jujube, turmeric, and barberry, as CAM adjunctive therapeutic strategies for T2D patients. The current review addressed different aspects of the potential impact of the abovementioned herbal products in improving glycemic indices and lipid profiles, including the effect size reported in the studies, their effective dose, possible side effects, herbs-drug interactions, and their potential action mechanisms.
... Type II diabetes mellitus is a growing epidemic characterized by insulin resistance, relative insulin deficiency, and islet β-cell failure. BBR can reduce HbA1c and fasting glucose levels in type II diabetes patients, and its efficacy and safety have been demonstrated in clinical trials (Yin et al., 2008). As an effective oral hypoglycemic agent, BBR can regulate glucose metabolism in vitro and in vivo, and its hypoglycemic effect is closely related to the regulation of insulin secretion and improvement of islet β cell function. ...
Background: Metabolic imbalance is the common basis of many diseases. As natural isoquinoline alkaloid, berberine (BBR) has shown great promise in regulating glucose and lipids metabolism and treating metabolic disorders. However, the related mechanism still lacks systematic research.
Aim: To discuss the role of BBR in the whole body’s systemic metabolic regulation and further explore its therapeutic potential and targets.
Method: Based on animal and cell experiments, the mechanism of BBR regulating systemic metabolic processes is reviewed. Potential metabolism-related targets were summarized using Therapeutic Target Database (TTD), DrugBank, GeneCards, and cutting-edge literature. Molecular modeling was applied to explore BBR binding to the potential targets.
Results: BBR regulates the whole-body metabolic response including digestive, circulatory, immune, endocrine, and motor systems through adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), sirtuin (SIRT)1/forkhead box O (FOXO)1/sterol regulatory element-binding protein (SREBP)2, nuclear factor erythroid 2-related factor (Nrf) 2/heme oxygenase (HO)-1, and other signaling pathways. Through these reactions, BBR exerts hypoglycemic, lipid-regulating, anti-inflammatory, anti-oxidation, and immune regulation. Molecular docking results showed that BBR could regulate metabolism targeting FOXO3, Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (Gpx) 4 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). Evaluating the target clinical effects, we found that BBR has the therapeutic potential of anti-aging, anti-cancer, relieving kidney disease, regulating the nervous system, and alleviating other chronic diseases.
Conclusion: This review elucidates the interaction between potential targets and small molecular metabolites by exploring the mechanism of BBR regulating metabolism. That will help pharmacologists to identify new promising metabolites interacting with these targets.
... Địa chỉ email: phamminhhuehup@gmail.com https://doi.org/10.25073/2588-1132/vnumps.4595 [6][7][8], khi sử dụng BBR dạng tự do đường uống với liều cao gây ra những tác dụng không mong muốn như: tiêu chảy, táo bón, đau bụng [9]. Độc tính của BBR nguyên liệu cũng đã được báo cáo trong một số nghiên cứu. ...
Berberine (BBR)-loaded liposomes have endogenous lipid-lowering and exogenous lipid-lowering, which are reported in our previous studies. However, the safety profile of BBR-loaded liposomes has not been disclosed. In this study, experiments were carried out to evaluate the potential toxicity of BBR-loaded liposomes through the methods of acute and sub-chronic oral administration in rats. Acute toxicity studies were conducted according to the Organization for Economic Cooperation and Development (OECD) guidelines No. 420 on female Wistar white rats for 14 days with a single dose of BBR-loaded liposomes equivalence with 2000 mg of BBR/kg body weight (b.w) for sighting study; 2000 mg of BBR/kg and 5000 mg of BBR/kg b.w for the main study. Sub-chronic toxicity studies were performed according to OECD guidelines No. 407 on Wistar white rats (both sexes) with daily oral doses of BBR-loaded liposomes equivalence with 150 mg, 450 mg of BBR/kg b.w for 28 days consecutively. The study results showed no signs of acute toxicity. In the sub-chronic toxicity study, there was no significant change in the general characters, body weight, and organ weights of the treated group of rats when compared to the control group of the same sex. Hematological, biochemical, and histological parameters also showed no toxic effects of BBR-loaded liposomes on rats. The overall findings of this study indicated that LD50 of BBR-loaded liposomes was above 5000 mg/kg; the doses of 150 mg and 450 mg of BBR/kg b.w could be considered safe doses of BBR-loaded liposomes for oral administration.
... Quantification was performed through the standard calibration process using the reference standard compound berberine chloride [57]. The main identified compound in the analyzed sample (AmexM) turned out to be BER (Figures 2-4), which has therapeutic uses [58] such as antioxidant [59], anti-inflammatory [60], antimicrobial, amebicidal/antihelminthic properties [44,61], as well as antineoplastic activity [56]. Similarly, methanol extracts and their partitions of A. mexicana have shown antimicrobial, antioxidant, antiparasitic [62], and cytotoxic potential [63]. ...
Argemone mexicana L. has been used in traditional Mexican medicine. Among its bioactive constituents, berberine (BER) has garnered attention for its cytotoxic properties against different tumor cell lines. This study investigates the in vitro toxicity against HEP-G2 (human hepatocellular carcinoma) and murine lymphoma (L5178Y-R) cells using the MTT assay of the methanol extract (AmexM), sub-partitions of A. mexicana, and BER. Selectivity indices (SIs) were determined by comparing their cytotoxic effects on VERO (monkey kidney epithelial) and PBMC (human peripheral blood mononuclear) non-tumoral cells. Additionally, the anti-hemolytic effect of these treatments was assessed using the AAPH method. The treatment with the most promising activity against tumor cells and anti-hemolytic efficacy underwent further evaluation for toxicity in Artemia salina and antioxidant activities using DPPH, ABTS, and FRAP assays. BER demonstrated an IC50 = 56.86 µg/mL in HEP-G2 cells and IC50 < 5.0 µg/mL in L5178Y-R cells, with SI values of 15.97 and >5.40 in VERO and PBMC cells, respectively. No significant hemolytic effects were observed, although AmexM and BER exhibited the highest anti-hemolytic activity. BER also demonstrated superior antioxidant efficacy, with lower toxicity in A. salina nauplii compared to the control. Additionally, BER significantly attenuated nitric oxide production. This study highlights the antiproliferative effects of A. mexicana, particularly BER, against HEP-G2 and L5178Y-R tumor cell lines, along with its selectivity towards normal cells. Furthermore, its anti-hemolytic and antioxidant potentials were demonstrated, suggesting that BER is a promising candidate for potent chemotherapeutic agents.
