Indian Journal of Research in Homeopathy

REVIEW ARTICLE
Year
: 2021  |  Volume : 15  |  Issue : 1  |  Page : 31--40

Preclinical updates of the homoeopathic medicines used in diabetes mellitus: A narrative review


G V Narasimha Kumar1, V Chitra2, Pankaj Gupta3, Bibaswan Biswas1, Renu Arya4,  
1 Department of Drug Standardization, Dr. Anjali Chatterji Regional Research Institute for Homoeopathy, Central Council for Research in Homoeopathy, Kolkata, West Bengal, India
2 Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, SRM University, Chennai, Tamil Nadu, India
3 Department of Drug Standardization, Dr D P Rastogi Central Research Institute for Homoeopathy, Central Council for Research in Homoeopathy, Noida, Uttar Pradesh, India
4 Department of Drug Standardization, Central Council for Research in Homoeopathy, New Delhi, India

Correspondence Address:
Mr. G V Narasimha Kumar
Dr. Anjali Chatterjee Regional Research Institute for Homeopathy, Central Council for Research in Homeopathy, Kolkata - 700 035, West Bengal
India

Abstract

Introduction: Homoeopathy, one of the most commonly employed alternative medicines globally, has a wide range of role in the management of diabetes. Screening of the action of homoeopathic medicines in diabetes on animal model not only helps in validating their antidiabetic potential but also aids in understanding their effect on living systems and their mechanism of action. The present review focusses on the collection of results of pre-clinical studies carried out on homoeopathic medicines employed in the management of diabetes. Methodology: PubMed, HomBRex portal, and published literature such as library catalogue were searched up to November 2019. The search terms employed were 'Homoeopathy', 'Diabetes' and their MeSH variations in PubMed and in HomBrex search was made using the condition 'Diabetes'. Results: Fifteen studies were included in the review. Twenty medicines were evaluated for their antidiabetic efficacy either in vivo or in vitro. Most of the preclinical research on diabetes was carried out on Syzygium jambolanum and Cephalandra indica in mother tincture form and potencies, substantiating their effectiveness in the management of diabetes. Apart from the medicines discussed in the current review, there are many other medicines in Homoeopathy which are used to treat diabetes and these also should be validated scientifically for global acceptance by the scientific fraternity. Conclusion: Considering the hypoglycaemic potential, availability and cost-effectiveness of homoeopathic medicines, future research should focus on screening their effectiveness in the management of diabetic complications and other metabolic disorders.



How to cite this article:
Kumar G V, Chitra V, Gupta P, Biswas B, Arya R. Preclinical updates of the homoeopathic medicines used in diabetes mellitus: A narrative review.Indian J Res Homoeopathy 2021;15:31-40


How to cite this URL:
Kumar G V, Chitra V, Gupta P, Biswas B, Arya R. Preclinical updates of the homoeopathic medicines used in diabetes mellitus: A narrative review. Indian J Res Homoeopathy [serial online] 2021 [cited 2021 Apr 20 ];15:31-40
Available from: https://www.ijrh.org/text.asp?2021/15/1/31/312634


Full Text



 Introduction



In the current global health scenario, diabetes mellitus (DM) is the most common endocrine disorder posing significant public health concern, producing substantial morbidity, mortality and long-term complications regardless of the latest advances in health care and management.[1] In the allopathic system of medicine, several orally administered drugs, recombinant drugs and genetically modified insulin are abundantly available in the market for the management of DM, which are reported to cause adverse effects.[2] The care of diabetic patients has been influenced by a growing interest in complementary and alternative medicine.[1]

Homoeopathy embraces a holistic approach in curing diverse diseases and it is used globally as an alternative medicine.[3] Homoeopathy seeks to cure in harmony with natural laws of healing. Potentized homoeopathic medicine, which undergoes a process of serial dilution along with succussion, is believed to retain properties of the original source substance. These homoeopathic medicines are employed in each case, on the basis of the homoeopathic principles, following the 'Law of similars'. Hydroalcoholic extract of the original drug substance termed as 'Mother tincture', which is prepared without potentisation is also used as a homoeopathic medicine.[4],[5]

