Pancreatic beta cell protection/regeneration with phytotherapy

Azar Hosseini Reza Shafiee-Nick Ahmad Ghorbani About the authors

Abstracts

Although currently available drugs are useful in controlling early onset complications of diabetes, serious late onset complications appear in a large number of patients. Considering the physiopathology of diabetes, preventing beta cell degeneration and stimulating the endogenous regeneration of islets will be essential approaches for the treatment of insulin-dependent diabetes mellitus. The current review focused on phytochemicals, the antidiabetic effect of which has been proved by pancreatic beta cell protection/regeneration. Among the hundreds of plants that have been investigated for diabetes, a small fraction has shown the regenerative property and was described in this paper. Processes of pancreatic beta cell degeneration and regeneration were described. Also, the proposed mechanisms for the protective/regenerative effects of such phytochemicals and their potential side effects were discussed.

Diabetes mellitus/treatment; Diabetes mellitus/phytotherapy; Phytotherapy/Diabetes mellitus; Islets/endogenous regeneration; Beta cells/protection; Beta cells/regeneration; Pancreas; Medicinal plants/regenerative properties


Embora medicamentos disponíveis atualmente sejam úteis no controle de complicações da Diabetes, complicações aparecem em grande número de pacientes. Considerando-se a fisiopatologia do Diabetes, a prevenção da degeneração de células beta e o estímulo da regeneração endógena de ilhotas será abordagem essencial para o tratamento de diabetes mellitus insulino-dependente. A presente revisão aborda compostos fitoquímicos, cujo efeito é provado na proteção/regeneração de células beta de pâncreas. Entre centenas de plantas que têm sido investigadas para o diabetes, pequena fração tem mostrado propriedade regenerativa, que será descrita neste trabalho. Os processos de degeneração e de regeneração das células beta do pâncrease são descritos. Além disso, mecanismos propostos para efeitos de proteção e regeneração desses compostos fitoquímicos e seus possíveis efeitos colaterais também serão discutidos neste trabalho.

Diabetes mellitus/tratamento; Diabetes mellitus/fitoterapia; Fitoterapia/Diabetes mellitus; Ilhotas/regeneração endógena; Células beta/proteção; Células beta/regeneração; Pâncreas; Plantas medicinais/propriedades regenerativas


INTRODUCTION

Diabetes mellitus is still one of the most important causes of death and disability in both developed and developing countries. According to the report by World Health Organization (WHO, 2015WORLD HEALTH ORGANIZATION. WHO. Diabetes. Fact Sheet No. 312. Geneva, 2015. Available at: <http://www.who.int/mediacentre/factsheets/fs312/en/>. Accessed on: Jan, 2014.
http://www.who.int/mediacentre/factsheet...
), 9% of adults in the world suffer from diabetes and this disease will be the 7th leading cause of death in 2030. Generally, diabetes is classified into two main types: type 1 diabetes (T1D) and type 2 diabetes (T2D), which were previously known as insulin- and non-insulin-dependent diabetes, respectively. T1D results from pancreatic beta cell degeneration and is characterized by lack of insulin production, while patients with T2D show a state of insulin resistance and usually relative insulin deficiency. Over time, diabetic patients with poor management undergo micro- and macro-vascular complications including nephropathy, retinopathy, neuropathy, and cardiovascular diseases (Deshpande, Harris-hayes, Schootman, 2008DESHPANDE, A.D.; HARRIS-HAYES, M.; SCHOOTMAN, M. Epidemiology of diabetes and diabetes-related complications. Phys. Ther., v.88, p.1254-1264, 2008.).

At present, only insulin and oral antihyperglycemic drugs are available for T1D management (Lorenzati et al., 2010LORENZATI, B.; ZUCCO, C.; MIGLETTA, S.; LAMBERTI, F.; BRUNO, G. Oral hypoglycemic drugs: pathophysiological basis of their mechanism of action. Pharmaceuticals, v.3, p.3005-3020, 2010.). Although the currently available drugs are useful in controlling early onset complications of diabetes, serious late onset complications appear in a large number of patients (Tzoulaki et al., 2009TZOULAKI, I.; MOLOKHIA, M.; CURCIN, V.; LITTLE, M.P.; MILLETT, C.J.; NG, A.; HUGHES, R.I.; KHUNTI, K.; WILKINS, M.R.; MAJEED, A.; ELLIOTT, P. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. Brit. Med. J., v.339, p.b4731, 2009.). Considering the physiopathology of diabetes, preventing beta cell degeneration and stimulating the endogenous regeneration of islets will be essential approaches in treatment of diabetes.

Phytochemicals have always been an important source of remedies for human health problems. Numerous experimental and clinical studies have documented beneficial effects of phytotherapy for managing diabetes (Ghorbani, 2013aGHORBANI, A. Best herbs for managing diabetes: A review of clinical studies. Braz. J. Pharm. Sci., v.49, p.413-422, 2013a.,bGHORBANI, A. Phytotherapy for diabetic dyslipidemia: evidence from clinical trials. Clin. Lipidol., v.8, p.311-319, 2013b.). Antidiabetic effect of phytochemicals is mediated through different mechanisms such as decreasing glucose absorption from intestine, inhibiting glucose production in the liver, increasing glucose uptake by tissues, enhancing insulin secretion from beta cells, and/or increasing pancreatic tissue regeneration (Asgary et al., 2008ASGARY, S; PARKHIDEH, S; SOLHPOUR, S; MADANI, H,; MAHZOUNI, P; RAHIMI, P. Effect of ethanolic extract of Juglans regia L on blood sugar in diabetes-induced rats.J. Med. Food, v.11, p.533-538, 2008.; Kamyab et al., 2010KAMYAB, H.; HEJRATI, S.; KHANAVI, M.; MALIHI, F.; MOHAMMADIRAD, A.; BAEERI, M. Hepatic mechanisms of the walnut antidiabetic effect in mice. Cent. Eur. J. Biol., v.5, p.304-309, 2010.; Jelodar, Mohsen, Shahram, 2007JELODAR, G.; MOHSEN, M.; SHAHRAM, S. Effect of walnut leaf, coriander and pomegranate on blood glucose and histopathology of pancreas of alloxan induced diabetic rats. Afr. J. Trad. CAM., v.4, p.299-305, 2007.; Shafiee-Nick et al., 2011SHAFIEE-NICK, R.; PARIZADEH, S.M.R.; ZOKAEI, N.; GHORBANI, A. Effect of hydro-alcoholic extract of Vaccinium arctostaphylos on insulin release from rat-isolated langerhans islets. Koomesh, v.12, p.447-452, 2011.; Shafiee-Nick et al., 2012aSHAFIEE-NICK, R.; PARIZADEH, S.M.R.; ZOKAEI, N.; GHORBANI, A. Effects of Ganoderma lucidum hydroalcoholic extract on insulin release in rat-isolated pancreatic islets. Avicenna J. Phytomed., v.2, p.206-211, 2012a.). The current review focused on phytochemicals, the antidiabetic action of which has been proved, at least in part, by pancreatic beta cell protection or regeneration (Table I).

Table 1.
Phytochemicals with protective/regenerative effects on pancreatic beta cells.

Method of literature review

Review of the related literature was carried out in the databases of Google Scholar, Medline, and Scopus. The search terms included diabetes, islets, pancreas, plant, herb, and regeneration. Cross references of the related articles were also retrieved. Papers were included if they reported the effect of a plant or phytochemical agent on histopathological features of islets of Langerhans in diabetic animals. Two authors (A.G. and A.H.) independently searched the databases and extracted data from each article.