... Plants produce phytochemicals as pharmacologically active compounds for their own protection and survival, either through primary or secondary metabolism. Numerous research studies have revealed the bioactivity of phytochemicals in mitigating oxidative stress (Upadhyay & Dixit, 2015), boosting immunity, preventing hemolysis (Dubey et al., 2017), maintaining blood glucose levels (Yin et al., 2008), sustaining blood pressure, decreasing the risks of cardiovascular diseases (Krga & Milenkovic, 2019), preventing oxidative stress and inflammation (Serafini & Peluso, 2016), wound healing (Thangapazham et al., 2016), and assessing humans with carminative, antimicrobial, anti-inflammatory, antioxidation, antispasmodic, antiallergic, antiaging, anticancer, neuroprotective, hepatoprotective, hypolipidemic, hypotensive, immunomodulatory, and analgesic benefits (Gupta & Prakash, 2014). ...
There is a growing interest in standardizing the biocompatible, cost‐effective, and eco‐friendly manufacturing techniques for metallic nanostructures due to their widespread applications in the industrial and medical sectors. In recent decades, green synthesis has been proven as the most suitable technique for synthesizing metal nanoparticles. The present research study investigates the use of Cassia angustifolia (senna) leaves and Pistacia vera (Pistachio) nuts to prepare crude aqueous extracts, ethanolic extracts, and biogenic silver nanoparticles (AgNPs). The prepared aqueous extracts were used as reducing, stabilizing, and capping agents for the production of silver nanoparticles. These AgNPs were characterized by scanning electron microscopy (SEM), Fourier‐transform infrared spectroscopy (FTIR), and ultraviolet–visible (UV–Vis) spectroscopy. The outcomes validated the formation of stable AgNPs with bioactive functional components. In vitro antibacterial, anticancer, anti‐inflammatory, and antioxidant potentials were assessed by Kirby–Bauer disk diffusion test, MIC test, MBC test, MTT assay, BSA denaturation inhibition assay, and DPPH antioxidant assay, respectively. Results confirmed that the tested plant extract possesses a variety of bioactive compounds with various biological activities and is therapeutically effective. These findings verified that C. angustifolia and P. vera are promising bioresources for the synthesis of therapeutic extracts and nanostructures with commendable therapeutic potency.
... Our findings align with previously published literature. 18 BEE has demonstrated efficacy comparable to metformin in lowering blood glucose and managing type 2 diabetes, and notably, no specific side effects have been reported. Therefore, it could serve as an effective and safe complementary therapy for diabetic patients. ...
Metabolic disorders pose significant global health challenges, necessitating innovative therapeutic approaches. This study focused on the multifaceted therapeutic potential of berberine-enriched extract (BEE) in mitigating metabolic impairment induced by streptozotocin (STZ) in a rat model and compared the effects of BEE with berberine (BBR) and metformin (MET) to comprehensively evaluate their impact on various biochemical parameters. Our investigation reveals that BEE surpasses the effects of BBR and MET in ameliorating metabolic impairment, making it a promising candidate for managing metabolic disorders. For this, 30 male Wistar rats were divided into five groups (n = 6): control (CN), STZ, STZ + MET, STZ + BBR, and STZ + BEE. The treatment duration was extended over 4 weeks, during which various biochemical parameters were monitored, including fasting blood glucose (FBG), lipid profiles, inflammation, liver and kidney function biomarkers, and gene expressions of various metabolizing enzymes. The induction of metabolic impairment by STZ was evident through an elevated FBG level and disrupted lipid profiles. The enriched extract effectively regulated glucose homeostasis, as evidenced by the restoration of FBG levels, superior to both BBR and MET. Furthermore, BEE demonstrated potent effects on insulin sensitivity, upregulating the key genes involved in carbohydrate metabolism: GCK, IGF-1, and GLUT2. This highlights its potential in enhancing glucose utilization and insulin responsiveness. Dyslipidemia, a common occurrence in metabolic disorders, was effectively managed by BEE. The extract exhibited superior efficacy in regulating lipid profiles. Additionally, BEE exhibited significant anti-inflammatory properties, surpassing the effects of BBR and MET in lowering the levels of inflammatory biomarkers (IL-6 and TNF-α), thereby ameliorating insulin resistance and systemic inflammation. The extract's superior hepatoprotective and nephroprotective effects, indicated by the restoration of liver and kidney function biomarkers, further highlight its potential in maintaining organ health. Moreover, BEE demonstrated potent antioxidant properties, reducing oxidative stress and lipid peroxidation in liver tissue homogenates. Histopathological examination of the pancreas underscored the protective effects of BEE, preserving and recovering pancreatic β-cells damaged by STZ. This collective evidence positions BEE as a promising therapeutic candidate for managing metabolic disorders and offers potential benefits beyond current treatments. In conclusion, our findings emphasize the remarkable therapeutic efficacy of BEE and provide a foundation for further research into its mechanisms, long-term safety, and clinical translation.
... Однако эти побочные эффекты были временными, и большинство из них наблюдались только в первые 4 недели. К тому же, при снижении дозы BBR до 0,3 г три раза в день ни у одного пациента не наблюдалось побочных эффектов на желудочно-кишечный тракт [72]. ...
The article highlights the pharmacological activity of berberine, as well as its place in the treatment of the current epidemic - metabolic syndrome. The review examines the molecular mechanisms that allows achieving anti-inflammatory, antimicrobial and antioxidant effects in detail. Berberine’s pharmacological profile makes it possible to have a positive effect on the pathway of obesity, non-alcoholic fatty liver disease, dyslipoproteinemia, the intestinal microbiome and insulin resistance. In addition, the article reviews the main pharmacokinetic parameters and side effects of chemically unmodified berberine.
... The beneficial pharmacological actions of BBR in the management and/or treatment of metabolic disorders and CVDs have been well-acknowledged (Feng et al., 2019). In vitro, preclinical and clinical investigations revealed the benefits of BBR against diabetes, atherosclerosis, thrombosis, IHD, hypertension, stroke, arrhythmias, and insulin resistance (Feng et al., 2019;Yin et al., 2008). It exerted positive effects on carbohydrate and lipid metabolism in steatohepatitis in vivo (Zhao et al., 2017) and prevented lipolysis in adipocytes in vitro (Zhou et al., 2011). ...
