Diabe 250 is a groundbreaking anti-diabetic Ayurvedic formulation by innoveda under the aegis of NirogStreet. Supported by the U.S. patent, Diabe 250 helps maintain healthy sugar levels for diabetes patients. It has been prepared by an expert team of researchers and scientists at CSIR-IIIM and comes after a clinically proven research of more than 10 years.
You can read the findings of the research and clinical trials as well as suggested dosage below (meant for Ayurvedic practitioners and specialists only):
Trade Name: Diabe 250
Dosage Form: 250 mg Tablet
Route of Administration: Oral
Constituents of Diabe 250 tablet:
Each 500 mg tablet comprises of 250 mg of active ingredients and 250 mg of excipients.
The active ingredients are the dried and powdered aqueous extract (traditional Ayurveda Kwatha / Kashaya type of extract, dried in vacuum) of 16 herbs.
The herbs contributing to the active ingredients of Diabe 250 and their ratio:
Botanical name of the herb
Qty. by wt. used in preparation of 250 mg active ingredient
Fruit with seed
Seed without Shell
Fruit without seed
Stem with bark
Fruit with Seed
The excipients used in Diabe 250 and their quantity and concentration in percentage:
Use and concentration permitted in medicines
Concentration in Diabe 250 Tablet
Filler / diluent 20-90%
Diluent / Disintegrant 3-25%
Sodium starch glycolate
Sodium lauryl sulphate*
Lubricant / Surfactant 1-2%
Lubricant / Diluent 1-10%
Lubricant 0.25-5 %
* Sodium lauryl sulphate aids in dissolution
- Keep out of reach of children
- Store at 5 - 32 degree Celsius
- Protect from Heat, light and moisture
- Do not use if blister is open / broken
- Do not use after expiry.
Expiry Date: Two years from date of manufacturing specified on packing.
How to use Diabe 250 tablet: (THIS INFORMATION IS STRICTLY FOR CLINICIANS)
General instruction on use:
One tablet twice a day or as directed by physician, with warm or room temperature water
Clinical decision guide for Physicians to prescribe Diabe 250 tablets:
- In the prediabetic stage: 2 tablets once a day for 6 months, with review every 3 months.
- For newly identified NIDDM or NIDDM not on any medications: 2 tablets for 14 days, followed by blood checkup for compliance, followed by one tablet a day for the next 75 days and review. In case on 14 th day review of blood sugar levels, the levels have not come down continue the same dose for 4 weeks and then 1 tablet a day for 60 days, followed by review
- If the patient (not on any medication for diabetes) suffers from blood glucose variations over the day, 1 tablet each, BD, morning and evening.
- If looking for more intense blood sugar reduction, for example: patients showing inadequate response to OHDs or Insulin, it may be taken more than once, and the dose may be increased upto four times a day. (one tablet is 250 mg, the maximum dose is 2000 mg per day, which is equal to 8 tablets, in divided doses across the day)
- As preventive for diabetic nephropathy, to reduce urinary micro albumin and blood urea, 1 tablet OD, for 6 weeks minimum.
- As preventive in Metabolic syndrome (Metabolic syndrome defined as: LDL cholesterol level greater than 130 mg/dL and < 160 mg/dl and Triglyceride level greater than 150 mg/dL and less than 250 mg/dl): 2 tablets (500 mg) OD
- For preventing weight gain in obese diabetics (as an adjuvant with insulin secretogouges- glibenclamide): 500 mg (2 tablets) OD
- To enhance effectiveness of Metformin (to prevent increase in dose of metformin): 1 tablet OD added to previously effective dose of metformin.
- To reduce effective dose of metformin: half the effective dose, plus two tablet of Diabe, OD.
- To reduce effective dose of glibenclamide, 2 tablets with glibenclamide.
- To improve blood glucose with Insulin injections: 1 tablet OD
- For uncontrolled Diabetes: 250 mg (1 tablet) a day, along with other drugs.
