Fitofarmacologia e aggiornamenti clinici sulle specie di Berberis contro il diabete e altre malattie metaboliche

Introduction

Diabetes mellitus (DM) is a metabolic disorder that is characterized by an abnormal long-term increase in plasma glucose levels. Diabetes is mainly classified into four types, i.e., type I diabetes (T1DM), type II diabetes (T2DM), gestational diabetes, and specific types of diabetes due to other causes ( ). Many factors, such as insulin deficiency or resistance as well as altered carbohydrate, protein, and fat metabolisms, are usually the reasons for high blood glucose levels leading to DM. Chronic hyperglycemia related to diabetes is often associated with many other complications, such as cardiovascular, dermatological, neurological, renal, retinal, and nerve diseases. Diabetes is one of the most common chronic disease, and it has shown an increasing rate of occurrence over the past decade ( ). According to the World Health Organization (WHO), the total number of people with diabetes worldwide substantially increased from 108 million in 1980 to 422 million in 2014 ( ). Along with diabetes, the incidence of other metabolic diseases, such as hyperlipidemia, is also increasing rapidly ( ).

Metabolic syndrome (MS) is associated with a group of disease conditions that occur together, and it is composed of central adiposity, hyperglycemia, hypertriglyceridemia, low high-density lipoproteins (HDL)-cholesterol, and hypertension. This disease cluster of diabetes and cardiovascular diseases is also known as “The Deadly Quartet”, “Syndrome X”, and “The Insulin Resistance Syndrome” ( ). Various treatment options are available to mitigate MS, including the diabetic condition and related disorders ( ). As MS is manifested by the cluster of diseases, use of a single drug candidate might not be able to provide necessary therapeutic effects. Plant extracts and isolated compounds can be possible options as adjuvants in such cases. Traditionally, various medicinal plants and their products (extracts and isolated compounds) have been used in the treatment of diabetes and hypertension ( ; ; ; ). Various research showed the protective/curative effect of plant extracts as a whole and/or an individual bioactive compound against diabetes and other metabolic diseases ( ; ).

Plants belonging to the genus Berberis (Family: Berberidaceae) are widely distributed worldwide with nearly 550 species. A decoction prepared from the roots of Berberis plants is one of the common traditional recipes for the treatment of diabetes ( ). Various studies have reported the traditional uses Berberis plants for the treatment of metabolic diseases (e.g., diabetes and hyperlipidemia) in many countries, including India, Pakistan, China, and Iran ( ; ; ; ). Various bioactive compounds, such as alkaloids, polyphenols, flavonoids, anthocyanins, etc., have been found in Berberis species along with various vitamins and mineral components ( ; ; ; ). Berberine (BBR), a quaternary ammonium salt belonging to a group of benzylisoquinoline alkaloids, is the most active compound reported from Berberis species, and it is considered to be highly effective against diabetes and other metabolic diseases ( ; ; ). BBR is also distributed in various plant species of other genera such as Coptis , Hydrastis , Mahonia , Tinospora , Xanthorhiza , and many others ( ). In the genus Berberis , the distribution of BBR and other alkaloids is mostly in its root part, followed by the stem bark and the stem itself ( ). In addition, its presence in trace amounts has been reported from leaves and berries. Various studies have been conducted to evaluate the effectiveness of Berberis extract or bioactive alkaloidal compounds against diabetes and other MS with promising results ( ; ; ; ). Moreover, various clinical trials were also conducted on testing their effectiveness against diabetes and other metabolic diseases and showed variable effects ( ; ).

Considering the Berberis species and their active alkaloidal components, the present review specifically focuses on their effectiveness against diabetes and other metabolic diseases. This review discusses various traditional uses of Berberis against metabolic diseases, along with its cell- and animal-model studies. The pharmacological effects of Berberis extracts and alkaloids against diabetes and other metabolic diseases are also discussed along with the molecular mechanism of action. Furthermore, based on the present studies of Berberis species against diabetes and metabolic diseases, research gaps were highlighted, and future recommendations were made.

Methodology

The scattered scientific information on Berberis species and isolated compounds used to counteract metabolic diseases was collected and documented. The synonyms of the various species were crosschecked with the plant name database The Plant List ( www.theplantlist.org , Retrieved on November 22, 2019). Afterwards, the available articles on respective species were retrieved using popular search engines and various databases, such as SciFinder, ScienceDirect, PubMed, Scopus, Mendeley, JOAP, Microsoft academic, and Google Scholar. The keywords used were Berberis , berberine, diabetes, metabolic diseases, metabolic syndrome, ethnopharmacology, ethnobotany, chemical constituents, alkaloids, in vitro , in vivo , clinical study, and clinical trials. The data were congregated through the Boolean information retrieval method by using a plant name along with an “AND” operator followed by diabetes and metabolic syndrome. No prerequisite limitations on publications, i.e., language, year, and publication type (original contribution, review article, or key editorial note), were taken into consideration.