Hyperlipidemia is a common clinically encountered health condition worldwide that promotes the development and progression of cardiovascular diseases, including atherosclerosis. Berberine (BBR) is a natural product with acknowledged anti-inflammatory, antioxidant, and metabolic effects. This study evaluated the effect of BBR on lipid alterations, oxidative stress, and inflammatory response in rats with acute hyperlipidemia induced by poloxamer-407 (P-407). Rats were pretreated with BBR (25 and 50 mg/kg) for 14 days and acute hyperlipidemia was induced by a single dose of P-407 (500 mg/kg). BBR ameliorated hypercholesterolemia, hypertriglyceridemia, and plasma lipoproteins in P-407-adminsitered rats. Plasma lipoprotein lipase (LPL) activity was decreased, and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was enhanced in hyperlipidemic rats. The expression of low-density lipoprotein receptor (LDL-R) and ATP-binding cassette transporter 1 (ABCA1) was downregulated in hyperlipidemic rats. BBR enhanced LPL activity, upregulated LDL-R, and ABCA1, and suppressed HMG-CoA reductase in P-407-administered rats. Pretreatment with BBR ameliorated lipid peroxidation, nitric oxide (NO), pro-inflammatory mediators (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon-γ, IL-4 and IL-18) and enhanced antioxidants. In addition, BBR suppressed lymphocyte ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) as well as NO and TNF-α release by macrophages isolated from normal and hyperlipidemic rats. In silico investigations revealed the binding affinity of BBR toward LPL, HMG-CoA reductase, LDL-R, PSK9, ABCA1, and E-NTPDase. In conclusion, BBR effectively prevented acute hyperlipidemia and its associated inflammatory responses by modulating LPL, cholesterolgenesis, cytokine release, and lymphocyte E-NTPDase and E-ADA. Therefore, BBR is an effective and safe natural compound that might be employed as an adjuvant against hyperlipidemia and its associated inflammation.
... Twenty patients (34.5%) reported temporary gastrointestinal adverse effects [8]. ...
MosawiNutritional supplements have been increasingly used in the prevention and treatment of a variety of chronic disorders including diabetes. Research evidence has been increasing suggesting the usefulness of several supplements including fenugreek, cinnamon, and lipoic acid in the management of diabetes.During the previous decades, berberines, a plant alkaloid that can be obtained from Rhizoma Coptidis and Coptis Chinensis Franch have been reported mostly by Chinese researchers to have beneficial effects in diabetes. This paper reviews the available evidence supporting the use of berberine in diabetes with the aim of providing expert opinion.Expert opinion: The available evidence suggests that berberine has anti-diabetic effects through improving insulin secretion and it can also improves lipids profile. Berberine has been reported to have pancreatic β-cells protective and can increase peripheral tissues insulin sensitivity. It can also stimulate glycolysis, and thus it can improve insulin resistance. In addition, it can inhibit intestinal α-glucosidase and reducing absorption of glucose decrease. However, the available evidence research also suggests the usefulness of several other supplements including fenugreek, cinnamon, and lipoic acid in the management of diabetes. Therefore, the choice of diabetic supplement depends to some extent on the availability and cost. It seems that berberine is the most available and cost effective diabetic supplement in China, however, it is not in other counties in the world including Iraq.
... Depression, however, is not associated with insulin resistance, still association of insulin resistance with oxidative stress can make berberine a potential candidate [43]. In a preclinical study, it protects against apoptosis and oxidative damage [44]. ...
Depression is a psychiatric disorder characterized by low self-esteem, social detachment, mood swings, and lost interest in life, which can finally lead to suicidal tendencies. The neurochemicals such as serotonin, dopamine, oxytocin, etc., present in the brain regions of cerebral cortex, hippocampus, hypothalamus, amygdala, olfactory bulb, etc., play the major role in regulating the mood and mental health. In addition, certain biochemical and molecular pathways have also been widely reported to influence the depressive pathology and symptoms. Some of these include oxidative stress, neuroinflammation, and angiogenesis. Oxidative stress can arise due to mitochondrial dysfunction and generation of reaction oxygen species. Besides, neuroinflammation can be due to inflammatory markers or several other inflammatory pathways either generated peripherally or centrally. The phenomenon of angiogenesis generally deals with blood and blood vessel formation which could be protective in depression. Since, currently available drugs give only symptomatic relief and are associated with adverse events. Hence, in this current chapter, these novel pathways were mainly explored, and some potential agents or drugs can target these pathways to alter or modify the depression havoc, thereby minimizing the complications associated with this life-threatening disease. Moreover, few of the drugs already used in some other diseases involving these pathways were also depicted to be repurposed in depression. Conclusively, this content will give further exploration in the attempt to find out new strategies for therapeutic option of depression which are lacking in conventional drugs.
Lung cancer is the most fatal cancer worldwide. The etiology of lung cancer has yet to be fully characterized. Smoking and air pollution are several risk factors for lung cancer. Berberine, an isoquinoline alkaloid, is an antihyperglycemic, antidepressant, antioxidative, anti‐inflammatory, and anticancer compound. Evidence substantiates that berberine has antitumor effects, exerting its effects by targeting a variety of cellular and molecular processes, such as apoptosis, autophagy, cell cycle arrest, migration, and metastasis. Although the beneficial effects of berberine have been reported, some limitations including low bioavailability and absorption as well as poor aqueous solubility have hindered its clinical application. Nanotechnology and nanodelivery bioformulation approaches may bypass these limitations. In addition, the combination of berberine with other therapies has been shown to result in greater treatment efficacy for lung cancer. Herein, we summarize cellular and molecular pathways that are affected by berberine, its clinical efficacy upon various combinations, and the potential for nanotechnology in lung cancer therapy.
Herbs for Disease Prevention and Treatment offers a comprehensive exploration of the therapeutic potential of herbs and their bioactive compounds in preventing and managing various diseases. This book delves into the use of marine macroalgae in diabetes management, the role of herbal supplements and nutraceuticals in disease prevention, and the application of herbs as dietary medicine. It also covers traditional medicinal plants, the historical and contemporary use of herbal medicine, and innovative techniques like GC-MS and LC-MS-MS for identifying phytochemicals effective against COVID-19. Additionally, it includes a review of the impact of repeated heating on plant edible oils and explores plant-based treatments for kidney diseases. Aimed at healthcare professionals, researchers, and students in the fields of herbal medicine, pharmacology, and nutrition, this book serves as an essential resource for understanding the role of herbs in modern healthcare.
This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses.
Neuroblastomas are the most common solid tumors outside of the brain that originate from immature neural crest cells, accounting for about 10% of all pediatric malignancies. The treatment for neuroblastomas involves a multimodal schedule, including surgery, radiation, chemotherapy, and immunotherapy. All these modalities are limited by side effects that might be severe, poor prognosis, and a high risk of recurrence. In the quest for additional therapeutic approaches, phytochemicals have attracted attention owing to their reported antitumor properties, safety, and multimechanistic mode of action. Several studies have used plant‐derived bioactive compounds such as phenolics and flavonoids, suggesting modulation of biomolecules and signal transduction pathways involved in neuroblastoma. We reviewed the findings of recent preclinical and clinical studies demonstrating the effects of phytochemicals on neuroblastoma, shedding light on their molecular mechanism of action and potential therapeutic applications.