Special instructions to be considered while prescribing:
- If taking as adjuvant to OHDs, better to take Diabe 250 half an hour or within half an hour, before OHD.
- If taking as adjuvant to insulin, Diabe 250 should be taken one hour or within one hour of insulin injection.
- No serious adverse reactions reported since the product launch in 2002
- No renal cell damage/ clinical deterioration of renal function or deterioration in renal function laboratory parameters reported since 2002.
- No hepato – cellular damage / clinical deterioration of liver function or deterioration in liver function laboratory parameters reported since 2002.
- Severe Hypoglycemia may be observed in 1/100000 users. (especially when concurrently administered with other OHDs or insulin).
- During first few days (upto 14 days) of use, fatigability has been reported by 1/1000 users.
- Mild GI irritability may be observed in 1/1000 users
- Mild Constipation may be observed in 1/10000 users
It has been clinically and experimentally proven that Diabe 250 increases the blood sugar lowering effects of Oral glucose lowering drugs such as Glibenclamide and Metformin, and also has a similar effect in Insulin. The details of drug-drug interaction of Diabe 250 with other drugs has not yet been studied systematically. Nevertheless, it has been co-administered with medications for Hypertension, High cholesterol, cardiac support, (most) anti-biotics, anti-inflammatories, proton-pump-inhibitors, and pain killers with apparently no observed drug-drug interaction effects reported.
- The effect of Diabe 250 on pregnant women and lactating mothers has not been studied as on December 2017. Therefore, it is not advisable for Pregnant and Lactating women.
- Similarly, since its effect has not been studied on pediatric population (as on December 2017), Diabe 250 is not to be given to children below 16 years of age.
- If Diabe 250 causes severe hypoglycemia, it should be stopped immediately, and should be restarted only under expert medical supervision and advise.
- If in the first two seeks of use, fatigability may be reported by 1/1000 users. This is overcome on its own by end of 2nd week. If fatigability persists after 2 weeks, the clinical is advised to reduce the dose of Diabe 250 or the concurrent anti-diabetic medication. If fatigability continues as a complaint at the end of 3 months, even after the necessary dosage correction, discontinue the medicine.
- Mild GI irritability may be observed in 1/1000 users. This is resolved on its own. In case of symptoms which can be classified as diarrhea is reported, discontinue the medicine.
- Mild Constipation may be observed in 1/10000 users. This is resolved by increasing the quantity of warm water intake. If severe constipation is reported discontinue the medicine.
Pharmacodynamics of Diabe 250:
Pharmacology of Diabe250 based on Ayurvedic knowledge:
Diabe 250 has 16 herbal ingredients in it. The combination of these 16 ingredients branches out functionally to seven different pharmacologically active functional groups and bestow on Diabe 250, seven distinct pharmacological actions. All these seven pharmacological properties of Diabe 250 are important for the health of a prediabetic / diabetic patient. The seven pharmacological functions and the corresponding ingredients of Diabe 250 are:
- Hypoglycemic: Salacia oblonga, Cyclea peltata, Biophytum sensitivum, Syzygium cumini, Mangifera indica
- Cell Protection, Regeneration, and Rejuvenation: Terminalia chebula, Emblica officinalis, Curcuma longa
- Cardiac anti-oxidant and cardio-vascular protective: Mangifera indica, Curcuma longa, Terminalia chebula, Embelia ribes
- Improving the health of the Urinary System: Cyclea peltata, Vetiveria zizanioides, Aerva lanata, Strychnos potatorum
- Anti-infective, Wound healing, and improving Vascular health: Embelia ribes, Curcuma longa, Biophytum sensitivum, Cyperus rotundus, Centella asiatica
- Improving health of Eye vasculature & Vision: Coscinium fenestratum, Emblica officinalis, Terminalia chebula, Strychnos potatorum
- Improve digestion, and cellular metabolism: Zizyphus jujuba, Curcuma longa, Cyperus rotundus
Pharmacology of Diabe250 based on Chemical compounds in Diabe 250:
Chemical and molecular structural analysis of Diabe 250 has proven the presence of several natural bioactive molecules in it. The main bioactive molecules of Diabe 250 are Epicatechin, Quercetin, Isorhamnetin, Betulin, Beta sitosterol, Oleanolic acid, Gallic Acid, Embelin, Curcumin, Kaempferol, Berberine hydrochloride, Berbamine dihydrochloride, Mangiferin, Isoorientin, Oleic Acid, Khusenic Acid, and Asiaticoside.