Homoeopathy is more effective in the management of Type II DM compared to Type I DM as, in the latter, insulin secretion is grossly affected due to damage of the beta cells of pancreas. Homoeopathic medicines can be given along with insulin therapy when beta cells of pancreas have not undergone a degenerative change.[6] The homoeopathic medicines for diabetes are depicted in [Figure 1].[7]{Figure 1}

Homoeopathic medicines are prepared following a well-defined procedure, starting from substances derived from the mineral, herbal, animal and energy sources.[8] Taking into consideration the growing interest of the public in homoeopathic system of medicine[9] and its cost-effectiveness, more research must be focused on screening these medicines for diabetes. This will help in scientifically establishing the effectiveness of homoeopathic medicines and may aid in attracting the global market for the manufacturing of such low-cost medicine which ultimately will come as a boon to financially weaker sections of the global population.

Over the past few years, there has been a rise in the number of preclinical (in vitro and in vivo) studies directed at assessing the efficacy of homoeopathic medicines in the management of diabetes and its complications[10] Thus, a review of literature of the pre-clinical studies was carried out to investigate homoeopathic medicines evaluated in the management of diabetes. The present review updates researchers regarding the work carried out to date in the area of pre-clinical screening of homoeopathic medicines for diabetes.

 Methodology



Search strategy

The literature for the present review was identified using electronic databases including PubMed, HomBRex and published literature, like library catalogue. The reference lists of articles were also reviewed for additional relevant studies. Keywords used for this literature review include 'Homoeopathy', 'Diabetes' and their MeSH variations in PubMed and in HomBrex search was made using the condition 'Diabetes'. The search strategy was designed to include all the pre-clinical studies containing the descriptors that were published until November 2019.

Study selection

All titles, abstracts and complete articles were independently reviewed by two authors to eliminate duplications.

Inclusion criteria

In vitro and in vivo studies on homoeopathic medicines in the area of diabetes. Publications of the English language only were included.

Exclusion criteria

All the clinical studies were excluded. Review articles, Letters to the editor, conference proceedings and comments were also excluded. Unpublished data such as dissertations, data not published in peer-reviewed journals, and websites were not included.

Data extraction

Two authors independently extracted data on the medicines, dose, positive control, duration of study, outcome, results in in vivo studies and medicines, study assay, the outcome in in vitro studies. Discrepancies were resolved between authors by mutual consensus.

 Results



The database search was carried out to find relevant scientific papers published up to November 2019 reporting original pre-clinical research on homoeopathic medicines in the area of diabetes. The database search yielded 80 records, of which 77 were identified after the removal of duplicates. Of these, 30 review articles, 28 clinical studies and 4 commentaries were excluded as per the exclusion crieteria. After exclusion, 15 studies, consisting of 12 in vivo and 3 in vitro studies, were included for the present review [Figure 2]. No studies found were from outside India.{Figure 2}

Preclinical research work was carried out on Homoeopathic medicines, namely Syzygium jambolanum, Cephalandra indica, Gymnema sylvestre, Abroma augusta, Momordica charantia, Pterocarpus marsupium, Absinthium/Resina laricis, Chionanthus virginica, Uranium nitricum, Achilea millefolium, Allium sativum, Atropa belladonna, Cinchona officinalis, Hamamelis virginiana, Pulsatilla nigrican, Rhus toxidendron, Strychnos Nux-vomic, Iodium, Phosphorous and Alloxan. The in vivo studies are summarised in [Table 1] and in vitro studies in [Table 2].{Table 1}{Table 2}