For many centuries, traditional medicine has played an essential role in health care. The treatment of many illnesses, including cancer, has greatly benefited from using herbal remedies derived from traditional medicine. The bioactive compounds, such as curcumin, silibinin, berberine, ginseng, and others present in traditional medicine have shown a wide range of properties, such as anti-inflammatory, antimicrobial, anti-oxidant as well as potent anti-cancer properties both in laboratory studies and animal experiments (in vitro and in vivo). In this review, we mainly emphasized the anticancer role of bioactive compounds present in traditional medicine, such as curcumin, cardamonin, piperine, berberine, ginseng, silibinin, epigallocatechin gallate, and asafoetida. We also discussed molecular evidence of these compounds in chemoprevention and anticancer effects. These compounds have the potential to interfere with cancer growth, proliferation, metastasis, and angiogenesis and induce apoptosis by targeting different pathways and the cell cycle. This review article also focuses on how these compounds can help overcome drug resistance and enhance the availability of other clinically approved drugs. The usage of these compounds synergistically with other forms of treatment is also of great fascination to new and upcoming research. Finally, we have discussed the bioavailability of these compounds and strategies employed to improve them so their full potential can be exploited.
Berberine (BBR), which is a widely used isoquinoline alkaloid derived from natural resources, exhibits aggregation-induced emission (AIE) characteristics and biological applications such as selective lipid droplet imaging and photodynamic therapy....
According to 2021 statistics, 29.7 million people in the US and 537 million people worldwide suffer from diabetes. New therapies are constantly being investigated due to the prevalence and severity of diabetes. Often, the latest therapies come in the form of prescription medications; however, dietary supplements could also provide benefits. This Systematic Review (SR) & Meta-Analysis (MA) aims to evaluate Randomized Control Trials (RCTs) on berberine to provide an unbiased overview of its safety and efficacy in treating diabetes. Six RCTs were reviewed for the systemic review. Six articles were statistically analyzed for HbA1c (A1c) reduction, and four were analyzed for fasting plasma glucose (FPG) reduction in a meta-analysis. The results concluded that berberine reduces A1c with statistical significance as stand-alone or add-on therapy. Additionally, it did not significantly reduce FPG (p-value <0.6), but a positive trend was observed. With positive and minimal adverse effects, berberine may be beneficial in controlling diabetes.
Genus berberis, an evergreen shrub of about 500 plant species found in subtropical and temperate regions but only some of them are investigated and evaluated for their phytochemistry and bioactivity. These plants are spread worldwide and help in the nourishment of humans and animals. Almost all parts of the plant are investigated for pharmacological and phytochemical purposes, including, roots, fruits, stems, buds, seeds, branches, flowers, leaves, and whole plant. Rasaut, an extract of either the stem or root of Berberis aristata is mentioned in the ancient Ayurvedic literature of India for treating indolent ulcers and eye disorders, and B. vulgaris is still used to treat malaria in North America. They have many medicinal properties and compounds that are bioactive like berberine. Berberine possesses anticancer, antimicrobial, and other activities. The plants contain a number of alkaloids, tannins, flavonoids, carotenoids, terpenoids, and other categories of chemical constituents. The alkaloidal compounds are isolated and evaluated for various activities and are found to be active. The researchers are continuously working to get novel exploration regarding the Genus Berberis . Here in the review, traditional and folkloric uses of the genus were also described. Apart from this, they possess numerous activities like anticancer, antimicrobial, antioxidant, anti-inflammatory, antidiabetic, antiulcer, antiviral and, wound healing and many more. These activities were authenticated by in-vitro and in-vivo methods. The aim of this review is to update and systematically arrange information in one platform. In this review, we extracted the current information from Pubmed, Googlescolar, Scifinder and many more databases.
This review compiles diverse plant materials and their phytoconstituents, exploring their potential as antidiabetic agents. It aims to highlight recent advancements in the field, showcasing various plants and their bioactive compounds that have shown promise in managing diabetes.
Pharmacologically screened components from plants like Phyllanthus urinaria, Indigofera tinctoria, Trichosanthes kirilowii, Ziziphus jujuba, Curcuma longa, Gymnema sylvestre, Momordica charantia, Camellia sinensis (green tea), berberine-containing plants, quercetin sources, resveratrol-rich plants, and Allium genus extracts exhibit diverse mechanisms in regulating glucose metabolism. These mechanisms include enhancing insulin sensitivity, stimulating insulin secretion, inhibiting carbohydrate-digesting enzymes, and improving glucose uptake by cells.
Despite the potential benefits of these plant-derived compounds in managing diabetes, challenges arise when incorporating them into antidiabetic products, affecting attributes like color, taste, and texture. Thus, adjustments in processing parameters become essential for effectively integrating these materials into diabetic-friendly products. This review underscores the potential of plant-derived materials in diabetes management while acknowledging the need for further research to optimize their use in developing effective and palatable antidiabetic interventions.
The prevalence of diabetes has surged worldwide, necessitating innovative approaches to complement conventional therapies. Dietary supplements derived from natural sources have gained attention for their potential roles in diabetes management. This review delves into the pharmacognosy and pharmacological aspects of select dietary supplements commonly employed in diabetes care, including cinnamon, fenugreek, bitter melon, Gymnema sylvestre, and berberine. The review synthesizes clinical evidence supporting their efficacy in glycemic control, elucidates safety considerations, and navigates regulatory challenges. While clinical studies exhibit promising outcomes, variability in individual responses and product quality underscores the importance of personalized approaches and robust quality control measures. The review also explores future research directions, such as personalized therapies, enhanced standardization methods, and novel delivery systems. In conclusion, dietary supplements offer potential as adjuncts to diabetes management, but a comprehensive understanding of their pharmacological properties, safety profiles, and regulatory context is essential for optimizing their role in diabetes care.
Berberine is a promising bioactive compound that has gained great attention against numerous diseases but its low solubility and poor systemic bioavailability hinders its clinical applicability. Therefore, this study attempted to enhance the therapeutic potential of berberine by its nanoencapsulation. Berberine loaded guar-acacia gum nanocomplexes (Ber/Gu-AGNCs) were prepared by ionic complexation method; characterized and evaluated for anti-obesity activity in high fat diet (HFD) induced obese rats. HFD was given to animals for 6 consecutive weeks. Orlistat (20 mg/kg, p.o.), berberine (10 mg/kg), Ber/Gu-AGNCs (10 and 20 mg/kg, p.o) and Gu-AGNCs (blank) were administered once a day after giving HFD for 6 weeks; and continued up to 12 weeks along with HFD. Obesity was evaluated by the measurement of morphological parameters, blood glucose, serum lipid profiles, liver enzymes and levels of oxidative stress markers. Moreover, histopathological studies of liver and adipose tissue were also carried out. The results showed that Ber/Gu-AGNCs exhibited spherical morphology and narrow size distribution. In addition, Ber/Gu-AGNCs were significantly more effective in controlling the body weight, BMI, adiposity index, liver index, blood glucose levels, serum lipids and oxidative stress levels in comparison to berberine in HFD-induced obese rats. Furthermore, histopathological examination of liver and adipose tissue revealed the anti-obesity effect of Ber/Gu-AGNCs (10 and 20 mg/kg), as indicated by decrease in hepatosteatosis and inflammation in liver tissue; and decrease in the size of adipocytes in fat depots. Thus, nanoencapsulation of berberine into gum nanocomplexes displayed better anti-obesity activity when compared to free berberine.