Taxonomy and Ecology of Genus Berberis

According to The Plant List database ( www.theplantlist.org , retrieved on September 20, 2019), the family Berberidaceae consists of a total of 19 genera. The members of the genus Berberis are reported to be difficult to identify taxonomically due to their extreme morphological variation in relation to the environmental factors and natural hybridization ( ; ). Various overlapping morphological characters, such as flowers, leaves, stems, and berries—which also depend upon the season—and plant age also make it difficult to identify during field tasks ( ; ; ). Berberis species are widely cultivated around the world due to their high medicinal and ornamental value. Most members of the genus Berberis are reported to be tolerant to shade, resistant to drought, and widely distributed in open and wooded habitats and wetlands. These plants are also studied as indicators of habitat degradation in the temperate region due traditionally to their thorny stem and unpalatable shoots ( ). Representative photographs of some Berberis species from the Indian Himalayan Region (IHR) are shown in , and their major plant parts used to extract berberine and other bioactive alkaloids are shown in .

Ethnopharmacology of Berberis spp. Against Diabetes and Other Metabolic Diseases

A literature review revealed that the ethnopharmacological uses of Berberis species have been documented from different parts of the world for the treatment of diabetes, hypertension, and obesity, and some of them also revealed the formulation methods. A majority of Berberis species were found to be used in the Himalayan region of India and Pakistan.

B. lycium Royle has been used traditionally for the treatment of diabetes mellitus and other diseases, particularly by the local inhabitants of the Himalayan region ( ). Apart from diabetes, B. lycium is also used to treat bone fractures, diarrhoea, fever, intestinal colic, internal wounds, jaundice, menorrhagia, ophthalmic disorders, piles, rheumatism, sun blindness, and throat pain ( ; ). Fruits and leaves of B. lycium are also reported to be used for the treatment of diabetes mellitus in south-west of Iran ( ) and Pakistan ( ). The water extract obtained by soaking the root bark in water is used for the treatment of diabetes ( ). The whole plant is used to treat diabetes in Chamba district of Himachal Pradesh, West Himalaya, India ( ). The Bhotiya tribal community of the Central Himalayan region of India used B. lycium roots with water for the treatment of diabetes ( ).

The stem of B. aristata DC. is widely used in Indian traditional medicine for the treatment of diabetes ( ), which is also reported in Ayurvedic Pharmacopoeia. The decoction (5–10 mL) of roots or stems of this species prepared with water was taken twice a day for 1–2 weeks to treat diabetes in Uttarakhand region ( ). It is also used by Uttarakhand people for the treatment of hypertension ( ). The root, stem, and fruit also have been used to treat obesity ( ). B. asiatica is also used for the treatment of diabetes by the tribal communities of Chhota Bhangal, Western Himalaya, India. The decoction prepared from the roots is concentrated and dried in shade and then used with the sap of bitter guard for the treatment of diabetes ( ).

In Iranian traditional medicine, B. vulgaris L. is extensively used to treat diabetes and hypertension ( ). Local people use a decoction from the fruits and roots of B. vulgaris to treat hypertension ( ). The fruits are most frequently used in traditional and modern medicine ( ). Dried roots of B. crateagina DC. were recorded to be used as anti-diabetic agents locally in Turkey, and the decoction or infusion prepared from dried roots was taken orally one to two times a day for the treatment of diabetes ( ). The anti-diabetic activity has also been reported for B. brevissima Jafri and B. parkeriana C.K.Schneid. ( ). reported that the inhabitant of Urmia, Iran, use boiled and steamed B. integerrima Bunge extract for the treatment of diabetes.

Alkaloids From Berberis Species: Potential Compounds Against Metabolic Diseases

A large number of studies have been conducted on the isolation and quantification of bioactive compounds from Berberis species. The phytochemical investigations of the genus Berberis have shown the presence of more than 105 compounds with varying structural confirmations. Most of the studies on Berberis species are focused on phytochemical screening; for the presence and estimation of different secondary metabolites, such as alkaloids, flavonoids, steroids, sugars, triterpenoids, tannins, and other preliminary assays such as total ash content, acid soluble ash content, and moisture content ( ; ; ; ; ). However, the isolation and characterization of alkaloids from genus Berberis is well documented. Alkaloids are one of the major bioactive chemical constituents of the Berberis species, and they are responsible for various pharmacological activities of either whole extract or isolated individual compounds. Berberine (BBR) is one of the most commonly reported alkaloids from various Berberis species along with palmatine, magnoflorine, and jatrorrhizine, etc. ( ) ( ; ). Simple isoquinolone alkaloids are mainly reported from these species; however, studies have also reported their dimmers or dimeric benzylisoquinoline alkaloids ( ). The detailed list of different alkaloids isolated from various Berberis species are given in . Among other compounds, BBR and its various natural and synthetic derivatives have also been evaluated and found effective in prevention and treatment of MS ( ; ; ).