Pancreatic beta cell degeneration/regeneration

T1D is primarily considered as an autoimmune disease resulting from the reaction of immune effector cells with endogenous beta cell antigens. Gradual invasion of T-cells, macrophages, and the released cytokines and oxidative radicals lead to insulitis. The proinflammatory cytokines, especially tumor necrosis factor alpha, interferon gamma, and interleukine-1 beta activate intracellular pathways and lead to beta cell dysfunction, apoptosis, and necrosis. Because of poor intracellular antioxidant capacity, beta cells are vulnerable to oxidative stress. Therefore, oxidative molecules are important mediators of beta cell damage induced by both T1D insulitis and T2D glucotoxicity (Sharma et al., 2009SHARMA, V.; KALIM, S.; SRIVASTAVA, M.K.; NANDA, S.; MISHRA, S. Oxidative stress and coxsackie virus infections as mediators of beta cell damage: A review. Sci. Res. Essay, v.4, p.42-58, 2009.).

Many of the advances in the pathogenesis of T1D have emerged from animal studies. Streptozotocin (STZ) or alloxan-induced diabetic rat or mouse is the most currently used animal model for diabetes. A single intraperitoneal or intravenous injection of STZ is well reported to induce insulin-dependent diabetes in rats (Ghorbani et al., 2010GHORBANI, A.; VAREDI, M.; HADJZADEH, M.R.; OMRANI, G.H. Type-1 diabetes induces depot-specific alterations in adipocyte diameter and mass of adipose tissues in the rat. Exp. Clin. Endocrinol. Diabetes, v.118, p.442-448, 2010.; Ghorbani et al., 2013GHORBANI, A.; OMRANI, G.H.; HADJZADEH, M.R.; VAREDI, M. Proinsulin C-peptide inhibits lipolysis in diabetic rat adipose tissue through phosphodiestrase-3B enzyme. Horm. Metab. Res., v.45, p.221-225, 2013.; Shafiee-Nick et al., 2012bSHAFIEE-NICK, R.; GHORBANI, A.; VAFAEE, F.; RAKHSHANDEH, H. Chronic administration of a combination of six herbs inhibits the progression of hyperglycemia and decreases serum lipids and aspartate amino transferase activity in diabetic rats. Adv. Pharmacol. Sci., v.2012, p.789-796, 2012b.). The histologic feature of islets from the pancreas of diabetic animals is characterized by a severe decrease in the number of islets, inflammation, vacuolation of the islets, and degranulation of the beta cells (Adeyemi et al., 2008ADEYEMI, D.O.; KOMOLAFE, O.A.; ADEWOLE, S.O.; OBUOTOR, E.M.; ADENOWO, T.K. Effects of Annona Muricata (Linn) on the morphology of pancreatic islet cells of experimentally-induced diabetic Wistar rats. Internet J. Altern. Med., v.5, 2008.; Aralelimath, Bhise, 2012ARALELIMATH, V.R.; BHISE, S.B. Anti-diabetic effects of Gymnema sylvester extract on streptozotocin induced diabetic rats and possible β-cell protective and regenerative evaluations. Dig. J. Nanomater. Biostruct., v.7, p.135-142, 2012.). In addition, regular arrangement of alpha and beta cells is disturbed and clumping of beta cells, pyknosis, and necrosis are seen in the islets (Singh et al., 2008SINGH, N.; GUPTA, M.; SIROHI, P.; VARSH, A. Effects of alcoholic extract of Momordica charantia (Linn) whole fruit powder on the pancreatic islets of alloxan diabetic albino rats. J. Environ. Biol., v.29, p.101-106, 2008.).

The subject of pancreatic beta cell regeneration is one of the most controversial topics of T1D research and treatment. It is believed that beta cell can regenerate through the replication of pre-existing beta cells or neogenesis from stem cells and progenitor cells inside or outside the islets (Bouwens, Rooman, 2005BOUWENS, L.; ROOMAN, I. Regulation of pancreatic beta-cell mass. Physiol. Rev., v.85, p.1255-1270, 2005.). Meier et al. (2006)MEIER, J.J.; LIN, J.C.; BUTLER, A.E.; GALASSO, R.; MARTINEZ, D.S.; BUTLER, P.C. Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia, v. 49, p. 1838-1844, 2006. showed a direct piece of evidence for beta cell regeneration through beta cell replication in T1D patients. Neogenesis can be originated from different cell types within pancreas: alpha cells, delta cells, duct epithelium, acinar cells, and centroacinar cells. However, this process depends on extra-pancreatic activators including hormones, growth factors, and others (Bouwens, Rooman, 2005BOUWENS, L.; ROOMAN, I. Regulation of pancreatic beta-cell mass. Physiol. Rev., v.85, p.1255-1270, 2005.). In adults, turnover of beta cells is slow and reduces with increasing age. However, during body growth and after injury, beta cells can replicate to maintain glucose homeostasis (Avolio et al., 2013AVOLIO, F.; PFEIFER, A.; COURTNEY, M.; GJERNES, E.; BEN-OTHMAN, N.; VIEIRA, A.; DRUELLE, N.; FAURITE, B.; COLLOMBAT, P. From pancreas morphogenesis to β-cell regeneration. Curr. Topics Develop. Biol., v.106, p.217-238, 2013.). Several approaches are currently being investigated to differentiate stem/progenitor cells into beta cells; but, none has been approved for use in diabetic patients yet. Therefore, further works on this issue are warranted.

Phytochemicals with protective/regenerative effects

Allium sativum

Garlic (Allium sativum) has been long used as an herbal remedy in treating different diseases because of its antioxidant, antihypertensive, and anticancer effects (Afshari et al., 2006AFSHARI, J.T.; HAJZADEH, M.A.; GHORBANI, A.; PARSAIE, H. Ethanolic extract of Allium sativum has antiproliferative effect on Hep2 and L929 cell lines. Pharmacogn. Mag., v.2, p.29-31, 2006.; Ashraf et al., 2013ASHRAF, R.; KHAN, R.A.; ASHRAF, I.; QURESHI, A.A. Effects of Allium sativum (garlic) on systolic and diastolic blood pressure in patients with essential hypertension. Pak. J. Pharm. Sci., v.26, p.859-863, 2013.; Benkeblia, 2005BENKEBLIA, N. Free-radical scavenging capacity and antioxidant properties of some selected onions (Allium cepa L) and garlic (Allium sativum L.) extracts.Braz. Arch. Biol. Technol., vol.48, p.753-759, 2005.; Hajzadeh et al., 2006HAJZADEH, M.R.; TAVAKOL AFSHARI, J.; GHORBANI, A.; SHAKERI, M.T. The effects of aqueous extract of garlic (Allium sativum L) on laryngeal cancer cells (Hep-2) and L929 cells in vitro. J. Med. Plants, v.5, p.41-48, 2006.). It is also one of the best-researched medicinal plants in terms of managing diabetes. Clinical trials have shown that the consumption of garlic decreases fasting blood glucose (FBG) and lipids in diabetic patients (Ghorbani, 2013aGHORBANI, A. Best herbs for managing diabetes: A review of clinical studies. Braz. J. Pharm. Sci., v.49, p.413-422, 2013a., bGHORBANI, A. Phytotherapy for diabetic dyslipidemia: evidence from clinical trials. Clin. Lipidol., v.8, p.311-319, 2013b.). According to the animal studies, it may also induce a protective/regenerative effect on pancreatic beta cells. Albajali et al. (2011)ALBAJALI, A.A.; NAGI, A.H.; SHAHZAD, M.; ULLAH, M.I.; HUSSAIN, S. Effect of Allium sativa L on pancreatic β. cells in comparison to Nigella sativa L. in streptozotocin induced diabetic rats. J. Med. Plants Res., v. 5, p.5779-5784, 2011. reported that the aqueous extract of A. sativum increased the diameter of pancreatic islets in STZ-induced diabetic rats. In another study, intraperitoneal injection of A. sativum oil decreased beta cell degeneration and level of anti-islet antibodies in the animals with T1D (Osman et al., 2012OSMAN, M.; ADNAN, A.; BAKAR, N.S.; ALASHKHAM, F. Allicin has significant effect on autoimmune anti-islet cell antibodies in type 1 diabetic rats. Pol. J. Pathol., v.63, p.248-254, 2012.). Alashkham et al. (2013)ALASHKHAM, F.A.; OSMAN, M.T.; ADNAN, A.; BAKAR, N.S. Histopathological and biochemical effects of Allium Sativum oil administration on type 1 diabetic rats. Res. J. Pharm. Biol. Chem. Sci., v. 4, p. 1045-1053, 2013. also showed regenerative action of this oil in the pancreatic islets of diabetic rats. Yet, in another study, there was no significant difference between the histopathology of the pancreas of garlic treated and untreated diabetic rats (Jelodar et al., 2005JELODAR, G.A.; MALEKI, M.; MOTADAYEN, M.H.; SIRUS, S. Effect of fenugreek, onion and garlic on blood glucose and histopathology of pancreas of alloxan-induced diabetic rats. Indian. J. Med. Sci., v.59, p.64-69, 2005.).