Berberis vulgaris ( B. vulgaris or barberry) is a medicinal plant that has been used for various purposes in traditional medicine. Berberine is one of the main alkaloids isolated from B. vulgaris and other plants. Both B. vulgaris and berberine have shown anti‐inflammatory, antioxidant, and immunomodulatory effects in different experimental models and clinical trials. This review aims to summarize the current evidence on the mechanisms and applications of B. vulgaris and berberine in modulating inflammation, oxidative stress, and immune responses. The literature search was performed using PubMed, Scopus, and Google Scholar databases until August 2023. The results indicated that B. vulgaris and berberine could inhibit the production of pro‐inflammatory cytokines, such as tumor necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), interleukin 6 (IL‐6), and interleukin‐17 (IL‐17), and enhance the expression of anti‐inflammatory cytokines, such as interleukin 10 (IL‐10) and transforming growth factor‐β (TGF‐β), in various cell types and tissues. B. vulgaris and berberine can also scavenge free radicals, increase antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and reduce lipid peroxidation and DNA damage. B. vulgaris and berberine have been reported to exert beneficial effects in several inflammatory, oxidative, and immune‐related diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, allergic diseases, and infections. However, more studies are needed to elucidate the optimal doses, safety profiles, and potential interactions of B. vulgaris and berberine with other drugs or natural compounds.
Berberine (BBR) is a principal component of Rhizoma coptidis known for its therapeutic potential in treating diseases such as type 2 diabetes mellitus (T2DM) and obesity. Despite the trace levels of BBR in plasma, it’s believed that its metabolites play a pivotal role in its biological activities. While BBR is recognized to promote GLP-1 production in intestinal L cells, the cytoprotective effects of its metabolites on these cells are yet to be explored. The present study investigates the effects of BBR metabolites on GLP-1 secretion and the underlying mechanisms. Our results revealed that, out of six BBR metabolites, berberrubine (BBB) and palmatine (PMT) significantly increased the production and glucose-stimulated secretion of GLP-1 in GLUTag cells. Notably, both BBB and PMT could facilitate GLP-1 and insulin secretion and enhance glucose tolerance in standard mice. Moreover, a single dose of PMT could markedly increase plasma GLP-1 and improve glucose tolerance in mice with obesity induced by a high-fat diet. In palmitic acid or TNF[Formula: see text]-treated GLUTag cells, BBB and PMT alleviated cell death, oxidative stress, and mitochondrial dysfunction. Furthermore, they could effectively reverse inflammation-induced inhibition of the Akt signaling pathway. In general, these insights suggest that the beneficial effects of orally administered BBR on GLP-1 secretion are largely attributed to the pharmacological activity of BBB and PMT by their above cytoprotective effects on L cells, which provide important ideas for stimulating GLP-1 secretion and the treatment of T2DM.
Novel methylenedioxyphenyl-based amides, especially
N-(4-methoxybenzyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide
(MDC) and N-(3-acetylphenyl)-6-nitrobenzo-[1,3]-dioxole-
5-carboxamide (ADC), potential cardiovascular preventive agents,
are successfully synthesized, and their chemical structures are
verified by 1H and 13C NMR, Fourier transform infrared (FT-IR),
high-resolution mass spectrometry (HRMS), and single-crystal Xray
diffraction (SC-XRD) analyses. Data obtained from SC-XRD
reveal that MDC and ADC are both monoclinic molecules with Z =
2 and 4, respectively. From density functional theory (DFT)
calculations, 3.54 and 3.96 eV are the energy gaps of the optimized
MDC and ADC structures, respectively. MDC and ADC exhibit an
electrophilicity index value of more than 1.5 eV, suggesting that they can act as an electrophile, facilitating bond formation with
biomolecules. Hirshfeld surface analysis demonstrates that more than 25% of atomic interactions in both MDC and ADC are from
H···H interactions. Based on pharmacokinetic predictions, MDC and ADC exhibit drug-like properties, and molecular docking
simulations revealed favorable interactions with active site pockets. Both MDC and ADC achieved higher docking scores of −7.74
and −7.79 kcal/mol, respectively, with myeloperoxidase (MPO) protein. From docking results, MPO was found to be most
favorable followed by dipeptidyl peptidase-4 (DPP-4) and α-glucosidase (α-GD). Antioxidant, anti-inflammatory, and in vitro
enzymatic studies of MDC and ADC indicate that MDC is more selective toward MPO and more potent than ADC. The application
of MDC to inhibit myeloperoxidase could be ascertained to reduce the cardiovascular risk factor. This can be supported from the
results of computational docking (based on hydrogen bonding and docking score), in vitro antioxidant and anti-inflammatory
properties, and MPO enzymatic inhibition (based on the percentage of inhibition and IC50 values).
Berberine is a natural product with a wide range of pharmacological effects. It has antimicrobial, anti-cancer, anti-inflammatory, anti-hyperlipidemic, neuroprotective, and cholesterollowering properties, among others. It has been used in traditional Chinese and Ayurvedic medicine for 3000 years and is generally well-tolerated with few side effects. Its main drawback is low oral bioavailability, which has hindered widespread clinical use. However, recent interest has surged with the emergence of evidence that berberine is effective in treating cancer, diabetes, Alzheimer’s disease, and cardiovascular disease via multiple mechanisms. It enhances insulin sensitivity and secretion by pancreatic β-cells in Type 2 Diabetes Mellitus in addition to reducing pro-inflammatory cytokines such as IL-6, IL-1β, TLR4 and TNF-α. These cytokines are elevated in Alzheimer’s disease, cardiovascular disease, and diabetes. Reductions in pro-inflammatory cytokine levels are associated with positive outcomes such as improved cognition, reduced cardiovascular events, and improved glucose metabolism and insulin sensitivity. Berberine is a natural PCSK9 inhibitor, which contributes to its hypolipidemic effects. It also increases low-density lipoprotein receptor expression, reduces intestinal cholesterol absorption, and promotes cholesterol excretion from the liver to the bile. This translates into a notable decrease in LDL cholesterol levels. High LDL cholesterol levels are associated with increased cardiovascular disease risk. Novel synthetic berberine derivatives are currently being developed that optimize LDL reduction, bioavailability, and other pharmacokinetic properties.
The mechanism of action of berberine as an antihyperglycaemic agent was investigated in the Caco-2 cell line. Berberine was found to effectively inhibit the activity of disaccharidases in Caco-2 cells. It also decreased sucrase activity after preincubation with Caco-2 cells for 72 hours. However gluconeogenesis and glucose consumption of Caco-2 cells were not influenced. 2-Deoxyglucose transporting through Caco-2 cell monolayers was decreased by berberine but the effect was not statistically significant. These results suggest that the antihyperglycaemic activity of berberine is at least partly due to its ability to inhibit alpha-glucosidase and decrease glucose transport through the intestinal epithelium.