Syzygium jambolanum

Syzygium jambolanum Q is prepared from coarse powder of seeds of the plant containing 82.0%–86.0% v/v alcohol.[11] Syzygium jambolanum has been screened for its antidiabetic potential in mother tincture and potentised dilutions. Maiti et al. had evaluated the effect of Syzygium jambolanum Q on carbohydrate and lipid metabolic disorders in Streptozotocin (STZ)-induced diabetic male rats.[12],[13] The results of the study indicated that Syzygium jambolanum Q treatment has a therapeutic effect on carbohydrate and lipid metabolic disorders and oxidative injuries in diabetic rats. Syzygium jambolanum Q has been found to decrease levels of blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDLc), very low-density lipoprotein cholesterol (VLDLc), serum urea, serum creatinine, serum uric acid and serum albumin in diabetic rats. It was found to increase body weight, plasma insulin, liver and skeletal muscle glycogen, hepatic and renal catalase, peroxidase and superoxide dismutase (SOD) levels. The Syzygium jambolanum Q has also been found out to improve carbohydrate metabolic key enzyme activities in hepatic tissue i.e., hexokinase, glucose-6-phosphate dehydrogenase and glucose 6-phosphatase in diabetic rats. This work also showed that Syzygium jambolanum Q treatment decreases serum glutamate oxaloacetate transferase and serum glutamate pyruvate transferase levels, thereby attenuating diabetes-induced hepatic injury in rats.

Another study elucidated the molecular mechanism of Syzygium jambolanum Q and its 6C and 30C potencies using a rat model of high fat and high fructose-induced Type 2 diabetes. Syzygium jambolanum Q and its 6C, 30C potencies exhibited antidiabetic effects, improving insulin levels and acting through activation of insulin signaling molecules (insulin receptor [IR], v-akt murine thymoma viral oncogene homologue [Akt], p-Aktser473 and glucose transporter-4 [GLUT4] proteins) in skeletal muscle of Type 2 diabetic rats. Variations were observed between SJMT and its potencies in the expression of insulin signaling molecules; however, ultra-molecular 30C dilution was the most effective in reducing fasting blood glucose.[14]

Increased glycation of proteins and accumulation of advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetic complications. In this respect, Rashmi et al. evaluated the effectiveness of Syzygium jambolanum Q, 30C and 200C in preventing glycation-induced structural modifications in albumin and their cellular protection ability in human erythrocytes in vitro. Syzygium jambolanum Q, 30Cand 200C inhibited glycation of albumin as evident from decreased levels of fructosamines, protein carbonyls, bound glucose and also protected thiol groups of albumin from oxidation. The medicine found to scavenge erythrocytes from glycation-induced oxidative stress and preventing free radical-induced erythrocytes membrane peroxidation which may have led to increased membrane rigidity, decreased cellular deformability, reduced erythrocyte survivaland lipid fluidity. The effects were much prominent with Syzygium jambolanum Q than compared to 30C and 200C.[15]

Cephalandra indica

Cephalandra indica Q is prepared from fresh pulp and leaves of the plant in 40.0% v/v alcohol.[11] Apart from Syzygium jambolanum, Cephalandra indica is also well used in homoeopathic system of medicine in the management of diabetes. In two studies, Rastogi et al. initially screened the hypoglycaemic potential of Cephalandra indica Q in alloxan-induced diabetic rats.[16],[17] The experimental studies revealed that regular administration of Cephalandra indica Q caused noticeable hypoglycaemic activity at a microdose level ranging from 25 to 75 μl/100 g. body weight and histopathological studies revealed the regeneration of pancreatic beta cells. Further, investigation of hypoglycaemic activity in alloxan induced diabetic rabbits was carried out and results revealed that Cephalandra indica Q and it's 3X preparations show a prominent drop in blood sugar levels.[18] Pal et al. had evaluated the antidiabetic effect of Cephalandra indica Q in STZ-induced diabetic rats at a dose of 75 μl/100 g. body weight and found a significant reduction in blood glucose levels, regain of body weight, recovery of beta-cells in the pancreas and partial recovery hepatic tissue of the Cephalandra indica Q-treated rats.[19]

Sathish et al. explained the molecular mechanism of Cephalandra indica Q and its 6C and 30C potencies by studying their effects on gastrocnemius muscle (Skeletal muscle) of high fat and high fructose-induced type-2 diabetic rats.[14] Cephalandra indica Q and its 6C, 30C potencies showed hypoglycaemic effect, restored insulin and lipid levels to normal levels. In gastrocnemius muscle of diabetic rats, these preparations improved insulin sensitivity by augmenting IR, v-akt murine thymoma viral oncogene homologue (Akt), p-Aktser473 and glucose transporter-4 (GLUT4) proteins. The effects were more prominent with 6C and 30C preparations compared to Cephalandra indica Q.