Allicin is the major active component of A. sativum and a precursor of many secondary compounds formed in crushed garlic preparations or aged garlic. This compound has been proposed to be responsible for the health promotion benefits of A. sativum and protective actions in pancreatic islets (Osman et al., 2012OSMAN, M.; ADNAN, A.; BAKAR, N.S.; ALASHKHAM, F. Allicin has significant effect on autoimmune anti-islet cell antibodies in type 1 diabetic rats. Pol. J. Pathol., v.63, p.248-254, 2012.).

Anastatica hierochuntica

Anastatica hierochuntica from Brassicaceae family is commonly called "Kaff Maryam" or "Rose of Jericho" and is one of the folk medicinal plants, which is widely used in Arab countries (Daur, 2012DAUR, I. Chemical properties of the medicinal herb Kaff Maryam (Anastatica hierochuntica L) and its relation to folk medicine use. Afr. J. Microbiol. Res., v.6, p.5048-5051, 2012.; Shaban, Al-Azzawie, Mohamme, 2011SHABAN, F.; Al-AZZAWIE, H.F.; MOHAMMED, A.S. Effect of alcoholic Anastatica hierochuntica extract on some biochemical and histological parameters in alloxan induced diabetic rats. Iraqi J. Sci., v.52, p.445-455, 2011.). Experimental studies have demonestrated that aqueous and methanolic extracts of A. hierochuntica have antioxidative, hypoglycemic, and hypolipidemic effects in diabetic rats (Rahmy, El-Ridi, 2002RAHMY, T.R.; El-RIDI, M.R. Action of Anastatica hierochuntica plant extract on islets of Langerhans in normal and diabetic rats. Egypt. J.Biol., v. 4, p. 87-94, 2002.; Shaban, Al-Azzawie, Mohamme, 2011SHABAN, F.; Al-AZZAWIE, H.F.; MOHAMMED, A.S. Effect of alcoholic Anastatica hierochuntica extract on some biochemical and histological parameters in alloxan induced diabetic rats. Iraqi J. Sci., v.52, p.445-455, 2011.). This hypoglycemic action may be due to its beneficial effects on pancreatic beta cells. Rahmy, El-Ridi (2002)RAHMY, T.R.; El-RIDI, M.R. Action of Anastatica hierochuntica plant extract on islets of Langerhans in normal and diabetic rats. Egypt. J.Biol., v. 4, p. 87-94, 2002. reported that A. hierochuntica increased the number of beta cells in pancreatic islets of diabetic rats. Similarly, Shaban, Al-Azzawie, Mohamme (2011)SHABAN, F.; Al-AZZAWIE, H.F.; MOHAMMED, A.S. Effect of alcoholic Anastatica hierochuntica extract on some biochemical and histological parameters in alloxan induced diabetic rats. Iraqi J. Sci., v.52, p.445-455, 2011. showed that this plant enhanced volume density of islets and percentage of beta cells in diabetic rats.

Annona muricata

Annona muricata from Annonaceae family (commonly called Soursop) is a small tree, all parts of which are used in natural medicine in the tropical areas in South and North America and west of Africa (Adewole, Caxton-Martins, 2006ADEWOLE, S.O.; CAXTON-MARTINS, E.A. Morphological changes and hypoglycemic effects of Annona Muricata Linn (Annonaceae) leaf aqueous extract on pancreatic Β-Cells of streptozotocin-treated diabetic rats. Afr. J. Biomed. Res., v. 9, p.173-187, 2006.). According to the animal studies on STZ-induced diabetic rats, the administration of extract of A. muricata leaves can increase the number of islets and beta cells in pancreas (Adewole, Caxton-Martins, 2006ADEWOLE, S.O.; CAXTON-MARTINS, E.A. Morphological changes and hypoglycemic effects of Annona Muricata Linn (Annonaceae) leaf aqueous extract on pancreatic Β-Cells of streptozotocin-treated diabetic rats. Afr. J. Biomed. Res., v. 9, p.173-187, 2006.; Adeyemi et al., 2008ADEYEMI, D.O.; KOMOLAFE, O.A.; ADEWOLE, S.O.; OBUOTOR, E.M.; ADENOWO, T.K. Effects of Annona Muricata (Linn) on the morphology of pancreatic islet cells of experimentally-induced diabetic Wistar rats. Internet J. Altern. Med., v.5, 2008.).

Azadirachta indica

Neem (Azadirachta indica), a tree in the mahogany family, is among the well-known medicinal plants in Africa. Using a clinical study, its hypoglycemic and hypolipidemic effects among diabetic patients have been shown in recent years (Kochhar, Sharma, Schdeva, 2009KOCHHAR, A.; SHARMA, N.; SCHDEVA, R. Effect of supplementation of tulsi (Ocimum sanctum) and neem (Azadirachta indica) leaf powder on diabetic symptoms, anthropometric parameters and blood pressure of non insulin dependent male diabetics. Etno-Med., v.3, p.5-9, 2009.; Kumari, 2010KUMARI, D.J. Hypoglycaemic effect of Moringa oleifera and Azadirachta indica in type 2 diabetes mellitus. Bioscan, v.5, p.211-214, 2010.). Two animal studies have demonstrated that A. indica has also a regenerative effect on the islets of Langerhans. According to the report by Akinola, Caxton-Martins, Dini (2010)AKINOLA, O.B.; CAXTON-MARTINS, E.A.; DINI, L. Chronic treatment with ethanolic extract of the leaves of Azadirachta indica ameliorates lesions of pancreatic islets in streptozotocin diabetes. Int. J. Morphol., v.28, p.291-302, 2010., oral feeding of ethanolic extract of A. indica leaves increased beta cell density and decreased oxidative stress in the pancreas of STZ-induced diabetic rats. Ebong et al. (2006)EBONG, P.E.; ATANGWHO, I.J..; EYONG, E.U..; UKWE, C..; OBI, A.U.. Pancreatic Beta cell regeneration: a probable parallel mechanism of hypoglycaemic action of Vernonia amygdalina Del and Azadirachta indica. In: INTERNATIONAL NEEM CONFERENCE, 2006, Kunming, China. Available at: <http://neem.tea-nifty.com/neem/files/14.%20Prof.Patrick%20Ebong.pdf>. Accessed on: Jan. 2014.
http://neem.tea-nifty.com/neem/files/14....
also showed regenerative action of this extract in alloxan-induced diabetic rats.