The effect of different habitat conditions (altitudinal variations and edaphic factors) of Berberis species has been investigated. investigated eight Berberis species from different altitudinal range for determining the BBR concentration in different parts. Among these, B. asiatica was found to contain higher content of BBR than other species. Lower altitudinal range was found to contain higher BBR content within a species as compared to high altitude habitat. Among plant parts, roots contained a higher concentration of BBR ( ). Similarly, variations in the BBR content of five Berberis species (i.e., B. aristata, B. asiatica, B. jaeschkeana, B. lycium , and B. pseudumbellata ) depending upon the habitat have also studied. The presence of higher BBR content was recorded from rocky habitats in B. jaeschkeana ( ). Both altitude and edaphic conditions were found to be responsible for the variation in BBR content in root and stem bark. Lower altitude populations showed significantly higher BBR content and positively correlated with moisture and potassium availability in soil species. Among these, B. asiatica contain significantly higher BBR content as compared to other species ( ) Seasonal variations in the BBR content revealed higher percentage in summer and lower in rainy season ( ). Low moisture and high soil potassium level is reported to be well correlated with high BBR content ( ).

In Vitro Activities Against Diabetes and Other Metabolic Diseases

It has been suggested that physical exercise and a proper diet can act as controllers of the cause of T2DM and metabolic diseases. Currently available pharmacological interventions can control many aspects of diabetes and metabolic diseases, like microvascular and macrovascular complications, hypertension, dyslipidemia, and obesity. However, there is also a need for novel therapeutic agents that work alone or in combination with currently available drugs. Within the pharmacological options, phytochemicals have a great potential to act against T2DM, MS, and associated complications ( ). Extracts of Berberis species and their components, especially alkaloids, have been documented for their potential activity against T2DM and MS in various in vitro studies ( ) ( )

Studies in mouse 3T3-L1 cells suggested that BBR has an pivotal role in regulating adipose tissues ( ). Experiments in mitochondria isolated from the liver of high-fat-fed rats have shown that BBR exhibited protective effects against MS that was associated with the increased mitochondrial sirtuin-3 (SIRT3) activity, normalizing mitochondrial function, and preventing a state of impaired oxidative phosphorylation (OXPHOS) that caused energetic deficit ( ). In the same way, the preventive effects of BBR on diet-induced insulin resistance (InsR) was suggested to be linked to sirtuin-1 (SIRT1) and mitochondrial biogenesis ( ). It has been suggested that BBR is a unique natural medicine against insulin resistance in T2DM and MS ( ). Different investigations have concluded that BBR as a new hypolipidemic drug works by a different mechanism of action to that of statin drugs ( ). BBR works on multiple molecular targets as an inhibitor of peroxisome proliferator-activated receptor (PPAR) γ and α and is a potential weight reducing, hypolipidemic, and hypoglycemic agent ( ). Prolonged activation of AMP-activated protein kinase (AMPK) by BBR improved CD36 expression in hepatocytes and was evoked in fatty acid uptake via processes associated with hepatocellular lipid accumulation ( ). Also, BBR improved insulin sensitivity (InsS) by inhibiting fat storage and adjusting the adipokine profile in human preadipocytes ( ). The hypoglycemic effects of BBR have also been attributed to its acute activation of the transport activity of glucose transporter 1 (GLUT1) ( ).

Numerous studies of BBR in in vitro models have shed light on its positive effect on T2DM. BBR promoted glucose uptake and inhibited gluconeogenesis by inhibiting SIRT3, and regulating the mitochondria-related pathways ( ). BBR treatment attenuated a palmitate-induced reduction in glucose uptake and consumption through a reduction in cellular diacylglycerol (DAG) levels and the accumulation of triacylglycerol (TAG) in H9c2 cells ( ). In addition, BBR displayed beneficial effects in the treatment of diabetes and obesity via stimulation of AMPK activity ( ). The mechanisms of action of BBR in treatment of T2DM are suggested to be different than that of metformin and rosiglitazone ( ). BBR, as an insulin signal activator, had shown insulin-mimicry effects through the inhibition of protein tyrosine phosphatase 1B (PTP1B) activity on both adipocytes and myocytes ( ) and acted as an effective insulin sensitizing and insulinotropic agent ( ). Moreover, BBR and metformin promoted glucose metabolism by stimulating glycolysis through the inhibition of mitochondrial respiratory chain complex I and independent of AMPK activation ( ). Besides, BBR circumvented the insulin signaling pathways and stimulated the glucose uptake through the AMP-AMPK-p38 MAPK pathway ( ). BBR modulated metabolism-related PPARs expression and differentiation-related positive transcription elongation factor b (P-TEFb) expression in adipocytes, which are associated with its hypoglycemic and hypolipidemic effects ( ). In addition, BBR upregulated LDL receptor expression through Ras-independent (but AMPK-dependent) Raf-1 activation in liver cells ( ). BBR and metformin induced glycolysis and glucose consumption but are not related to the AMPK status ( ).