Glycation and AGEs formation accompanied by the formation of free radicals through auto-oxidation of glucose and glycated proteins leads to microvascular and macrovascular complications of diabetes. Cephalandra indica Q, 30C and 200C preparations were evaluated for their effectiveness in inhibiting glycation-induced structural modifications on protein albumin and their protective effect on human erythrocytes in vitro. The antiglycation potential of Cephlandra indica was manifested with reduced levels of fructosamines, protein carbonyls and bound glucose which are normally increased during albumin glycation. Cephalandra indica Q showed the highest efficacy when compared to 30C and 200C for antiglycation potential. The preparations also protected free thiol and amino groups of albumin from oxidation-inhibiting glycation. These Cephalandra indica Q and diluted preparations protected erythrocytes from haemolysis and also antioxidant power of erythrocytes was increased as evidenced by a rise in ferric-reducing ability of plasma activity. Erythrocyte protection was maximum with 200C dilution of Cephalandra indica.[15]

Kishore and Singh screened Cephalandra indica Q, 6C, and 30C potencies in the management of diabetic neuropathic pain and nephropathy in STZ-induced diabetic rats.[20],[21] Cephalandra indica Q and 6C and 30C potencies increased pain threshold and improved motor nerve conduction velocity in rats experiencing neuropathy. In rats suffering from nephropathy, Cephalandra indica Q, 6C and 30C increased body weight, serum insulin levels, HDLc and decreased fasting blood glucose, urea, uric acid, creatinine, LDLc and VLDLc. Further, oxidative stress in sciatic nerve and kidneys was found to be significantly reduced as evidenced by improvement in SOD, reduced glutathione (GSH) and lipid peroxide levels. AGE's levels were also decreased in sciatic nerve and kidneys of rats treated with the preparations. Histopathology of kidneys indicates a structural improvement in nephrons by the action of Cephalandra indica Q, 6C and 30C. The studies conclude that Cephalandra indica Q, 6C and 30C confer a protective effect against diabetic nephropathy and neuropathic pain through inhibition of oxidative stress and AGEs. The effects were more pronounced with 30C dilution compared to Cephalandra indica Q and 6C dilutions.

Gymnema sylvestre

Gymnema sylvestre Q is prepared from coarse powder of leaves of the plant containing 76.0%–80.0% v/v alcohol.[11] Kishore and Singh reported that Gymnema sylvestre mother tincture, 6C and 30C preparations had potent antiglycation activity in vitro. The preparations were found to act by inhibiting AGEs formation, sorbitol accumulation and aldose reductase enzyme.[22] The same preparations were then evaluated for their role in attenuating diabetic nephropathy in STZ-induced diabetic rats in vivo.[23] In diabetic animals, there were increases in fasting blood glucose, urea, uric acid, creatinine, blood urea nitrogen, total cholesterol, triglycerides, low-density lipoproteins and very low-density lipoproteins with a reduction in high-density lipoproteins. Gymnema sylvestre Q, 6C and 30C preparations improved the lipid profile, renal profile and fasting blood glucose in diabetic animals. Moreover, these preparations also restored the depleted antioxidant enzymes such as SOD, GSH and catalase in diabetic nephropathic rats. The AGEs level was also reduced by these preparations in kidneys and histopathological data indicates that structural changes induced by STZ in kidneys, liver and pancreas were reversed by these preparations. Amongst the preparations, 30C dilution was found to be more effective, and effects were comparable to Glimipride, in attenuating diabetic nephropathy in STZ rats.