Berberine

Berberine is an isoquinoline alkaloid which is present in the root, rhizome, and stem bark of many plants, such as Berberis vulgaris, Coptidis rhizoma, Hydrastis canadensis, Mahonia aquifolium, and Mohonia nervosa (Ye et al., 2009YE, M.; FU, S.; PI, R.; HE, F. Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research. J. Pharm. Pharmacol., v.61, p.831-837, 2009.). Berberine has been demonstrated to have beneficial effects on hyperglycemia and dyslipidemia in diabetic patients (Yin et al., 2008YIN, J.; XING, H.; YE, J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism, v.57, p.712-717, 2008.). Regarding its protective/regenerative effect on pancreas, Tang et al. (2006)TANG, L.Q.; WEI, W.; CHEN, L.M.; LIU, S. Effects of berberine on diabetes induced by alloxan and a high-fat/high-cholesterol diet in rats. J. Ethnopharmacol., v.108, p.109-115, 2006. demonstrated that oral administration of berberine decreased the levels of FBG and serum lipids and restored the damage of pancreas tissue in alloxan-induced diabetic rats. Another study reported that berberine increased insulin sensitization, insulin secretion, and beta cell regeneration in STZ- and high carbohydrate/fat diet-induced diabetic rats (Zhou et al., 2009ZHOU, J.; ZHOU, S.; TANG, J.; ZHANG, K.; GUANG, L.; HUANG, Y.; XU, Y.; YING, Y.; ZHANG, L.; LI, D. Protective effect of berberine on beta cells in streptozotocin- and high-carbohydrate/high-fat diet-induced diabetic rats. Eur. J. Pharmacol., v.606, p.262-268, 2009.).

Crocus sativus

Saffron (Crocus sativus) is a perennial stemless herb of the Iridaceae family which is widely cultivated in Iran and also in some other countries such as India. Crocin (crocetin glycoside) and safranal (C10H14O) are the main constituents of C. sativus and responsible for the pharmacological effects of this plant. Safranal has been reported to have a number of medicinal attributes including antioxidative and cytoprotective effects (Alinejad, Ghorbani, Sadeghnia, 2013ALINEJAD, B.; GHORBANI, A.; SADEGHNIA, H.R. Effects of combinations of curcumin, linalool, rutin, safranal, and thymoquinone on glucose/serum deprivation-induced cell death. Avicenna J. Phytomed., v.3, p. 321-328, 2013.; Sadeghnia et al., 2013SADEGHNIA, H.R.; KAMKAR, M.; ASSADPOUR, E.; BOROUSHAKI, M.T.; GHORBANI, A. Protective effect of safranal, a constituent of Crocus sativus, on quinolinic acid-induced oxidative damage in rat hippocampus. Ir. J. Basic Med. Sci., v.16, p.73-82, 2013.). Safranal, C. sativus, and crocin show antihyperglycemic, hypolipidemic, and blood insulin elevating effects in insulin-dependent diabetic animals (Kianbakht, Hajiaghaee, 2011KIANBAKHT, S.; HAJIAGHAEE, R. Anti-hyperglycemic effects of saffron and its active constituents, crocin and safranal, in alloxan-induced diabetic rats. J. Med. Plants, v.10, p.82-89, 2011.; Mohajeri, Mousavi, Doustar, 2009MOHAJERI, D.; MOUSAVI, G.; DOUSTAR, Y. Antihyperglycemic and pancreas-protective effects of Crocus sativus L (saffron) stigma ethanolic extract on rats with alloxan-induced diabetes. J. Biol. Sci., v.9, p. 302-310, 2009.; Samarghandian et al., 2013SAMARGHANDIAN, S.; BORJI, A.; DELKHOSH, M.B.; SAMINI, F. Safranal treatment improves hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats. J. Pharm. Pharm. Sci., v.16, p.352-362, 2013.). In addition, C. sativus has beneficial effects on the histological structure of pancreas in alloxan-induced diabetic rats (Elgazar, Rezq, Bukhari, 2013ELGAZAR, A.F.; REZQ, A.A.; BUKHARI, H.M. Anti-hyperglycemic effect of saffron extract in alloxan-induced diabetic rats. Eur. J. Biol. Sci., v.5, p.14-22, 2013.). Recovery of beta cells and increase of insulin immunoreactivity are of beneficial effects induced by C. sativus in the islets of Langerhans of diabetic rats (Mohajeri, Mousavi, Doustar, 2009MOHAJERI, D.; MOUSAVI, G.; DOUSTAR, Y. Antihyperglycemic and pancreas-protective effects of Crocus sativus L (saffron) stigma ethanolic extract on rats with alloxan-induced diabetes. J. Biol. Sci., v.9, p. 302-310, 2009.).

Curcumin

Curcumin (diferuloylmethane) is an active ingredient of Curcuma longa, a spice employed as a flavoring and coloring supplement in foods. Evidence has suggested that it has potent antioxidant and cytoprotective effects (Alinejad, Ghorbani, Sadeghnia, 2013ALINEJAD, B.; GHORBANI, A.; SADEGHNIA, H.R. Effects of combinations of curcumin, linalool, rutin, safranal, and thymoquinone on glucose/serum deprivation-induced cell death. Avicenna J. Phytomed., v.3, p. 321-328, 2013.; Park et al., 2008PARK, S.Y.; KIM, H.S.; CHO, E.K.; KWON, B.Y.; PHARK, S.; HWANG, K.W.; SUL, D. Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food Chem. Toxicol., v.46, p.2881-2887, 2008.). In diabetic rats, curcumin inhibits lymphocytes infiltration in the islets of Langerhans and keeps the number of islets and beta cells (Chanpoo, Petchpiboonthai, 2010CHANPOO, M.; PETCHPIBOONTAI, H.; PANYARACHUN, B.; ANUPUNPISIT, V. Effect of curcumin in the amelioration of pancreatic islets in streptozotocin-induced diabetic mice. J. Med. Assoc. Thai., v.93, p.s152-s159, 2010.; Abdel Aziz et al., 2013ABDEL AZIZ, M.T.; El-ASMAR, M.F.; REZQ, A.M.; MAHFOUS, S.M.; WASSEF, M.A.; FOUAD, H.H.; AHMED, H.H.; TAHA, F.M. The effect of a novel curcumin derivative on pancreatic islet regeneration in experimental type-1 diabetes in rats (long term study). Diabetol. Metab. Syndr., v.5, p.75, 2013.). These effects are accompanied by decreased FBG and increased serum insulin and C-peptide (Abdel Aziz et al., 2013ABDEL AZIZ, M.T.; El-ASMAR, M.F.; REZQ, A.M.; MAHFOUS, S.M.; WASSEF, M.A.; FOUAD, H.H.; AHMED, H.H.; TAHA, F.M. The effect of a novel curcumin derivative on pancreatic islet regeneration in experimental type-1 diabetes in rats (long term study). Diabetol. Metab. Syndr., v.5, p.75, 2013.).

Gymnema sylvestre

Accumulating evidence has demonstrated that G. sylvestre (commonly known as Gurmar in India) improves glycemic control in both T1D and T2D. Clinical trials have demonstrated that the administration of this herb decreases FBG, PPBG, and HbA1c in diabetic patients (Ghorbani, 2013bGHORBANI, A. Phytotherapy for diabetic dyslipidemia: evidence from clinical trials. Clin. Lipidol., v.8, p.311-319, 2013b.). The potential ability of G. sylvestre in regenerating pancreatic beta cells has been tested in recent years. It has been shown that aqueous extract of G. sylvestre leaves increases serum insulin level in streptozotocin treated rats. This effect is accompanied by a double increase in the number of beta cells ( Shanmugasundaram et al., 1990SHANMUGASUNDARAM, E.R.B.; RAJESWARI, G.; BASKARAN, K.; KUMAR, B.R.R.; SHANMUGASUNDARAM, K.R.; AHMATH, B.K. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J. Ethnopharmacol., v.30, p.281-294, 1990.). Regenerative effect of G. sylvestre has been also observed following long-term treatment of diabetic rats using a standardized dry extract of leaves (Aralelimath, Bhise, 2012ARALELIMATH, V.R.; BHISE, S.B. Anti-diabetic effects of Gymnema sylvester extract on streptozotocin induced diabetic rats and possible β-cell protective and regenerative evaluations. Dig. J. Nanomater. Biostruct., v.7, p.135-142, 2012.). Gymnemic acid is considered to be the active ingredient responsible for the regenerative action of G. sylvestre on beta cells (Ahmed, Rao, Rao, 2010AHMED, A.B.; RAO, A.S.; RAO, M.V. In vitro callus and in vivo leaf extract of Gymnema sylvestre stimulate β-cells regeneration and anti-diabetic activity in Wistar rats. Phytomedicine, v.17, p.1033-1039, 2010.).