To explore the anti-diabetic effects of berberine and its influence on insulin secretion.
Impaired glucose tolerance rats induced by iv injection of streptozotocin 30 mg/kg were treated with berberine 187.5 and 562.5 mg/kg while fed with high fat laboratory chow. After rats were treated for 4 weeks, oral glucose tolerance was determined, and for 8 weeks, the fasting blood glucose, insulin, lipid series were determined. In insulin secretion experiments, berberine 93.75, 187.5, and 562.5 mg/kg was administered orally to BALB/c mice at a bolus. The murine serum was collected 2 h after the berberine administration for insulin determination. Insulin released from HIT-T15 cells and pancreatic islets incubated with berberine 1-100 micromol/L for 12 h was determined.
The levels of fasting blood glucose (7.4+/-1.5 or 7.3+/-1.3 vs 9.3+/-1.3 mmol/L), triglycerides (0.61+/-0.22 or 0.63+/-0.17 vs 1.8+/-0.7 mmol/L), total cholesterol (1.8+/-0.3 or 1.9+/-0.3 vs 2.2+/-0.2 mmol/L), free fatty acid (456+/-93 or 460+/-72 vs 550+/-113 micromol/L) and apolipoprotein B (0.37+/-0.02 or 0.42+/-0.05 vs 0.46+/-0.04 g/L) were reduced greatly in berberine-treated groups at doses of 187.5 and 562.5 mg/g/d, respectively as compared with those in control group (P<0.05 or P<0.01), whereas high density lipoprotein-cholesterol (1.5+/-0.3 or 1.4+/-0.3 vs 1.1+/-0.1 g/L), apolipoprotein AI (0.80+/-0.08 or 0.87+/-0.08 vs 0.71+/-0.06 g/L) were significantly increased (P<0.05 or P<0.01), and oral glucose tolerance was improved. In vitro experiment showed that berberine 1-10 micromol/L facilitated insulin secretion of HIT-T15 cells and murine pancreatic islets in a dose-dependent manner. Meanwhile murine serum insulin level (27.5+/-2.7 or 29+/-4 or 29+/-4 vs 24.3+/-2.8 pIU/L) was undoubtedly promoted and blood glucose (4.52+/-0.31 or 4.45+/-0.29 or 4.30+/-0.19 vs 4.87+/-0.21 mmol/L) was reduced after berberine administration at doses of 93.75, 187.5, and 562.5 mg/kg, respectively in the BALB/c mice.
Berberine possesses anti-diabetic effects, which is related to the property of stimulating insulin secretion and modulating lipids.
We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5' proximal section of the LDLR mRNA 3' untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.
Pioglitazone, metformin, and gliclazide lower HbA(1c) and fasting plasma glucose in patients with type 2 diabetes. We compared the effects of these three drugs, used as monotherapy and in combination, on postload glycemia and composite insulin sensitivity index (CISI) in these patients.
Postload glycemia and CISI were analyzed for 940 patients who had oral glucose tolerance tests (OGTTs) in four multicenter, randomized, double-blind, double-dummy, parallel group clinical trials (pioglitazone versus metformin, pioglitazone versus gliclazide, pioglitazone plus sulfonylurea versus metformin plus sulfonylurea, and pioglitazone plus metformin versus gliclazide plus metformin). Plasma glucose and insulin were determined during the 3-h OGTT performed at baseline and after 1 year of therapy. Incremental area under the curve for glucose was the surrogate for postload glycemia. CISI was calculated using the formula {10,000/ radical of [(fasting glucose x fasting insulin) x (mean glucose x mean insulin)]} during the OGTT.
In monotherapy, pioglitazone reduced postload glycemia and enhanced CISI more than metformin and gliclazide. In combination therapy, pioglitazone plus sulfonylurea reduced postload glycemia and increased CISI more than metformin plus sulfonylurea. Pioglitazone plus metformin also decreased postload glycemia and increased CISI more than gliclazide plus metformin.
Pioglitazone improves postload glycemia and CISI more than metformin or gliclazide when used as monotherapy or in combination therapy in patients with type 2 diabetes.
The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits cholesterol and TG synthesis in a similar manner to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-beta-ribofuranoside (AICAR). Significant increases in AMPK phosphorylation and AMPK activity were observed when the cells were incubated with BBR. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK, correlated with a subsequent increase in fatty acid oxidation. All of these effects were abolished by the mitogen-activated protein kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. These effects could account for the strong reduction of plasma TGs observed with this drug in clinical trials.
Berberine has been shown to have antidiabetic properties, although its mode of action is not known. Here, we have investigated the metabolic effects of berberine in two animal models of insulin resistance and in insulin-responsive cell lines. Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat-fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 3' kinase-independent manner, and reduced lipid accumulation in 3T3-L1 adipocytes. These findings suggest that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity.
Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C2C12 myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3-O-methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser307/312), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for > or =16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.
Although low-density lipoprotein (LDL)-cholesterol lowering with the statins reduces the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Berberine upregulates the LDL receptor (LDLR) by a mechanism distinct from that of the statins, which involves stabilising the LDLR mRNA. In hamsters fed a high-fat and high-cholesterol diet for 2 weeks, the oral administration of berberine 100 mg/kg for 10 days reduced total serum cholesterol from &SIM; 4.8 to 2.7 mmol/l, and LDL-cholesterol from &SIM; 2.5 to 1.4 mmol/l. In subjects with hypercholesterolaemia, berberine hydrochloride (0.5 g b.i.d. for 3 months) reduced LDL-cholesterol (from 3.2 to 2.4 mmol/l) without any effect on high-density lipoprotein-cholesterol. Berberine also caused a reduction in triglyceride levels from 2.3 to 1.5 mmol/l. As berberine and statins both upregulate LDLR, their lipid-lowering profiles are similar. Thus, this mechanism is unlikely to make berberine an attractive alternative to statins for lipid lowering in most circumstances. However, the other effects of berberine (anti hypertensive, inotropic and class III antiarrhythmic properties) may make it a useful agent in the treatment of cardiovascular disease.