Different natural and synthetic derivatives of berberine are also evaluated for their in vitro activities. A BBR derivative, thalifendine, showed upregulatory activities for both LDLR and InsR, proving to be a potential treatment of both hyperlipidemia and hyperglycemia ( ). Similarly, BBR amide derivatives improved the glucose-lowering effects ( ). Mannose-modified BBR derivative exhibited high anti-diabetic activity at both high and low drug concentrations ( ). Palmatine showed anti-diabetic activity mediated through an insulin-dependent pathway by the activation of IRTK and PI3K ( ). Pseudoberberine (pBBR) has exhibited a potential effect on AMPK activation and LDLR upregulation as compared with BBR ( ).

In the same way, the effects of extracts of species of the genus Berberis have been studied in several in vitro models and found effective. For instance, B. mycrophylla root extracts showed hypoglycemic effects and stimulated glucose uptake in HepG2 cells with and without resistance by activating AMPK protein ( ). B. aristata bark methanolic extracts also inhibited the dipeptidyl peptidase–IV (DPP-IV) enzyme activity ( ). B. vulgaris roots (ethanolic extract) and BBR showed α-glucosidase inhibition, where the inhibition caused by the extract was found to be higher than that of the BBR alone ( ), and the extract also showed α-amylase inhibition activity ( ).

Some of the mechanisms of Berberis species and BBR against diabetes and metabolic diseases are depicted in .

In Vivo Activities Against Diabetes and Metabolic Diseases

Extracts of Berberis species and their components, especially alkaloids, have been documented for their potential activity against T2DM and MS in in vivo models ( ). In the MS condition, BBR improved vascular inflammation and remodeling that was found to be correlated with the ability to inhibit p38 MAPK activation, ATF-2 phosphorylation, and MMP-2 expression ( ). Long-term treatment with BBR diminished the adipose tissue weight and decreased the renal injury (MS related diseases) in spontaneously hypertensive rats ( ). In normal diet-fed mice treated with BBR, hepatic CD36 expression and TG levels were increased; however, these effects were prevented when hepatic CD36 was silenced with an adenovirus containing CD36-specific short hairpin RNAs (shRNA) ( ). BBR also improved the insulin-mediated vasodilatation of mesenteric arteries in diabetic rats through upregulation of insulin receptor-mediated signaling and increasing vascular InsS ( ). Similarly, BBR increased both InsR and the low-density lipoprotein receptor (LDLR) expression, which resulted in a cellular response against InsR ( ). In hyperlipidemic hamsters, the cholesterol-lowering effect of BBR was found to be due to its activity on upregulation of hepatic LDLR ( ). Administration of BBR in hyperlipidemic and InsR rats decreased blood free fatty acid levels and increased the activity of lipoprotein lipase, leading to the amelioration of blood lipid and glucose metabolism ( ). BBR administration resulted in the decrease of fasting blood glucose (FBL) level and ameliorated glycogen structural fragility ( ). Furthermore, BBR displayed beneficial effects in the treatment of obesity, and this was in part via improvement of adipose tissue fibrosis ( ). BBR was reported to act in the liver to regulate lipid utilization and to maintain whole-body energy metabolism by mediating autophagy and FGF21 activation ( ). Additionally, BBR is also reported to reduce the systemic low-grade inflammation of T2DM mice to alleviate disease, and this effect may be achieved through regulating the gut microbes or inhibiting the TLR4 signaling pathway ( ). Other in vivo investigations also showed the hypoglycemic effects of BBR through the improvement in gut-derived hormones and the attenuation of both intestinal mucosal mechanic and immune barrier damages ( ). In the same way, the gut microbiota modulation was also suggested to be an effective mechanism of the antidiabetic effect of BBR ( ). The lipid-lowering effect of BBR chloride treatment in hyperlipidemic rats was found to be associated with a global change in the metabolism of lipids, carbohydrates, and amino acids as well as the structure of microbiota ( ).