Juglans regia

Juglans regia (walnut) has been widely used in the traditional medicine of Asian countries as a remedy for various ailments. Its leaves have shown a significant hypoglycemic effect in diabetic animals. Increase of hepatic glycogenolysis, decrease of gluconeogenesis, inhibition of glucose absorption from the intestine, and enhancing serum insulin are the proposed mechanisms for hypoglycemic effect of J. regia (Asgary et al., 2008ASGARY, S; PARKHIDEH, S; SOLHPOUR, S; MADANI, H,; MAHZOUNI, P; RAHIMI, P. Effect of ethanolic extract of Juglans regia L on blood sugar in diabetes-induced rats.J. Med. Food, v.11, p.533-538, 2008.; Kamyab et al., 2010KAMYAB, H.; HEJRATI, S.; KHANAVI, M.; MALIHI, F.; MOHAMMADIRAD, A.; BAEERI, M. Hepatic mechanisms of the walnut antidiabetic effect in mice. Cent. Eur. J. Biol., v.5, p.304-309, 2010.; Jelodar, Mohsen, Shahram, 2007JELODAR, G.; MOHSEN, M.; SHAHRAM, S. Effect of walnut leaf, coriander and pomegranate on blood glucose and histopathology of pancreas of alloxan induced diabetic rats. Afr. J. Trad. CAM., v.4, p.299-305, 2007.). Increase of insulin level can be mediated through regenerative actions of J. regia on pancreatic islets. It has been shown that density of islets, percent of beta cells, and islets size significantly increase in pancreatic tissue of diabetic rats receiving walnut leaf (Jelodar, Mohsen, Shahram, 2007JELODAR, G.; MOHSEN, M.; SHAHRAM, S. Effect of walnut leaf, coriander and pomegranate on blood glucose and histopathology of pancreas of alloxan induced diabetic rats. Afr. J. Trad. CAM., v.4, p.299-305, 2007.). Regenerative property of J. regia is accompanied by increase in the serum insulin level (Asgary et al., 2008ASGARY, S; PARKHIDEH, S; SOLHPOUR, S; MADANI, H,; MAHZOUNI, P; RAHIMI, P. Effect of ethanolic extract of Juglans regia L on blood sugar in diabetes-induced rats.J. Med. Food, v.11, p.533-538, 2008.; Javidanpour et al., 2012JAVIDANPOUR, S.; TABTABAEI, S.R.F.; SIAHPOOSH, A.; MOROVATI, H.; SHAHRIARI, A. Comparison of the effects of fresh leaf and peel extracts of walnut (Juglans regia L) on blood glucose and β-cells of streptozotocin-induced diabetic rats. Vet. Res. Forum, v.3, p.251-255, 2012.). Yet, in contrast to leaf, treatment with the shell septum of J. regia has no effects on the pancreatic structure of diabetic rats (Dehghani, Mashhoody, Panjehshahin, 2012DEHGHANI, F.; MASHHOODY, T.; PANJEHSHAHIN, M. Effect of aqueous extract of walnut septum on blood glucose and pancreatic structure in streptozotocin-induced diabetic mouse. Ir. J. Pharmacol. Ther., v.11, p.10-14, 2012.).

Momordica charantia

Momordica charantia (Karela, Ampalaya, bitter melon) has acquired a reputation for the management of diabetes. It has passed several animal and clinical studies and its beneficial effects on blood glucose and lipids have been shown in diabetic patients since 36 years ago (Ghorbani, 2013bGHORBANI, A. Phytotherapy for diabetic dyslipidemia: evidence from clinical trials. Clin. Lipidol., v.8, p.311-319, 2013b.). Effect of M. charantia fruit on pancreatic histopathological changes has been determined by at least five experimental studies. In adult diabetic animals, the results indicate that M. charantia increases the number of beta cells per islets and leads to the neoformation of islets from the pre-existing islet cells (Ahmed et al., 1998AHMED, I.; ADEGHATE, E.; SHARMA, A.K.; PALLOT, D.J; SINGH, J. Effects of Momordica charantia fruit juice on islet morphology in the pancreas of the streptozotocin-diabetic rat. Diabetes Res. Clin. Pract., v.40, p.145-151, 1998.; Singh, Gupta, 2007bSINGH, N.; GUPTA, M. Regeneration of beta cells in islets of Langerhans of pancreas of alloxan diabetic rats by acetone extract of Momordica charantia (Linn) (bitter gourd) fruits. Indian J. Exp. Biol., v.45, p.1055-1062, 2007b.; Singh et al., 2008SOLTANI BAND, K.; FARKHAD, N.K.; FAROKHI, F.; TOGMECHI, A. Effects of hydro-alcoholic extract of Prangos ferulacea (L) Lindle on histopathology of pancreas and diabetes treatment in STZ- induced diabetic rats. Avicenna J. Phytomed., v. 2, p.31-38, 2011.). In addition, the hypoglycemic effect of M. charantia remains after the cease of treatment (Singh et al., 2008SINGH, N.; GUPTA, M.; SIROHI, P.; VARSH, A. Effects of alcoholic extract of Momordica charantia (Linn) whole fruit powder on the pancreatic islets of alloxan diabetic albino rats. J. Environ. Biol., v.29, p.101-106, 2008.). In neonatal diabetic rats, administration of aqueous or ethanolic extract of M. charantia fruit alleviates pancreatic damage and induces the renewal of pancreatic beta cells (Abdollahi et al., 2011ABDOLLAHI, M.; ZUKI, A.B.; GOH, Y.M.; REZAEIZADEH, A.; NOORDIN, M.M. Effects of Momordica charantia on pancreatic histopathological changes associated with streptozotocin-induced diabetes in neonatal rats. Histol. Histopathol., v.26, p.13-21, 2011.; Hafizur, Kabir, Chishti, 2011HAFIZUR, R.M.; KABIR, N.; CHISHTI, S. Modulation of pancreatic β-cells in neonatally streptozotocin-induced type 2 diabetic rats by the ethanolic extract of Momordica charantia fruit pulp. Nat. Prod. Res., v.25, p.353-367, 2011.).