Although low-density lipoprotein (LDL)-cholesterol lowering with the statins reduces the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Berberine upregulates the LDL receptor (LDLR) by a mechanism distinct from that of the statins, which involves stabilising the LDLR mRNA. In hamsters fed a high-fat and high-cholesterol diet for 2 weeks, the oral administration of berberine 100 mg/kg for 10 days reduced total serum cholesterol from 4.8 to 2.7 mmol/l, and LDL-cholesterol from 2.5 to 1.4 mmol/l. In subjects with hypercholesterolaemia, berberine hydrochloride (0.5 g b.i.d. for 3 months) reduced LDL-cholesterol (from 3.2 to 2.4 mmol/l) without any effect on high-density lipoprotein-cholesterol. Berberine also caused a reduction in triglyceride levels from 2.3 to 1.5 mmol/l. As berberine and statins both upregulate LDLR, their lipid-lowering profiles are similar. Thus, this mechanism is unlikely to make berberine an attractive alternative to statins for lipid lowering in most circumstances. However, the other effects of berberine (antihypertensive, inotropic and class III antiarrhythmic properties) may make it a useful agent in the treatment of cardiovascular disease.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus (NIDDM) in the United States. Recently, however, metformin has been approved for the treatment of NIDDM.
We performed two large, randomized, parallel-group, double-blind, controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet (protocol 1: metformin vs. placebo; 289 patients), or diet plus glyburide (protocol 2: metformin and glyburide vs. metformin vs. glyburide; 632 patients). To determine efficacy we measured plasma glucose (while the patients were fasting and after the oral administration of glucose), lactate, lipids, insulin, and glycosylated hemoglobin before, during, and at the end of the study.
In protocol 1, at the end of the study the 143 patients in the metformin group, as compared with the 146 patients in the placebo group, had lower mean (+/- SE) fasting plasma glucose concentrations (189 +/- 5 vs. 244 +/- 6 mg per deciliter [10.6 +/- 0.3 vs. 13.7 +/- 0.3 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.6 +/- 0.2 percent, P < 0.001). In protocol 2, the 213 patients given metformin and glyburide, as compared with the 210 patients treated with glyburide alone, had lower mean fasting plasma glucose concentrations (187 +/- 4 vs. 261 +/- 4 mg per deciliter [10.5 +/- 0.2 vs. 14.6 +/- 0.2 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.7 +/- 0.1 percent, P < 0.001). The effect of metformin alone was similar to that of glyburide alone. Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia, as compared with 3 percent in the glyburide group and 2 percent in the metformin group. In both protocols the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations, whereas the values in the respective control groups did not change. There were no significant changes in fasting plasma lactate concentrations in any of the groups.
Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone.
To observe the effects of berberin on insulin sensitivity in high fat diet rats.
Before and after ingesting berberin, glucose insulin tolerance test was used to measure the insulin sensitivity, and determining fasting blood glucose, insulin, blood lipid and muscle triglyceride content.
Compared with normal feeding rats, high fat feeding impaired insulin action (5.02 +/- 1.08 vs 8.72 +/- 0.91, P < 0.005), decreased liver glycogen level and raised fasting blood glucose, insulin and blood lipid levels. Berberin and metformin improved insulin resistance (6.31 +/- 0.95 and 6.24 +/- 0.65) and liver glycogen level in insulin resistance models, but had no effect on blood glucose, insulin, lipid levels and muscle triglyceride depots.
It is confirmed that berberin could raise insulin sensitivity of high fat diet rats similar to metformin.
Four diacylated pelargonidin (Pg: SOA-4 and SOA-6), cyanidin (Cy: YGM-3), and peonidin (Pn: YGM-6) 3-sophoroside-5-glucosides isolated from the red flowers of the morning glory, Pharbitis nil cv. Scarlett O'Hara (SOA), and the storage roots of purple sweet potato, Ipomoea batatas cv. Ayamurasaki (YGM), were subjected to an alpha-glucosidase (AGH) inhibitory assay, in which the assay was performed with the immobilized AGH (iAGH) system to mimic the membrane-bound AGH at the small intestine. As a result, the acylated anthocyanins showed strong maltase inhibitory activities with IC(50) values of <200 microM, whereas no sucrase inhibition was observed. Of these, SOA-4 [Pg 3-O-(2-O-(6-O-(E-3-O-(beta-D-glucopyranosyl)caffeyl)-beta-D-glucopyranosyl)-6-O-E-caffeyl-beta-D-glucopyranoside)-5-O-beta-D-glucopyranoside] possessed the most potent maltase inhibitory activity (IC(50) = 60 microM). As a result of a marked reduction of iAGH inhibitory activity by deacylating the anthocyanins, that is, Pg (or Cy or Pn) sophoroside-5-glucoside, acylation of anthocyanin with caffeic (Caf) or ferulic (Fer) acid was found to be important in the expression of iAGH (maltase) inhibition. In addition, the result that Pg-based anthocyanins showed the most potent maltase inhibition, with an IC(50) value of 4.6 mM, and the effect being in the descending order of potency of Pg > Pn/Cy strongly suggested that no replacement at the 3'(5')-position of the aglycon B-ring may be essential for inhibiting iAGH action.
The action of berberine was compared with metformin and troglitazone (TZD) with regard to the glucose-lowering action in vitro. HepG2 cell line, phenotypically similar to human hepatocytes, was used for glucose consumption (GC) studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. In moderate high glucose concentration (11.1 mmol/L), GC of HepG2 cells was increased by 32% to 60% (P <.001 to P <.0001) with 5 x 10(-6) mol/L to 1 x 10(-4) mol/L berberine, which was comparable to that with 1 x 10(-3) mol/L metformin. The glucose-lowering effect of berberine decreased as the glucose concentration increased. The maximal potency was reached in the presence of 5.5 mmol/L glucose, and it was abolished when the glucose concentration increased to 22.2 mmol/L. The effect was not dependent on insulin concentration, which was similar to that of metformin and was different from that of TZD, whose glucose-lowering effect is insulin dependent. TZD had a better antihyperglycemic potency than metformin when insulin was added (P <.001). In the meantime, a significant toxicity of the drug to HepG2 cells was also observed. The betaTC3 cell line was used for insulin release testing, and no secretogogue effect of berberine was observed. These observations suggest that berberine is able to exert a glucose-lowering effect in hepatocytes, which is insulin independent and similar to that of metformin, but has no effect on insulin secretion.
To study the absorption characteristics of berberine and its influence on glucose absorption.
Rat recirculating perfusion model was used to study berberine absorption characteristics and Caco-2 cell model was used to explore the influence of berberine on disaccharidase, using HPLC to assay the appearance of glucose to indicate enzyme activities.
Berberine was found to be hardly absorbed in the intestine (less than 5% in 2.5 h). However, sucrase and maltase activities were found to be inhibited by berberine, its ID50 to sucrase is 1.830 mg.L-1, and showed no dose dependent influence on maltase activity. Berberine also showed influence on glucose absorption. However, this effect is not significant.
Berberine may act as an alpha-glucosidase inhibitor, which is its main mechanism in diabetes treatment.