Each batch of Diabe 250 manufactured are spectroscopically analyzed to confirm the qualitative and quantitative presence of four of the bioactive compounds, Mangiferin, Berberine, Kaempferol, and Curcumin. This confirms that the tablet delivers a specific amount of these natural compounds to its user.
Bioactive compounds in 250 mg herbal extract
Quantity per tablet
0.29 ± 0.01 mg
0.0075 ± 0.005 mg
0.0025 ± 0.005 mg
0.0075 ± 0.005 mg
(ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Some information on quantified bioactive ingredients in Diabe:
Mangiferin: A xanthonoid. This molecule is a glucoside of norathyriol.
Mangiferin's xanthonoid structure with C-glucosyl linkage and polyhydroxy component is believed to be crucial for its free radical-scavenging ability leading to a potent antioxidant effect.
A number of biological activities of Mangiferin have been suggested, including antidiabetic and anti-inflammatory abilities. These might be explained by its antioxidant ability as well as its ability to modulate several key inflammatory pathways.
Mangiferin has also been shown to be an effective inhibitor of NF-κB signaling pathway. This partially explains its anti-inflammatory ability and, additionally, points towards its anticancer potential. The anticancer effects of this compound are emerging.
Berberine: An isoquinoline alkaloid
Berberine has demonstrated significant antimicrobial activity against bacteria, fungi, protozoans, viruses, helminths and chlamydia. In addition, berberine's actions include: antagonism of the effects of cholera and E. coli heat-stable enterotoxin, inhibition of intestinal ion secretion, inhibition of smooth muscle contraction, inhibition of ventricular tachyarrhythmias, reduction of inflammation, elevation of platelet count in patients with primary and secondary thrombocytopenia, and stimulation of bile secretion and bilirubin discharge. Berberine's most common clinical uses include: bacterial diarrhea, intestinal parasites, and ocular trachoma infections. Evidence also suggests intravenous berberine administration can play a role in preventing the onset of recurrent ventricular tachyarrhythmias and sudden coronary death after myocardial ischemic damage.
Berberine when administered in diabetic patients reduces blood glucose levels significantly and also the patients had less thirst, consumed less water and urinated less, had improved strength, and had lower blood pressure. Laboratory studies suggest that berberine may have at least two functions in relation to reducing blood sugar: inhibiting absorption of sugars from the intestine and enhancing production of insulin.
Kaempferol: 3,4',5,7-Tetrahydroxyflavone (Flavonoid)
Keampferol is a strong antioxidant and helps to prevent oxidative damage of cells, lipids and DNA. Kaempferol prevents arteriosclerosis by inhibiting the oxidation of low density lipoprotein and the formation of platelets in the blood. Studies have also confirmed that kaempferol acts as a chemopreventive agent, which means that it inhibits the formation of cancer cells.
An in vitro study by Jan Kowalski et al (Pharmacological Reports, 2005) showed that kaempferol inhibits monocyte chemoattractant protein (MCP-1). MCP-1 plays a role in the initial steps of atherosclerotic plaque formation.
A study "Inhibition of P-glycoprotein function and expression by kaempferol and quercetin" by the Chiang Mai University, Thailand, found that kaempferol can help to fight cancer because it reduces the resistance of cancer cells to anti-cancer drugs such as vinbalstine and paclitaxel
Curcumin: A Polyphenol.