Nigella sativa

N. sativa (black seed) has been used for centuries as a natural remedy for various ailments. Hypoglycemic and hypolipidemic effects of black seed have been reported in diabetic patients (Ghorbani, 2013aGHORBANI, A. Best herbs for managing diabetes: A review of clinical studies. Braz. J. Pharm. Sci., v.49, p.413-422, 2013a.). Kanter et al. (2003)KANTER, M.; MERAL, I.; YENER, Z.; OZBEK, H.; DEMIR, H. Partial regeneration/proliferation of the beta-cells in the islets of Langerhans by Nigella sativa L. in streptozotocin-induced diabetic rats. Tohoku J. Exp. Med., v.201, p.213-219, 2003. investigated the effect of N. sativa volatile oil on histopathology of pancreatic beta cells in diabetic rats and found that N. sativa treatment decreased the elevated serum glucose, increased the insulin concentration, and partially regenerated pancreatic beta cells in these animals. Afterward, they showed that the beneficial effect of N. sativa on the number of beta cells was accompanied by decreasing lipid peroxidation and increasing antioxidant enzyme activity (Kanter et al., 2004KANTER, M. Protective effects of thymoquinone on β-cell damage in streptozotocin-induced diabetic rats. T.A.D., v.7, p.64-70, 2009.). In another experiment, it was represented that the administration of N. sativa oil to STZ-induced diabetic rats increased the diameter of islets of Langerhans (Albajali et al., 2011ALBAJALI, A.A.; NAGI, A.H.; SHAHZAD, M.; ULLAH, M.I.; HUSSAIN, S. Effect of Allium sativa L on pancreatic β. cells in comparison to Nigella sativa L. in streptozotocin induced diabetic rats. J. Med. Plants Res., v. 5, p.5779-5784, 2011.). The protective effect of N. sativa against beta cell destruction is attributed to its active constituent, thymoquinone. Treatment with thymoquinone inhibits STZ-induced islet degeneration and necrosis and leads to the partial regeneration of the islet and beta cells of diabetic animals (Abdelmeguid et al., 2010ABDELMEGUID, N.E.; FAKHOURY, R.; KAMAL, S.M.; AL WAFAI, R.J. Effects of Nigella sativa and thymoquinone on biochemical and subcellular changes in pancreatic β-cells of streptozotocin-induced diabetic rats. J. Diabetes, v.2, p.256-266, 2010.; Kanter, 2009KANTER, M.; COSKUN, O.; KORKMAZ, A.; OTER, S. Effects of Nigella sativa on oxidative stress and beta-cell damage in streptozotocin-induced diabetic rats. Anat. Rec. A Discov. Mol. Cell Evol. Biol., v.279, p.685-691, 2004.; Sankaranarayanan, Pari, 2011SANKARANARAYANAN, C.; PARI, L. Thymoquinone ameliorates chemical induced oxidative stress and β-cell damage in experimental hyperglycemic rats. Chem. Biol. Interact., v.25, p.148-154, 2011.).

Vernonia amygdalina

Vernonia amygdalina, also called bitter leaf, is a vegetable from compositae family and is commonly used in west of Africa for treating various diseases including diabetes (Atangwho et al., 2007ATANGWHO, I.J.; EBONG, P.E.; EYONG, E.U.; ETENG, M.U.; OBI, A.U. Effect of Vernonia amygdalina Del leaf on kidney function of diabetic rats. Int. J. Pharm., v.3, p.142-148, 2007.). Pre-treatment with the aqueous extract of V. amygdalina protects the islets of Langerhans against alloxan-induced pancreatic degeneration (Sunday et al., 2012SUNDAY, J.J.; SPENCER, C.O.; KINGSLEY, O.; AKINTOLA, A.A.; BINYELUM, N.; FAVOUR, A.O. Possible revival of atrophied islet cells of the pancreas by Vernonia amygdalina in alloxan induced diabetic rats. J. Appl. Pharm. Sci., v. 2, p.127-131, 2012.). Also, administration of V. amygdalina induces regeneration of the islet cells and decreases FBG in diabetic rats (Atangwho et al., 2007ATANGWHO, I.J.; EBONG, P.E.; EYONG, E.U.; ETENG, M.U.; OBI, A.U. Effect of Vernonia amygdalina Del leaf on kidney function of diabetic rats. Int. J. Pharm., v.3, p.142-148, 2007.).