Our preliminary study demonstrated that 70% ethanol Cortidis Rhizoma extracts (CR) had a hypoglycemic action in diabetic animal models. We determined whether CR fractions acted as anti-diabetic agent, and a subsequent investigation of the action mechanism of the major compound, berberine ([C(20)H(18)NO(4)](+)), was carried out in vitro. The 20, 40 and 60% methanol fractions from the XAD-4 column contained the most insulin sensitizing activities in 3T3-L1 adipocytes. The common major peak in these fractions was berberine. Treatment with 50 microM berberine plus differentiation inducers significantly reduced triglyceride accumulation by decreased differentiation of 3T3-L1 fibroblasts to adipocytes and triglyceride synthesis. Significant insulin sensitizing activity was observed in 3T3-L1 adipocytes which were given 50 microM berberine plus 0.2 nM insulin to reach a glucose uptake level increased by 10 nM of insulin alone. This was associated with increased glucose transporter-4 translocation into the plasma membrane via enhancing insulin signaling pathways and the insulin receptor substrate-1-phosphoinositide 3 Kinase-Akt. Berberine also increased glucose-stimulated insulin secretion and proliferation in Min6 cells via an enhanced insulin/insulin-like growth factor-1 signaling cascade. Data suggested that berberine can act as an effective insulin sensitizing and insulinotropic agent. Therefore, berberine can be used as anti-diabetic agent for obese diabetic patients.
Our recent studies identified berberine (BBR) as a novel cholesterol-lowering drug that upregulates low-density lipoprotein (LDL) receptor expression through mRNA stabilization. Here, we investigated mechanisms underlying regulatory effects of BBR on LDL receptor (LDLR) messenger.
We show that the extracellular signal-regulated kinase (ERK) signaling pathway is used primarily by BBR to attenuate the decay of LDLR mRNA in HepG2 cells. Using different reporter constructs, we demonstrate that BBR affects LDLR mRNA stability entirely through 3' untranslated region (UTR) in an ERK-dependent manner, and this stabilizing effect is more prominent in liver-derived cells than nonhepatic cell lines. In contrast to BBR, the mRNA stabilizing effect of bile acid chenodeoxycholic acid is mediated through the LDLR coding sequence, whereas the 5'UTR, 3'UTR, and the coding sequence of LDLR mRNA are all implicated in the action of phorbol 12-myristate 13-acetate. By performing UV cross-linking and SDS-PAGE, we identify 2 cytoplasmic proteins of 52 and 42 kDa that specifically bind to the LDLR 3'UTR in BBR-inducible and ERK-dependent manners.
These new findings demonstrate that the BBR-induced stabilization of LDLR mRNA is mediated by the ERK signaling pathway through interactions of cis-regulatory sequences of 3'UTR and mRNA binding proteins that are downstream effectors of this signaling cascade.
Much attention has been focused on food that may be beneficial in preventing diet-induced body fat accumulation and possibly reduce the risk of diabetes and heart disease. Cornelian cherries (Cornus mas) are used in the preparation of beverages in Europe and also to treat diabetes-related disorders in Asia. In this study, the most abundant bioactive compounds in C. mas fruits, the anthocyanins and ursolic acid, were purified, and their ability to ameliorate obesity and insulin resistance in C57BL/6 mice fed a high-fat diet was evaluated. Mice were initially fed a high-fat diet for 4 weeks and then switched to a high-fat diet containing anthocyanins (1 g/kg of high-fat diet) and ursolic acid (500 mg/kg of high-fat diet) for an additional 8 weeks. The high-fat diet induced glucose intolerance, and this was prevented by anthocyanins and ursolic acid. The anthocyanin-treated mice showed a 24% decrease in weight gain. These mice also showed decreased lipid accumulation in the liver, including a significant decrease in liver triacylglycerol concentration. Anthocyanin and ursolic acid treated mice exhibited extremely elevated insulin levels. Both treatments, however, showed preserved islet architecture and insulin staining. Overall, these data suggest that anthocyanins and ursolic acid purified from C. mas fruits have biological activities that improve certain metabolic parameters associated with diets high in saturated fats and obesity.
Berberine is the major active constituent of Rhizoma coptidis. The present study was carried out to investigate the effect of berberine on diabetes in rats and its possible mechanisms. Diabetes was induced by tail vein injection with alloxan in Wistar rats. The amount of alloxan administered was 55 mg/kg. Diabetic rats were fed with a high-cholesterol diet. The fasting blood glucose, total cholesterol (TC), triglyceride (TG) and low density lipoprotein-cholesterol (LDL-c), high density lipoprotein-cholesterol (HDL-c), nitric oxide (NO) levels in serum and malondialdehyde (MDA),superoxide dismutase (SOD),glutathione peroxidase (GSH-px) contents in heart tissue were assayed by spectrophotometry. Pancreas samples collected after 3 weeks of alloxan treatment were stained with hematoxylin-eosin (HE) and examined under a light microscope, and scored. Intragastric administration of berberine (100 and 200 mg/kg) significantly decreased fasting blood glucose levels, serum content of TC, TG, LDL-c, and effectively increased HDL-c, NO level in diabetic rats. Furthermore, berberine treatment significantly blocked the increase of MDA, increased SOD and GSH-px levels in diabetic rats. Histopathological scores showed that berberine had restored the damage of pancreas tissues in rats with diabetes mellitus. The results showed berberine significantly inhibited the progression of diabetes induced by alloxan, and the inhibitory effect of berberine on diabetes might be associated with its hypoglycemic effect, modulating lipids metabolic effects and its ability to scavenge free radical.
Berberine exerts a hypoglycemic effect, but the mechanism remains unknown. In the present study, the effect of berberine on glucose uptake was characterized in 3T3-L1 adipocytes. It was revealed that berberine stimulated glucose uptake in 3T3-L1 adipocytes in a dose- and time-dependent manner with the maximal effect at 12 hours. Glucose uptake was increased by berberine in 3T3-L1 preadipocytes as well. Berberine-stimulated glucose uptake was additive to that of insulin in 3T3-L1 adipocytes, even at the maximal effective concentrations of both components. Unlike insulin, the effect of berberine on glucose uptake was insensitive to wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and SB203580, an inhibitor of p38 mitogen-activated protein kinase. Berberine activated extracellular signal-regulated kinase (ERK) 1/2, but PD98059, an ERK kinase inhibitor, only decreased berberine-stimulated glucose uptake by 32%. Berberine did not induce Ser473 phosphorylation of Akt nor enhance insulin-induced phosphorylation of Akt. Meanwhile, the expression and cellular localization of glucose transporter 4 (GLUT4) were not altered by berberine. Berberine did not increase GLUT1 gene expression. However, genistein, a tyrosine kinase inhibitor, completely blocked berberine-stimulated glucose uptake in 3T3-L1 adipocytes and preadipocytes, suggesting that berberine may induce glucose transport via increasing GLUT1 activity. In addition, berberine increased adenosine monophosphate-activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation. These findings suggest that berberine increases glucose uptake through a mechanism distinct from insulin, and activated adenosine monophosphate-activated protein kinase seems to be involved in the metabolic effect of berberine.