Abroma augusta

Abroma augusta Q is prepared from the moist leaves of the plant and contains 42.0%–46.0% v/v alcohol.[11] Rastogi et al. reported that Abroma augusta Qhas mild hypoglycaemic potential at doses of 50 μl, 75 μl and 0.1 ml/100 g. b.w. in alloxan-induced diabetic rats without stabilisation of blood glucose levels.[16]

Momordica charantia

Momordica charantia Q is prepared from fresh pulp of the fruits of the plant in 57.0% v/v alcohol.[11] Sundaram studied the effects of Momordica charantia Q on blood sugar, serum growth hormone and prolactin levels in alloxan-induced hyperglycaemic rabbits. The report indicates that Momordica charantia Q at a dose of 20 μl/100 g body weight had significantly decreased blood sugar while increasing growth hormone and prolactin levels in diabetic rabbits.[24]

Absinthium X/Resina laricis 3X

Absinthium Q is prepared from coarse powder of leaves, seeds of the Artemisia absinthium in 63.0%–67.0% v/v alcohol. Resina laricis mother tincture is prepared from a highly viscous resin obtained by drilling trunks of Larix decidua.[11] Absinthium X/Resina laricis 3X formulation was found to exhibit perceptible hypoglycaemic activity at a microdose level ranging from 25 to 75 μl/100 g. body weight in alloxan-induced diabetic rats.[16]

Chionanthus virginica

Chionanthus virginica Q is prepared from coarse powder of bark of the plant and contains 61.0%–63.0% v/v alcohol.[11] Chionanthus virginica Q at a dose of 15 μl/100 g body weight was found to exhibit a decrease in blood sugar levels in alloxan-induced hyperglycaemic rabbits.[18]

Pterocarpus marsupium

Sundaram found that Pterocarpus marsupium Q and 3X preparations at a dose of 15 μl/100 g body weight significantly decreased blood glucose in alloxan-induced diabetic rats.[18]

Uranium nitricum

Uranium nitricum stock solution is prepared from Uranium nitricum, yellow-colored crystals with green fluorescence and contains 90% v/v alcohol.[11] Uranium nitricum 3X and 6X preparations were reported of showing hypoglycaemic activity at a dose of 15 μl/100 g body weight in alloxan-induced hyperglycaemic rabbits.[18]

Alloxan

Alloxan stock solution is prepared from anhydrous and orthorhombic crystals of alloxan.[11] A study evlauted dynamised and undynamised alloxan in 6X, 30X, 200X and 1000X potencies for its hypoglycaemic activity using alloxan-induced diabetic albino rats.[25] Results indicated that dynamised alloxan in 6X, 30X, 200X and 1000X potencies decreased blood sugar levels along with an increase in growth hormone levels in diabetic rats compared to undynamised alloxan at same potencies. Hypoglycaemic activity of dynamised alloxan was attributed to reactivation/restoration of beta cells by acting through hypothalamo–hypophysial–pancreatic beta cells axis as evidenced from histological analysis of brain and pancreas of diabetic rats. Animals were even found to show stabilization of blood sugar levels even after withdrawal of dynamised alloxan in 30X, 200X and 1000X potencies for 10–25 days after completion of treatment period (30 days). Dynamised alloxan at 200X and 1000X potencies had shown a significant antidiabetic effect compared to 6X and 30X potencies.

In vitro alpha-glucosidase inhibitory activity of Homoeopathic mother tinctures

Rehman et al. had investigated the in vitro alpha-glucosidase inhibitory activity of eight homoeopathic medicines Achilea millefolium, Allium sativum, Atropa belladonna, Cinchona officinalis, Hamamelis virginiana, Pulsatilla nigrican, Rhus toxidendron and Strychnos Nux vomica in mother tincture form. Results indicated that Strychnos Nux vomica and Atropa belladonna showed the highest activity even greater than positive control and the effect was correlated to the presence of secondary metabolites such as alkaloids and flavonoids in these medicines. Rhus toxidendron and Hamamelis virginiana showed moderate inhibition and other mother tinctures were not able to inhibit α-glucosidase up to 50% and so were considered to be weak inhibitors.[26]

 Discussion



The present review highlights that many medicines are employed in the homoeopathic system of medicine for the management of diabetes, but a few medicines have had their usage scientifically corroborated. Amongst these medicines, most of the preclinical research in diabetes in the past decade was carried out on Syzygium jambolanum and Cephalandra indica in mother tincture and potency formulations. These medicines have shown efficacy in reducing blood sugar levels, protecting beta cell destruction, restoring insulin levels, inhibiting the formation of AGEs and their probable molecular mechanism of action has also been elucidated. Apart from these two medicines, other medicines that have been evaluated earlier need to be revaluated for their antidiabetic potential as the earlier studies lack robust study protocols, comparison with a standard drug and histopathological evidences, etc.