On the other hand, BBR protects against metformin-associated lactic acidosis (MALA) in streptozotocin (STZ)-induced T2DM ( ). BBR attenuated hyperglycemia and its associated oxidative stress and inflammation through, possibly, the potentiation of the antioxidant defenses and upregulation of PPARγ expression ( ). BBR decreased 2-hour postprandial plasma glucose (2h-PPG) level in STZ-induced diabetic rats by locally inhibiting intestinal DPP-IV ( ). Moreover, BBR also reduced the blood glucose level in diabetic rats, improving the blood lipid and decreasing the retinal vascular injury, suggesting its association with the reduced expressions of Nrf2/HO-1 ( ). BBR also upregulated protein expressions of LKB1, AMPK, p-AMPK, and p-TORC2 and also inhibited the translocation of TOCR2 into the cell nucleus ( ). Moreover, BBR was also found to be effective in lowering blood glucose and lipid levels, reducing the body weight, and alleviating the oxidative stress in diabetic hamsters ( ).

The anti-diabetic effect of BBR was suggested to be mainly due to its activity in the regulation of glycometabolism and lipometabolism and the activation of AMPK ( ; ). BBR improved glucose metabolism through an insulin-independent pathway ( ). BBR also significantly inhibited the progression of diabetes induced by alloxan, and the effect of BBR on diabetes was suggested to be associated with its hypoglycemic effect, modulating lipids metabolic effects and its ability to scavenge free radicals ( ). BBR improved glucolipid metabolism in diabetic rats both in the blood and liver, possibly through modulating the metabolic related PPARα/δ/γ protein expression in liver ( ). BBR targeted MAPK to suppress Th17 and Th1 differentiation in T1DM NOD mice and showed a novel role of ERK in Th17 differentiation through downregulation of STAT3 phosphorylation and RORt expression ( ). Altered hepatic SREBPs, LXRα, and PPARα transcriptional programs were suggested to be involved in the therapeutic mechanisms of BBR on fat-induced hepatic insulin resistance (FIHIR) in T2DM hamsters ( ). The inhibitory effect on intestinal disaccharidases and β -glucuronidase of BBR might be one of the mechanisms for BBR as an antihyperglycaemic agent ( ). BBR caused the glucose metabolism modulation by the GnRH-GLP-1 and MAPK pathway in the gut ( ). The treatment of BBR chloride notably protected the blood components ( ) and significantly reversed the abnormal levels of lipids, oxidant status, and insulin signaling molecules in the diabetic rat model ( ). BBR also reduced the release of lipopolysaccharides and ameliorated inflammation by reducing the level of lipolysaccharide binding protein (LBP), thus alleviating intestinal injury and improving InsR ( ).

The combination of Ortosiphon staminensis , policosanol, red yeast rice extract, BBR, folic acid, and coenzyme Q 10 provided an antihypertensive effect, which allowed for an effective control of blood pressure in patients with MS ( ). The berberine-metformin hybrid compound BMH473 was found to be beneficial for maintaining glucose and lipid homeostasis in T2DM rats, and it exhibited better anthyperlipidaemic effects compared to metformin and BBR alone ( ).

Combining timosaponin B2 (TB-2) and BBR in a single formulation enhanced the anti-diabetic efficacy by improving the intestinal absorption ( ). Glycyrrhizic acid was also reported to improve the oral absorption of BBR by inhibiting P-gp, and it thus increased the anti-diabetic effects of BBR in db/db mice ( ). Lipid-lowering effects of BBR were also reported to be increased with resveratrol, which may be associated with upregulation of a low-density-lipoprotein (LDL) receptor ( ). Similarly, gelucire44/14 was found to enhance the oral absorption of BBR and thus improve the antidiabetic efficacy of BBR ( ). Berberine organic acids (BOAs) were found to be comparable to berberine hydrochloride (BH) in terms of hypoglycaemic effects, they were but superior with regard to safety from hyperchloraemia in T2DM rats ( ). Coptis chinensis (containing berberine) and BBR exerted similar effects when used for the treatment of T2MD rats, mainly via the stimulation of the pancreatic secretion of insulin ( ). Berberine chloride was a stronger antidiabetic agent than BBR or canagliflozin alone with fewer side effects on kidneys in the diabetic mice ( ). BBR and ginsenoside Rb1 (Rb1) improve abnormal metabolism of glucose and lipid ( ).

Extracts of Berberis plants have shown interesting results in in vivo models. The ethanolic extract of B. aristata showed antidiabetic activity due to its significant dose-dependent reduction effect on the blood glucose levels ( ; ), which were also reported to be better than glibenclamide ( ) and comparable to metformin in diabetic rats ( ). In addition, the aqueous extract of B. aristata showed significant antidiabetic activity, decreased total cholesterol, increased HDL-C levels, and prevented the body weight loss in diabetic rats ( ).