Other plants with protective effects on pancreas

In addition to the above-mentioned herbs, a number of others has been found to have potential protective or regenerative properties on beta cells: Abroma augusta (Mir, Darzi, Mir, 2013MIR, S.H.; DARZI, M.; MIR, M.S. Efficacy of Abroma augusta on biochemical and histomorphological features of alloxan-induced diabetic rabbits. Iran. J. Path., v.8, p.153-158, 2013.), Alchornea cordifolia (Eliakim-Ikechukwu, Obri, 2009ELIAKIM-IKECHUKWU, C.F.; OBRI, A.I. Histological changes in the pancreas following administration of ethanolic extract of Alchornea cordifolia leaf in alloxan-induced diabetic Wistar rats. Nigerian J. Physiol. Sci., v.24, p.153-155, 2009.), Amaranthus caudatus (Girija et al., 2011GIRIJA, K.; LAKSHMAN, K.; UDAYA, C.; SABHYA, S.G.; DIVYA, T. Anti-diabetic and anti-cholesterolemic activity of methanol extracts of three species of Amaranthus. Asian Pac. J. Trop. Biomed., v.2, p.133-138, 2011.), Amaranthus spinosus (Girija et al., 2011GIRIJA, K.; LAKSHMAN, K.; UDAYA, C.; SABHYA, S.G.; DIVYA, T. Anti-diabetic and anti-cholesterolemic activity of methanol extracts of three species of Amaranthus. Asian Pac. J. Trop. Biomed., v.2, p.133-138, 2011.), Amaranthus viridis (Girija et al., 2011GIRIJA, K.; LAKSHMAN, K.; UDAYA, C.; SABHYA, S.G.; DIVYA, T. Anti-diabetic and anti-cholesterolemic activity of methanol extracts of three species of Amaranthus. Asian Pac. J. Trop. Biomed., v.2, p.133-138, 2011.), Artanema sesamoides (Selvan et al., 2008SELVAN, V.T.; MANIKANDAN, L.; SENTIL, G.P.; SURESH, R.; KAKOTI, B.B.; GOMATHI, P.; KUMAR, D.A.; SAHA, P.; GUPTA, M.; MAZUMDER, U.K. Antidiabetic and antioxidant effect of methanol extract of artanema sesamoides in streptozocin-induced diabetic rats. Int. J. Appl. Res. Nat. Prod., v.1, p. 25-33, 2008.), Bauhinia variegata (Koti et al., 2009KOTI, B.C.; BIRADAR, S.M.; KARADI, R.V.; TARANALLI, A.D.; BENADE, V.S. Effect of Bauhinia variegata bark extract on blood glucose level in normal and alloxanised diabetic rats. J. Nat. Remed., v.9, p.27-34, 2009.), Cassia alata (Eliakim-Ikechukwu et al., 2013ELIAKIM-IKECHUKWU, C.F.; EDEM, A.A.; WILLIAM, U.; OKORI, S.O.; IHENTUGE, C.J. Phytochemical composition of Cassia alata leaf extract and its effect on the histology of the pancreas of diabetic wistar rats. IOSR. J. Pharm. Biol. Sci., v.5, p.07-13, 2013.), Cassia occidentalis (Verma et al., 2010VERMA, L.; KHATRI, A.; KAUSHIK, B.; PATIL, K.; PAWAR, R.S. Antidiabetic activity of Cassia occidentalis (Linn) in normal and alloxan-induced diabetic rats. Indian J. Pharmacol., v.42, p.224-228, 2010.), Clitoria ternatea (Verma, Itankar, Arora , 2013VERMA, P.R.; ITANKAR, P.R.; ARORA, S.K. Evaluation of antidiabetic anti-hyperlipidemic and pancreatic regeneration, potential of aerial parts of Clitoria ternatea. Rev. Bras. Farmacogn., v.23, p.819-829, 2013.), Elephantopus scaber (Daisy et al., 2007DAISY, P.; RAYAN, N.A.; RAJATHI, D. Hypoglycemic and other related effects of Elephantopus scaber extracts on alloxan induced diabetic rats. J. Biol. Sci., v.7, p.433-437, 2007.), Epicatechin (Chakravarthy, Gupta, Gode, 1982CHAKRAVARTHY, B.K.; GUPTA, S.; GODE, K.D. Functional beta cell regeneration in the islets of pancreas in alloxan induced diabetic rats by (-)-epicatechin. Life Sci., v.31, p.2693-2697, 1982.), Leucaena leucocephala (DarmonoSyamsudin, Simanjuntak, 2006DARMONOSYAMSUDIN, S.; SIMANJUNTAK, P. The effects of Leucaena leucocephala (lmk) De Wit seeds on blood sugar levels: an experimental study. Int. J. Sci. Res., v.2, p.49-52, 2006.), Mangiferin (Wang et al., 2014WANG, H.L.; LI, C.Y.; ZHANG, B.; LIU, Y.D.; LU, B.M.; SHI, Z.; AN, N.; ZHAO, L.K.; ZHANG, J.J.; BAO, J.K.; WANG, Y. Mangiferin facilitates islet regeneration and β-cell proliferation through upregulation of cell cycle and β-cell regeneration regulators. Int. J. Mol. Sci., v.15, p.9016-9035, 2014.), Morus alba (Mohammadi, Prakash, 2008MOHAMMADI, J.; PRAKASH, R.N. Evaluation of hypoglycemic effect of Morus alba in an animal model. Indian. J. Pharmacol., v.40, p.15-18, 2008.), Prangos ferulacea (Soltani Band et al., 2011SOLTANI BAND, K.; FARKHAD, N.K.; FAROKHI, F.; TOGMECHI, A. Effects of hydro-alcoholic extract of Prangos ferulacea (L) Lindle on histopathology of pancreas and diabetes treatment in STZ- induced diabetic rats. Avicenna J. Phytomed., v. 2, p.31-38, 2011.), Pterocarpus marsupium (Chakravarthy et al., 1980CHAKRAVARTHY, B.K.; GUPTA, S.; GAMBHIR, S.S.; GODE, K.D. Pancreatic beta cell regeneration: a novel antidiabetic mechanism of Pterocarpus marsupium. Indian J. Pharmacol., v.12, p.123-127, 1980.), Sansevieria trifasciata (Qomariyah, Sarto, Pratiwi, 2012QOMARIYAH, N.; SARTO, M.; PRATIWI, R. Antidiabetic effects of a decoction of leaves of Sansevieria trifasciata in alloxan- induced diabetic white rats. ITB J. Sci., v.44, p.308-316, 2012.), Syzygium cumini (Singh, Gupta, 2007aSINGH, N.; GUPTA, M. Effects of ethanolic extract of Syzygium cumini (Linn) seed powder on pancreatic islets of alloxan diabetic rats. Indian J. Exp. Biol., v.45, p.861-867, 2007a.), Teucrium polium (Yazdanparast, Esmaeili, Ashrafi, 2005YAZDANPARAST, R.; ESMAEILI, M.A.; ASHRAFI, H.J. Teucrium polium extract effects pancreatic function of streptozotocin diabetic rats: a histopathological examination. Ir. Biomed. J., v.9, p.81-85, 2005.), Thunbergia laurifolia (Aritajat, Wuteerapol, Saenphet,, 2004ARITAJAT, S.; WUTEERAPOL, S.; SAENPHET, K. Anti-diabetic effects of Thunbergia laurifolia L. aqueous extract. Southeast Asian J. Trop. Med. Public Health, v.35, p.53-58, 2004.), Tinospora cordifolia (Rajalakshmi et al., 2009RAJALAKSHMI, M.; ELIZA, J.; PRIYA, C.E.; NIRMALA, A.; DAISY, P. Anti-diabetic properties of Tinospora cordifolia stem extracts on streptozotocin- induced diabetic rats. Afr. J. Pharm. Pharmacol., v.3, p.171-180, 2009.), Trigonella foenum-graceum (Kulkarni et al., 2012KULKARNI, C.P.; BODHANKAR, S.L.; GHULE, A.E.; MOHAN, V.; THAKURDESAI, P.A. Antidiabetic activity of Trigonella foenum-graecum L seed extract (IND01) in neonatal streptozotocin-induced (N-STZ) rats. Diabetologia Croat., v.41, n.1, p.29-36, 2012.), Vinca rosea (Ahmed et al., 2010AHMED, M.F.; KAZIM, S.M.; GHORI, S.S.; MEHJABEEN, S.S.; AHMED, S.R.; ALI, S.M.; IBRAHIM, M. Antidiabetic activity of Vinca rosea extracts in alloxan-induced diabetic rats. Int. J. Endocrinol., v.2010, p.841090, 2010.), Urtica dioica (Golalipour et al., 2010GOLALIPOUR, M.J.; GHAFARI, S.; KOURI, V.; KESTKAR, A.A. Proliferation of the β-Cells of pancreas in diabetic rats treated with Urtica Dioica. Int. J. Morphol., v.28, p.399-404, 2010.), and Urtica pilulifera (Kavalali et al., 2003KAVALALI, G.; TUNCEL, H.; GOKSEL, S.; HATEMI, H.H. Hypoglycemic activity of Urtica pilulifera in streptozotocin-diabetic rats. J. Ethnopharmacol., v.84, p.241-245, 2003.). However, for each one, only one study from independent authors was found to support their protective or regenerative effects on beta cells. Therefore, further studies are needed to establish the therapeutic value of these herbs in the management of insulin-dependent diabetes.

Proposed mechanisms for protective/regenerative effect of phytochemicals

In this review, the protective effects of several plants on drug-induced β-cells destruction, increasing islets size, and beta cell population were presented. Although these pieces of evidence did not fully reveal the involved molecular mechanisms, decreasing apoptosis, increasing cells' antioxidant capacity, and immunomodulation wee the postulated mechanisms of action.

Beta cell apoptosis and replication rates, islet size, and islet neogenesis are the major determinants of pancreatic endocrine capability for insulin secretion and glucose homostasis (Montanya, Tellez, 2009MONTANYA, E.; TÉLLEZ, N. Pancreatic remodeling: beta-cell apoptosis, proliferation and neogenesis, and the measurement of beta-cell mass and of individual beta-cell size. Methods Mol. Biol., v.560, p.137-158, 2009.). Changing the balance of beta cell replication and apoptosis alters the length of beta cell cycle which contributes to the islet size and insulin release. Decreasing apoptosis results in the enhancement of beta cell viability and increase in insulin production.

Intrinsic and extrinsic pathways are considered as two general routes for the activation of apoptosis. The former is activated by stress factors including growth factor deprivation, cell cycle disturbance, and DNA damage, which lead to mitochondrial release of cytochrome c and subsequent stimulation of caspase-9. The latter begins with cell death receptors and the associated activation of caspase-8. Finally, both pathways stimulate effector caspases (3, 6, and 7) which target the substrates that promote DNA fragmentation and cell death (Sharma et al., 2009SHARMA, V.; KALIM, S.; SRIVASTAVA, M.K.; NANDA, S.; MISHRA, S. Oxidative stress and coxsackie virus infections as mediators of beta cell damage: A review. Sci. Res. Essay, v.4, p.42-58, 2009.; Forouzanfar et al., 2013FOROUZANFAR, F.; GOLI, A.A.; ASSADPOUR, E.; GHORBANI, A.; SADEGHNIA, H.R. Protective effect of Punica granatum L against serum/glucose deprivation-induced PC12 cells injury. Evid. Based Complement. Alternat. Med., v.2013, p.716-730, 2013.).