Curcumin is known for its antitumor, antioxidant, anti-amyloid, anti-diabetic and anti-inflammatory properties. Its anticancer effects stem from its ability to induce apoptosis in cancer cells without cytotoxic effects on healthy cells. Curcumin can interfere with the activity of the transcription factor NF-κB ( NF-kB ), which is often highly overexpressed in many cancer cells.
A 2004 UCLA-Veterans Affairs study involving genetically altered mice suggests that curcumin might inhibit the accumulation of destructive beta-amyloid in the brains of Alzheimer's disease patients and also break up existing plaques associated with the disease.
It is published that curcumin inhibits cyclooxygenase-2 (COX-2) as well as lipoxygenase (LOX), two enzymes involved in inflammation.
Intellectual Property Information:
US Patent: 8,163,312 B2
Development history of Diabe 250:
The formula of Diabe 250 got developed and finalized over a period of five years from 1996 to 2000 at Sanjeevani Ayurveda Hospital, Trivandrum, Kerala. The specific combination was identified as a stabilizer of blood glucose levels as early as 1997. The clinician researcher working on Diabe 250 formulation noticed that the combination, among several other permutations tried as add-on medications, had the best blood glucose stabilizing effect on inpatient Diabetics. In the beginning, this effect was noticed in chronic Diabetic patients who had been admitted to the hospital for treatment of Diabetic retinopathy (D-Rp). Most of these D-Rp patients were under multiple oral drug therapy for their blood level controls or under insulin therapy, with or without oral hypoglycemic as add-ons.
In Kerala, it is a culturally inbuilt practice to use drinking water boiled with some suitable herbs in households. This water is prepared every day, and supplied fresh. During Ayurvedic treatment it is substituted with medicated water. The preparation of such medicated drinking water is termed “Toya paka” or “Pana kalpana” in Ayurveda. The classical process of preparing Toya paka is to boil 48 grams (1 palam) of the herbal medicine in 3072 mL, (1 Adaka) of water, boiled and reduced to 1536 mL. For daily practical purposes 50 grams of the medicine mixture is boiled in 3200 mL of water and reduced to 1600 mL.
Preliminary Efficacy and Safety of Diabe 250 formulation.-Drinking Water
The D-Rp patients were given 1.6 liters of freshly prepared medicated drinking water made of Diabe 250 formulation as described above (Toya paka) and requested to consume this instead of regular drinking water, as part of the treatment regimen. Later, the same herbal combination was advised to patients who approached the outpatient clinic for Ayurvedic management of Diabetes and also to other in-patients who had no complaints of D-Rp. The researcher was encouraged by the results and set upon the task of systematically following the blood glucose values of more than 50 patients between the years 1998-1999. A significant reduction in random blood glucose levels in these patients were noticed corresponding to their use of Diabe 250 formulation, irrespective of their in-patient / out-patient status.
Encouraged by the consistent result, the clinician started using the formulation on all Diabetic patients who visited his OPD. During this period, few patients who did not consume the entire 1600 mL per day dose (50 grams of the drug) also showed good reduction in blood glucose. From the information collected by enquiring in detail with the patients, it was observed that even patients taking 200 mL of the prepared medicated water had improvement in the blood glucose values and in certain cases these improvements were at par with the 1600 mL consumption. Another aspect noticed was that, the out-patients who prepared the medicine at home, many a time deviated from the prescribed format of preparation. On enquiry it was understood that many boiled the drug in 1600 mL for some time and then used it, while some others added 1 or 2 tablespoon scoops of the drug into 1 or 2 glasses of water and boiled it. 1 to 2 tablespoons of the drug would mean 6 to 12 grams approximately of Diabe 250 formulation in the herbal mixture form. Some patients boiled the drug in 1-2 glasses of water and drank it twice a day. Most satisfied reduction in blood glucose levels were observed in patients using the full dose every day.