The aqueous extract of B. lycium roots showed an antihyperlipidemic effect ( ). B. lycium leaf extracts alleviated lipid profile levels and might be used efficiently in hyperglycemic and diabetic patients ( ). Also, the root extract of B. lycium reduced the serum glucose levels in normal and diabetic rats ( ). In chicken Broilers, the powder of B. lycium reduced the serum cholesterol ( ). The oral administration of extracts of B. lycium showed hypoglycemic activity ( ) and alleviated lipid profile levels ( ). Similarly, the methanolic extract of the B. lycium root and its main alkaloid BBR showed hypoglycemic activity ( ) and showed antiglycation activity ( ).

On the other hand, in diabetic rats, the beneficial effects of B. vulgaris extracts showed positive effects in attenuating the side effects of T2DM ( ), ameliorating oxidative stress ( ), decreasing the liver damage by influencing hepatic histopathological and biochemical markers ( ), and showed that the serum cholesterol and serum triglycerides levels were decreased ( ).

Other species of Berberis have also been studied. For instance, B. asiatica hydro-ethanolic root extracts have shown to be a potent orally effective antidiabetic extract ( ). Likewise, the B. dictyophylla cortex could significantly reduce the level of fasting blood glucose, ICAM-1, and ANG II expression ( ). The B. holstii extract showed the reduction of blood glucose levels ( ). Furthermore, the aqueous extract of B. integerrima roots improved renal dysfunction in STZ-induced diabetic rats through controlling blood glucose, and it also showed renal protective effects ( ). The anthocyanin fraction of the fruits of B. integerrima also showed hypoglycemic effects ( ). Moreover, the methanolic extract of B. julianae roots was also reported to possess promising beneficial effects for the treatment of T2DM with the possible mechanism via stimulating AMPK activity ( ).

Other alkaloids isolated from Berberis species have also shown promising activities against T2DM and MS. For example, berbamine increased the activity of metabolic enzymes and preserved the glucose homeostasis in HFD/STZ induced diabetic rats ( ). Jatrorrihizine (JAT) induced an important decrease in FBG in normal and hyperglycemic mice, attributed to improve in aerobic glycolysis ( ). JAT, BBR, and a combination of BBR and JAT decreased the FBG of diabetic and normal mice at different degrees. JAT also possessed the function of decreasing FBG, which was found less than that of BBR at the same dose level ( ). Palmatine was also found to decrease FBG and suppressed the increase of blood glucose level in normal rats ( ).

Studies in Humans

Several pilot studies as well as pre-clinical studies and clinical trials have evaluated the beneficial effects of Berberis extracts and isolated compounds on diabetes, metabolic syndrome, and other metabolic diseases ( ).

The administration of BBR in patients with MS was found to be effective in regulating the blood glucose and blood lipid levels, improving the InsR, and reducing the level of inflammatory responses in the body ( ). BBR also decreased the waist circumference, systolic blood pressure (SBP), triglycerides, and total insulin secretion along with an increase in InsS ( ). BBR was suggested as a promising new hypolipidemic drug that acts through signaling pathways distinct from those of statins in the treatment of hyper mild mixed hyperlipidemia patients ( ). Besides, BBR has been shown to have a good potential as a drug to control lipid metabolism alone or in combination with other drugs for hyperlipidemic hepatitis or liver cirrhosis patients ( ). Moreover, BBR improved the InsS by limiting fat storage and adjusting adipokine profile in human preadipocytes and MS patients ( ), and attenuated some of the metabolic and hormonal derangements in women with polycystic ovary syndrome (PCOS ( ). The administration of BBR was found to be effective in the regulation of blood glucose and blood lipid in T2DM patients ( ) and in improving diabetic kidney disease by reducing UACR and serum Cys C ( ). On the other hand, BBR had also shown glucose-lowering activity with a mechanism different from metformin and rosiglitazone ( ). In pilot study, BBR demonstrated a potent oral hypoglycemic activity with positive effects on lipid metabolism ( ). Also, the benefits of BBR in lowering blood glucose, lipids, body weight, and blood pressure have been confirmed in T2DM and MS patients ( ). BBR played an important role in the treatment T2DM through downregulating the higher levels of free fatty acids ( ). In another study, BBR reduced the fasting plasma glucose, post-meal blood glucose, and fructosamine; however, no signification changes were found in lipid profiles, fasting insulin, HOMA-IR, and HOMA-β% in T2DM patients ( ).

In addition, BBR improved the glycemic parameters comparable to metformin in T2DM patients ( ). BBR significantly ameliorated T2DM via modulation of Bifidobacterium species, TNF-α, and LPS ( ). BBR improved the blood lipid level in mild hyperlipidemia patients ( ). Likewise, it reduced the plasma LDL-C and TG in mixed hyperlipidaemic subjects ( ).