In the above-reviewed studies, the rationale for the selection of the dose(s) of the medicines at which their efficacy was evaluated was not described. Moreover, some of the researchers had diluted mother tinctures and potencies in water before administration,[12],[13],[21],[23] while a few had used undiluted medicines,[14],[16],[17],[18],[20],[24] and the justification for the same was not stated in any of the reviewed papers. Keeping in view of the above points, further research should be carried out to address the above dissimilarities in animal models, and the results should be made open to biomedical researchers for bringing out uniformity in preclinical homoeopathic research.

Considering the small number of studies carried out, more pharmacological investigations (in vivo or in vitro) assuring their antidiabetic effect, the underlying mechanisms of action, long-term safety and potential toxicological effects are necessary to substantiate their appropriate use in humans. Most of these medicines are clinically employed in potentised forms i.e., in 6C, 30C and 200C, etc., and there is an ambiguity regarding their efficacy amongst the scientific fraternity. Hence, scientifically controlled studies devoted to potentised forms in investigating their mechanism and efficacy are encouraged. Moreover, these studies should report not only the magnitude of the effects but also the potential side effects and long-term safety.

In the reviewed studies, microvascular complications of diabetes such as neuropathic pain and nephropathy, respectively, were shown to be reduced by Cephalandra indica medicine in an animal model,[20],[21] and nephropathy was found to be ameliorated by Gymnema sylvestre in diabetic rats.[23] Hence, screening of other homoeopathic medicines having hypoglycaemic activity in the management of diabetic complications including both microvascular and macrovascular should be the prime motive of future research. As these medicines have effectively shown to combat DM, these may be effective in the treatment of other metabolic disorders such as obesity and hyperlipidaemia, and hence screening of these medicines in the management/treatment of these disorders seems encouraging.

Most of the homoeopathic medicines discussed in this review are derived from plants and it is noteworthy that the hypoglycaemic effect of plant-derived medicines can interfere with allopathic hypoglycaemic drugs and insulin, which are standard treatments for diabetic patients.[27] Most physicians counsel their patients to avoid herbal medicine, but in some cases, the diabetic patients take it without informing their physicians. This type of therapy may lead to drug interaction or false and unstable blood glucose level monitoring.[28] Therefore, studies assessing the effect of homoeopathic medicines when given along with allopathic medicines in animal models of diabetes are encouraging and may provide valuable information on potential toxicities or possible herb–drug interactions or significant risks.

Many in vitro methods based on chemicals, isolated organs, cells and membranes are available to study the safety and efficacy of medicines in the management of diabetes.[29],[30],[31],[32],[33] These assays provide a platform for rapid screening of medicines and also may help in understanding the cellular and molecular effects of drugs which may substantiate their efficacy when screened in animal models. Hence, given the handful number of homoeopathic medicines available for the management of diabetes, applying the in vitro models will help in the swift analysis of these medicines for their efficacy.

 Conclusion



The present review provides the researchers with an updated information on the status of pre-clinical antidiabetic research carried out on homoeopathic medicines and can guide them in planning future studies. Reproducibility of effects in basic pre-clinical research has the utmost importance and future antidiabetic studies may be planned as multiinstitutional, controlled, blinded studies to ensure quality and reproducibility in the evaluations carried out.

Acknowledgement

The author would like to thank Dr. Anil Khurana, Director General, Central Council for Research in Homoeopathy, New Delhi and Dr. D. B. Sarkar, and Dr. P. S. Chakraborty Dr. Anjali Chatterjee Regional Research Institute for Homoeopathy for their guidance and encouragements.

Financial support and sponsorship

Nil.

Conflicts of interest

None declared.

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