Side effects of the drug was also observed during this period in patients who were consuming the full dose of the drug. 1 in-patient, who was on insulin and was started with Diabe 250 formulation developed hypoglycemia. 2 more patients on insulin complained of extreme tiredness after consuming the water that they requested to withdraw the medicine. Diarrhea was another common complaint. Nearly 12 patients complained of diarrhea and discontinued the medicine. Another complaint was severe itching in lower limbs, which was presented by 4 patients. About 10 patients complained of increased gas formation in the intestine and flatulence. It was also noticed that these side-effects were presented by those patients who were using 50 grams dosage and none of those who had been using the drug in smaller doses presented with any such side-effects. A general complaint from the patients was the bitter taste of the water, which needed to be taken throughout the day.
Based on these observations, it was believed that the drug might work in smaller doses. Reduced dosage offered the added benefit of possibility of reduced side-effects. Towards the beginning of the year 2001, Investigator started prescribing smaller doses and more easy preparation methods to the patients. The doses tried were 25 grams (1/2 of 50 grams), 12 grams (1/4 of 1 Pala) and 6 grams (1/8 of 1 Pala). It was observed that patients taking 6 grams and boiling it in 1.5-2 liters of water even for 2 minutes and consuming the entire water in 24 hours also showed comfortable blood glucose reduction similar and comparable to the larger doses. It was also observed during this period that not everyone prescribed with 6 grams daily dose of the medicine in the outpatient clinic reported an appreciable decrease in the blood glucose levels, though every one of the in-patients showed a definite beneficial effect.
The questions that were raised with these findings were:
1. Was the drug effective or was it giving a placebo effect at 6 grams per day dose? and
2. Was the drug beneficial enough along with modern anti-Diabetic drugs, which most of the patients approaching an Ayurvedic doctor were already on as the standard therapy?
It is to be noted here that most of the Diabetic patients approach an Ayurvedic doctor and present the desire to reduce or completely withdraw the modern medical drugs. Thus, in India, concurrent therapy with Ayurvedic and modern medical drugs is a very common routine which Diabetic patients electively undertake.
Meanwhile in the year 2002, the Investigator registered an Ayurvedic manufacturing company and licensed the 6 grams daily dose medication as an Ayurvedic drug from the drugs controller of Kerala State. The product was marketed as an effective drinking water supplement for Diabetics through advertisement in Kerala, and the medicine was a success as an OTC product in Kerala.
Efficacy and Safety of different doses of Diabe 25 formulation (Drinking water):
To address the question raised during early efficacy observations, efficacy of 2.5 grams, 5 grams and 7.5 gram daily dose of Diabe 250 formulation was compared during 2001-2002. This clinical observation was done in newly identified diabetic patients who approached the Ayurvedic OPD. 48 patients were enrolled in this observational study. All patients were newly identified diabetics who wanted to try Ayurvedic medication before attempting allopathic drugs. All doses of the drug were given to the patients and followed up for 3 months. Their fasting blood glucose levels were observed at interval of 15 days. All doses were made available in 90 individual packets of specified dosage each and dispensed on the first day after the mandated blood sample collection at the clinic. The patients were given written detailed prescriptions to boil the medicine in 1.5 liters of water for 2-3 minutes and drink in 5 -8 divided doses, so as to finish the entire water on the same day. No change in their other ongoing medication (if any) was mandated. No extra diet / exercise precautions were advised to these patients. Two glycosylated hemoglobin check-ups were performed, one before commencing the medicine and other after 3 months of medication. At the end of 90 days patients came for follow-up visit with their intermittent FBS readings. Patients were asked to come for another follow-up after 15 days of completion of 90-days study period. Statistical analysis showed significant benefits in all groups, though 7.5 grams group offered the best glucose control outcome. Nevertheless, the difference in HbA1c reduction and PPBS reduction between the groups were not statistically significant. At the same time it was noticed that 7.5 grams group had complaints of palatability.