The combination of BBR and simvastatin (SIMVA) in hypercholesterolemic patients significantly improved LDL-receptor upregulation and LDL-cholesterol downregulation compared to monotherapies, and the combined effect also reduce the statins dosage ( ). The administration of BBR along with red yeast and policosanol on a daily basis was found to be effective in reducing cholesterol levels and was associated with the enhancement of endothelial function and InsS ( ). The administration of this supplementation in patients with familial hypercholesterolemia heterozygotes on stable treatment with LDL-C-lowering validated that the supplement reduced the LDL-C superior to that obtained by doubling the dose of statins ( ).

Also, the dietary supplement Armolipid Plus™ composed of BBR, red yeast rice, policosanol, folic acid, coenzyme Q 10 , and astaxanthin showed significant reduction of cholesterolemia and positive plasma LDL-C levels in elderly (statin-intolerant) hypercholesterolemic patients ( ). Moreover, it reduced LDL-C levels as well as total cholesterol/HDLc and ApoB/ApoA1 ratios, and it increased the Apo A1; tjos demonstrated the improvements in CVD risk indicators in patients with hypercholesterolemia ( ) and amelioration of blood lipids and significant reduction of global CVD risk in dyslipidemic patients ( ). In patients with low- to moderate-risk hypercholesterolemia, Armolipid Plus ™ in association with a hypolipidic diet significantly reduced the total cholesterol and LDL-C levels ( ). In addition, Armolipid Plus ™ improved the lipid profile similar to a low dose of a standard statin and also increased the HDL-C levels and improved the leptin-to-adiponectin ratio in patients with moderate dyslipidemia and MS ( ). Armolipid Plus™ alone or in combination with ezetimibe enhanced the lipid profile in statin-intolerant patients with coronary heart disease ( ). BBR and Armolipid Plus™ could be a useful alternative to correct dyslipidemias and to reduce CVD risk in subjects with moderate mixed dyslipidemias ( ).

Other food supplements containing BBR, including Body Lipid™, were suggested as an alternative to pharmacological treatment for patients with mild-to-moderate hypercholesterolemia ( ). A new nutraceutical formulation containing BBR, monacolin K, chitosan, and coenzyme Q 10 has proven effective in reducing non-HDL/LDL-C levels, representing an emergent therapeutic strategy in dyslipidemic patients ( ). On the other hand, the combination of BBR and isoflavones was found to be effective in lowering CVD risk factors in menopausal women with moderate dyslipidaemia ( ).

Treatment with BBR and rho iso-alpha acids, vitamin D3, and vitamin K1 produced a more favorable bone biomarker profile, indicative of healthy bone metabolism in postmenopausal women with MS ( ). In a case–control study, BBR is more effective in decreasing the serum MGO levels and InsR through increasing the glycemic control in newly diagnosed T2DM patients ( ). The intake of the natural formulation (containing BBR, orthosiphon, red yeast rice equivalent to monacolin, policosanol, folic acid, and coenzyme Q 10 ) has evidenced the effective control of plasma lipids and keeps borderline high blood pressure within normal values compared with diet alone ( ).

Stem powder of B. aristata was found to be effective in improving glycemic control and lipid profiles with no major adverse effects on T2DM patients ( ). The effect of B. vulgaris extract on T2DM and MS patients has been widely studied in humans. The intake of 3 g/d of B. vulgaris fruits aqueous extract for 3 months may have beneficial effects on lipoproteins, apoproteins, glycemic control, and TAC in T2DM patients ( ). B. vulgaris juice reduced oxidative burden in patients with MS ( ). Other study showed the beneficial effects of processed B. vulgaris on certain atherosclerosis risk factors in T2DM patients ( ). B. vulgaris fruit extract showed beneficial metabolic effects in T2DM patients, improving the glucose catabolism via the glycolysis pathway, stimulating the insulin secretion or improving the insulin function, and later decreasing the glucose uptake ( ). Another study demonstrated that the B. vulgaris juice evoked regulatory roles on HOMA-IR and improved HOMA-B with the metabolic controlling insulin-related indices in benign breast disease ( ). Also, B. vulgaris supplementation in patients with MS significantly diminished anti-HSPs 27 and 60 and hs-CRP levels and improved lipid profiles ( ). It is reported that the Hsp60 protein is able to induce the production of anti-Hsp60 antibodies, which leads to the destruction of β-islet cells. In the same way, Hsp60 acts as a proinflammatory signaling molecule, which plays a role in the non-resolved vascular inflammation, and this is recognized as one of the characteristic of T2DM ( ). Others natural formulations containing Berberis have also been tested in humans. A clinical trial demonstrated that daily intake of polyherbal capsule composed by B. aristata and Cyperus rotundus , Cedrus deodara , Emblica officinalis , Terminalia chebula , and T. bellirica decreased the glucose level, enhanced lipid homeostasis, and maintained other serum biochemical levels to the normal in patients with T2DM ( ).