It has been well documented that oxidative stress plays an important role in beta cell dysfunction and apoptosis (Yang et al., 2011YANG, H.; JIN, X.; LAM, C.W.; YAN, S.K. Oxidative stress and diabetes mellitus. Clin. Chem. Lab. Med., v.49, p.1773-1782, 2011.). Because of poor antioxidant capacity, beta cells are vulnerable to the oxidative stress induced by both T1D insulitis and T2D glucotoxicity (Sharma et al., 2009SHARMA, V.; KALIM, S.; SRIVASTAVA, M.K.; NANDA, S.; MISHRA, S. Oxidative stress and coxsackie virus infections as mediators of beta cell damage: A review. Sci. Res. Essay, v.4, p.42-58, 2009.). Therefore, drugs and phytochemicals that improve glycemia and/or oxidative stress ameliorate or prevent islet lesions. In this regard, protective effect of some phytochemicals on pancreas has been found to be mediated through their antioxidant effects. Zhou et al. (2009)ZHOU, J.; ZHOU, S.; TANG, J.; ZHANG, K.; GUANG, L.; HUANG, Y.; XU, Y.; YING, Y.; ZHANG, L.; LI, D. Protective effect of berberine on beta cells in streptozotocin- and high-carbohydrate/high-fat diet-induced diabetic rats. Eur. J. Pharmacol., v.606, p.262-268, 2009. reported that treatment with berberine restored the reduced superoxide dismutase activity and increased lipid peroxidation of pancreas of diabetic animals to the near control level. These antioxidant effects of berberine, therefore, mediate its anti-apoptotic action against beta cell apoptosis in insulin-resistant animal models and against palmitate-induced lipoapoptosis in HIT-T15 insulin producing cells (Gao, Zhao, Li, 2011GAO, N.; ZHAO, T.Y.; LI, X.J. The protective effect of berberine on β-cell lipoapoptosis. J. Endocrinol. Invest., v.34, p.124-130, 2011.; Wu, Lu, Dong, 2011WU, S.; LU, F.E.; DONG, H. Effects of berberine on the pancreatic beta cell apoptosis in rats with insulin resistance. Chin. J. Integr. Tradit. West. Med., v.31, p.1383-1388, 2011.). Similarly, the beta cell protective effect of N. sativa can be attributed to the antioxidant properties of this plant, which increases superoxide dismutase activity, inhibites lipid peroxidation, and decreases the generation of reactive oxygen species (ROS) in pancreas tissue (Abdelmeguid et al., 2010ABDELMEGUID, N.E.; FAKHOURY, R.; KAMAL, S.M.; AL WAFAI, R.J. Effects of Nigella sativa and thymoquinone on biochemical and subcellular changes in pancreatic β-cells of streptozotocin-induced diabetic rats. J. Diabetes, v.2, p.256-266, 2010.). Also, reduction of lipid peroxidation in the pancreas of diabetic rats treated with A. indica suggests the beneficial potential of this plant in the amelioration of ROS-induced pancreatic islet lesions (Akinola, Caxton-Martins, Dini, 2010AKINOLA, O.B.; CAXTON-MARTINS, E.A.; DINI, L. Chronic treatment with ethanolic extract of the leaves of Azadirachta indica ameliorates lesions of pancreatic islets in streptozotocin diabetes. Int. J. Morphol., v.28, p.291-302, 2010.). In addition to the direct evidence for pancreas, protective/regenerative effects of the phytochemicals on other tissues may support their beneficial actions on pancreatic structure of diabetic rats. For example, hepatoprotective property of Allicin (Vimal, Devaki, 2004VIMAL, V.; DEVAKI, T. Hepatoprotective effect of allicin on tissue defense system in galactosamine/endotoxin challenged rats. J. Ethnopharmacol., v.90, p.151-154, 2004.), N. sativa (Al-Ghasham et al., 2008AL-GHASHAM, A.; ATA, H.S.; EL-DEEP, S.; MEKI, A.R.; SHEHADA, S. Study of protective effect of date and nigella sativa on aflatoxin B1 toxicity. Int. J. Health Sci. (Qassim), v.2, p.26-44, 2008.), and A. indica (Oyewole, 2011OYEWOLE, O.I. Ameliorating effect of methanolic leaf extract of Azadirachta indica (neem) on arsenic-induced oxidative damage in rat liver. Int. J. Toxicol. Appl. Pharmacol., v.1, p.25-28, 2011.; Ezz-Din et al., 2011EZZ-DIN, D.; GABRY, M.S.; FARRAG, A.H.; MONEIM, A.E.A. Physiological and histological impact of Azadirachta indica (neem) leaves extract in a rat model of cisplatin-induced hepato and nephrotoxicity. J. Med. Plants Res., v.5, p.5499-5506, 2011.) and nephroprotective action of N. sativa (Al-Ghasham et al., 2008AL-GHASHAM, A.; ATA, H.S.; EL-DEEP, S.; MEKI, A.R.; SHEHADA, S. Study of protective effect of date and nigella sativa on aflatoxin B1 toxicity. Int. J. Health Sci. (Qassim), v.2, p.26-44, 2008.) and A. indica (Ezz-Din et al., 2011EZZ-DIN, D.; GABRY, M.S.; FARRAG, A.H.; MONEIM, A.E.A. Physiological and histological impact of Azadirachta indica (neem) leaves extract in a rat model of cisplatin-induced hepato and nephrotoxicity. J. Med. Plants Res., v.5, p.5499-5506, 2011.) have been demonstrated. Also, berberine can promote axonal regeneration in the injured nerves of rats' peripheral nervous system (Han, Heo, Kwon, 2012HAN, A.M.; HEO, H.; KWON, Y.K. Berberine promotes axonal regeneration in injured nerves of the peripheral nervous system. J. Med. Food, v.15, p.413-417, 2012.).

Immunomodulatory action and stimulation of proliferation and differentiation of progenitor cells may be also among the mechanisms involved in beta cell protective/regenerative effects of some phytochemicals (Abiramasundari, Sumalatha, Sreepriya, 2012ABIRAMASUNDARI, G.; SUMALATHA, K.R.; SREEPRIYA, M. Effects of Tinospora cordifolia (Menispermaceae) on the proliferation, osteogenic differentiation and mineralization of osteoblast model systems in vitro. J. Ethnopharmacol., v.141, p.474-480, 2012.; Ghazanfari, Hassan, Ebrahimi, 2002GHAZANFARI, T.; HASSAN, Z.M.; EBRAHIMI, M. Immunomodulatory activity of a protein isolated from garlic extract on delayed type hypersensitivity. Int. Immunopharmacol., v.2, p.1541-1549, 2002.).

CONCLUSION

Destruction of pancreatic islets is the major determinant for the onset of hyperglycemia and development of complications in insulin-dependent diabetic patients. Preventing beta cell degeneration, stimulating endogenous regeneration of islets, and islet transplantation will be of essential approaches for T1D management. At present, the limited supply of donor islets prevents tissue transplantation from being used in the patients. Therefore, development of phytochemical products with beta cell regenerative property can be a promising option for the patients who have lost their mass of functional islet cells. Among the hundreds of plants that have been investigated for diabetes, a small fraction has shown the regenerative property, which was described in this paper. For most of these herbs, however, the number of studies supporting their beneficial effects on pancreas is not enough. Only A. sativum, A. indica, berberine, C. sativus, G. sylvestre, J. regia, M. charantia, and N. sativa had more than one piece of evidence for their regenerative property so that their consumption may decrease insulin dependence on diabetic patients. The exact mechanism responsible for the protective/regenerative effects of phytochemicals on pancreatic islets is yet to be elucidated. However, antioxidant property of phytochemicals may in part mediate their protective action against pancreatic beta cell apoptosis. Regardless of the molecular mechanisms, it seems that patients at the earliest stages of diabetes can be treated with these plants to delay or prevent the full destruction of pancreatic islets. Also, construction of polyherbal compounds through the combination of these phytochemicals may yield more potent regenerative agents for beta cells. Upcoming clinical trials on this topic are particularly warranted.

ACKNOWLEDGMENT

Salary support was provided by Mashhad University of Medical Sciences. The authors have no other relevant affiliations or financial involvement with any other organization.

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Publication Dates

  • Publication in this collection
    Jan-Mar 2015

History

  • Received
    30 Jan 2014
  • Accepted
    28 Jan 2015
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br