After this observation Diabe 250 formulation was marketed outside Kerala in other Southern Indian States via direct marketing route. Several Franchisees were established in the States of Tamilnadu, Karnataka, Andhara Pradesh and metros like Mumbai and Kolkota through advertisements in national and local newspaper and magazines. The franchisees worked as direct marketing units. Each franchisee had direct marketing agents called as “Diabetic councilors”. These Diabetic councilors identified the Diabetic patients through different options (free Diabetic check-up camps, Diabetic awareness camps, collecting information from local chemists and laboratories, referrals from known people and existing customers etc.); and contacted them individually and convinced them about usefulness of the medicine. Two blood glucose check-ups were offered and conducted, one before the consumption of the drug and another after one month of usage, for each sale.
The product presentation was changed during this period. In the beginning the drug had been marketed as powder of herbal mixture in vacuumed 5 layer plastic cover, put in an HDPE plastic container with lid. The main disadvantage with this presentation was that patients were not able to take the exact dosage prescribed and used different doses depending on the individual perceptions. To overcome this challenge, the packing of the product was made into tins, which contained 30 tea-bags of 2.5 grams each. The product was also registered as herbal food supplement under the Bangalore corporation licensing authority. The franchisee operation proved to be an unintentional but very useful resource for information regarding the effectiveness of the drug. This automatically led to the collective information of before and after blood glucose level results. It also meant that the complaints and suggestions of the patients were constantly reviewed and responded to, during this period.
In the 2003, the drug formulation in tablet form was started in few small laboratory scale batches at laboratory. The tablet was named as “Diabe” and launched in the market in early 2004, along with Diabedrink.
Diabe picked-up a lot of market including among patients who were on Diabedrink.
First Randomized Placebo controlled study on the Diabe 250 formulation
During the 2003-2004 period the first placebo-controlled study of the Diabe 250 formulation was conducted, to assess the effectiveness of supplementation with Diabe 250 formulation (Diabedrink), on patients using Glibenclamide (a Sulfonylurea). The study protocol was approved by the ethics committee headed by Dr Raveendranathan Nair, Director, College of Pharmaceutical Sciences, Medical College, Thiruvananthapuram, Kerala. Patients were recruited from the out-patient departments of Sanjeevani Ayurveda hospital, Thiruvananthapuram, Kerala, Mahabodhi Mallige Hospital, Jaya Nagar, Bangalore, and Sanjeevani Holistic Health Care Center, Singasandra, Bangalore, during the monthly diabetic specialty clinics run by ROOTS, Bangalore. Following the prescribed inclusion and exclusion criteria, and the due consenting process, 30 patients each, were recruited into each of the group. This prospective, subject blinded, placebo controlled, outpatient-based study recruited consenting subjects fulfilling the requirements of the inclusion and exclusion criteria, on alternate basis into each group. The study period for each subject was 90 days with a follow-up of 15 days thereafter. The entire evaluation was completed in 11 months.
Both the study drug as well as the placebo was provided to the subjects in wide mouthed plastic jars with air-tight lids, containing 33 unmarked, plain-white, sealed paper packets. Each of the paper packet contained 2.5 grams of the drug or the placebo, in coarse powder form. The subjects were advised to use contents of one packet for the preparation of medicines per day. They were advised to put the contents of one packet, in 1 liter of water, then apply heat and once the water starts boiling, allow boiling for 2 minutes. Thereafter they had to sieve the decoction off the herbal ingredients and store the clear decoction in a hygienic container. They were informed that the prepared drink was good to be consumed within 24 hours and they had to make the drink every day. The subjects were requested to come to the OPD for review and sample collection any day between the 28th and 32nd day, from the date of every visit.
The subjects were advised to use the drink as an alternative to drinking water and to spread its use across the day, drinking it in divided doses, as and when they felt thirsty. They were informed that they were allowed to consume other fluids, including normal water, in case they felt the need to, during the course of the day, while participating in the study. Glibenclamide was maintained at the same dose that the patients were taking, throughout the study period.