The nutraceutical product Berberol ® , containing a B. aristata extract (titrated in 85% BBR) plus a Silybum marianum extract (titrated in 60% silymarin), has been evaluated for its antidiabetic potential in humans. Berberol ® was demonstrated to be more effective than BBR alone (administered at the same dose), reducing HbA1c in T2DM patients ( ). The incorporation of Berberol ® into insulin therapy in patients with T1DM has the effect of a diminution of the insulin dose necessary for adequate glycemic control ( ). In dyslipidemic patients, Berberol ® has proven to be safe and effective in improving lipid profile, InsR, and adipocytokines levels ( ). Berberol ® also improved the cholesterol-lowering properties of statins and showed the positive effects on liver enzymes and glycemic control in patients with T2DM ( ). In addition, Berberol ® significantly lowered abdominal adiposity and decreased the circulating uric acid level in overweight/obese patients with T2DM ( ). Berberol ® was suggested as a good candidate for an adjunctive treatment option in diabetes, especially in patients with suboptimal glycemic control ( ). Berberol ® administered as a single or add-on therapy in statin-intolerant subjects is an effective treatment to improve the lipidic and glycemic profiles in T2DM and hypercholesterolemia patients ( ). The combination of Berberol ® and a reduced dosage of statin is found effective for the treatment of hyperlipidemia in patients intolerant to statins at high dosage ( ) and in dyslipidemic euglycemic patients ( )

Berberol K ® , was found to be a potentially good alternative in primary intervention in low cardiovascular-risk subjects with dyslipidemia, as an add-on therapy in mildly statin-intolerant patients, and as an alternative for dyslipidemic patients with a negative perception of statins ( ). Berberol K ® reduced lipid profile effectively and improved the inflammatory parameters under a safe dose ( ). It was also found to be effective in diabetic subjects with dyslipidemia statin intolerant or with diarrhea caused by IBS or metformin ( ).

Few studies have also reported the effectiveness of BBR in non-alcoholic fatty liver disease (NAFLD). NAFLD is a result of abnormal fat accumulation in the liver due to the reasons other than alcohol, and it is considered to be a hepatic manifestation of MS. NAFLD results in the overproduction of sugars and triglycerides and plays a central role in the development of InsR and various other glucose- and lipid metabolism-related diseases ( ). Recently, conducted a randomized, parallel controlled, open-label clinical trial in 188 NAFLD patients. Patients received lifestyle intervention (LSI) or LSI and 15 mg of pioglitazone qd or LSI and of BBR for 16 weeks. Parameters, including hepatic fat content, serum glucose level, serum lipid profiles, liver enzymes, and serum and urine BBR concentrations, were measured before and after treatment. LSI and BBR showed a reduction in hepatic fat content as compared to LSI and were better than pioglitazone in reducing body weight and resulted in better lipid profiles ( ). Furthermore, a mechanism-based study revealed that BBR reduced hepatic TG accumulation and decreased the expressions of hepatic stearyl-coenzyme A desaturase 1 (SCD1) and other TG synthesis-related genes ( ). Berberine administration was also reported to recruit and activate BAT in both humans and mice ( ).

Conclusion

Although there are many effective therapeutic drugs for the treatment of metabolic diseases, the current treatment did not control the rapid increasing trend in diabetes mortality and morbidity. Various therapeutic agents from both natural and synthetic sources are being investigated in patients with clinical signs of diabetic and other metabolic diseases. Formulations prepared from the various plant parts of Berberis species were found to be used traditionally in the treatment of diabetes and other metabolic diseases and related complications. A review of the scientific literature revealed that the extracts, isolated alkaloids from Berberis species including BBR and their derivatives, have shown promising effects in the studies related to diabetes and other metabolic diseases. The relatively low cost of BBR or supplements or extracts containing BBR, compared to other synthetic medications, will be of an advantage to the patients living in developing countries with poor socioeconomic circumstances. However, currently available scientific evidence is still not fully sufficient to prove their efficacy clinically. Further randomized double-blind clinical trials with a large number of patients and standardized clinical assessments are required to prove the effectiveness of the Berberis extracts and isolated compounds on metabolic diseases alone or in combinations. Novel pharmacological assessment techniques and analytical techniques will further provide additional opportunities for these agents. Moreover, the development of novel formulations of berberine could be an effective strategy for increasing its effectiveness against diabetes and other metabolic diseases.

Author Contributions

TB, IB and JE conceptualized the manuscript. TB, AB, HD, HU, HK, IB and JE wrote the initial manuscript. TB, HD, HU, AP, IB and JE revised the manuscript. All authors agreed on the final version of the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.