The Trail period was 105 days. During the first 90 days (from screening) the add-on therapy was introduced to the subjects’ daily routine. Day 91 to 105 was the period of add-on free follow-up, during which the add-on drugs related to the study were completely withdrawn and the subjects continued to take glibenclamide in the same dose.
The study results showed without any reason for doubt that the Diabe 250 formulation improves glycemic control when co-administered with glibenclamide. It reduces Fasting and Post Prandial blood sugar levels by an average mean value of 30 mg/dL more than the Placebo. It also reduces the HbA1c values by nearly 1% in a period of 90 days. It was concluded that the Diabe 250 formulation may be used as a safe herbal add-on to glibenclamide to improve therapeutic action and increase effective dose duration. (ref: Pharmacological integration: adjunct effect of db14201, a new herbal formulation developed based on Ayurvedic Principles, when co-administered with glibenclamide: Results of a placebo controlled trial. Annals of Geriatric Education and Medical Sciences, January – June 2015)
Efficacy and Safety of Diabe 250 (Tablet) compared with Diabe 250 (Drinking water) and Placebo
Two franchisees, one at Trivandrum, Kerala and another at Bangalore, Karnataka, enrolled 2-3 new patients each per month into the observational program. As a part of recruitment, these patient customers were supplied medications, offered regular blood checkups and Ayurvedic medical consultations for 8 months. Type 1 Diabetics and pregnant women were not selected. The observational program was continued for two years and two months (August-2004 to September-2006). Each patient was to be followed through for 230 days from the day of participation and first blood check-up. The Diabetic councilors were able to recruit the 150 patients by January 2006, after which no new patients were included.
Both Diabedrink and Diabe tablets were dispensed in the commercially marketed packing. The placebo (coarsely powdered mixture of Ricinus communis and corn sheath) was introduced as the new drug and dispensed in 2.5 grams teabags, 30 each being packed in labeled and numbered brown cartons. The new medicine (placebo) was advised to be prepared and used in a similar manner to Diabedrink. Diabe tablet was to be consumed 4 times a day. Diabetic councilors supplied only 30 days of medicine at a time or till his / her next visit to the subject.
Enrolled patients were given Diabedrink, Placebo and Diabe, in that order within the 8 months. The stretch of 8 months also included 3 windows of no medication, stretching for 30 days, 10 days and 10 days each. Throughout the period those patients who were under conventional anti-Diabetic drugs were advised to maintain their dose, as prescribed by their GP/ Endocrinologist.
The introduction of the 30 day no-medication period was to reconfirm the effect of Diabedrink on a larger population than earlier and also to see if there were any residual effects of the medicine at 30 days after withdrawal. The 10 day windows of no-medication were intended to avoid any residual medication or placebo effect on the patients, influencing the effect of the next medication.
35 of these patients did not complete the 8 months period of the program making only 115 patients who completed the entire 230 days. 18 patients who were enrolled into the program had been discontinued since the Diabetic councilors who recruited these patients and were dealing with them left the job and new trained counselors could not be recruited in time which led to non-completion of the requisite formalities of the program. These patients were given Diabedrink to complete the 8 months. Another 7 patients had to discontinue the medications owing to unrelated sporadic diseases, which included viral fever (4 cases), chicken-pox (2 cases) and road accident (1 case).8 patients left the study on their own not assigning any reason for doing so.
Relevant signs and symptoms were recorded at regular intervals during the course of the observational program. Blood test reports recorded were Fasting and Post Prandial Glucose levels and Glycosylated hemoglobin levels. Clinical symptoms such as ease of bowel evacuation and pain, were also enquired about and data recorded. Data were recorded on day 0, day 30, day 60, day 90, day 100, day 130, day 140, day 170, day 200 and day 230. HbA1c was assessed only on day 0, day 140 and day 230. Whenever patients were in the habit of checking their Fasting and Post Prandial Blood Glucose values as part of their daily routine, the same data were used. Such patients were provided the required number of test-strips used in their respective monitors. Others were checked using blood glucose monitors carried by the Diabetic councilors who visited them at home / office. Subjective symptoms were recorded by the Diabetic councilors on the respective days while personally visiting the patients to check their blood, or over the telephone, in case the patients were testing blood on their own.
The compilation of the data established that FBS and PPBS levels were affected differently by the drug.
Diabedrink powder reduced FBS and PPBS in 30 days of use. Glucose levels significantly lowered from day 0 to day 30 and again from day 60 to day 90.
Withdrawing Diabedrink elevated blood glucose levels significantly. The sugar level rose significantly, from day 31 to day 60 and from day 91 to day 100. At day 60, the patients were on no medicine for 30 days, whereas on day 100, the patients were on no medicine for just 10 days. Correspondingly the increase in sugar levels from day 31 & day 60 was significantly more than the increase from Day 90 to Day 100. Thus, glucose levels were significantly higher after 30 days of Diabedrink withdrawal than 10 days, showing a residual effect of the drug at 10 days.
Fasting Sugar levels at day 60 (where the patients were off Diabedrink for 30 days) was significantly more than the FBS levels at day 130 (where the patients were on placebo drink for 30 days, after being on no medicine for 10 days).
This finding suggests that placebo also had an effect in FBS level reduction.
Sugar levels decreased significantly after 30 days of Diabe tablet use. There was no further significant reduction in the next 30 and 60 days after the initial reduction, suggesting that the effect plateaued after the initial decrease. 30 days use of Diabe tablet showed a significant reduction in sugar levels in comparison to 30 days use of Diabedrink powder, showing that the tablets were probably more effective than the powder in drinking water form.
Further history of Diabe 250 formulation
With analysis of the compiled data of the two-year program, it was decided to develop the drug through the pharmacological route as the effort seemed worthy and justified enough. Investigator was convinced that the drug had to be marketed as an ethically promoted prescription drug, then an OTC or directly marketed product. It was decided to withdraw the drug from the market and concentrate on its Research & Development activity, to facilitate its reentry as an herbal drug, which had been scientifically proven.
With marketing being discontinued from 2007, the production unit at Bangalore was also closed down in the same year and the entire resources pooled into drug research. Existing regular customers had since been serviced by utilizing the production facilities of T-Stanes Herbal Division, which is a GMP certified unit at Coimbatore, Tamil Nadu. T-Stanes also have a DST / AYUSH approved, DSIR-SIRO certified laboratory for drug standardization and herbal research and that of Surya Herbals, a WHO GMP certified herbal drug manufacturing unit in NOIDA, Uttar Pradesh.
Outsourcing work to Dabur Research Foundation, initially and later forging a strategic collaboration with IIIM (CSIR) several research projects were undertaken on the Diabe formulation, including drug characterization and standardization, short and long-term safety studies, and a number of efficacy and mechanistic studies.
Studied Pharmacological actions of Diabe 250:
Anti-hyperglycemic effects of Diabe 250 formulation
The anti-hyperglycemic effect of Diabe 250 formulation administered by oral route in STZ induced Type I diabetic rats was studied. After 14-days of continuous treatment with Diabe 250 formulation in 500 mg/kg treatment group, the blood glucose levels decreased by 85.24% showing a significant (P<0.01) anti-hyperglycemic potential of extract with reference to the hyperglycemic control animals. In conclusion, the study clearly demonstrated the ability of Diabe 250 formulation extract to effectively bring down blood sugar levels in hyperglycemic rats after 14-day continuous oral administration and this activity is seen best at a dose of 500 mg/kg/day body weight. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation on polyuria, polydipsia, fur-coat, polyphagia.
Treatment with Diabe 250 formulation seemed to offer protection against the hyperglycemic clinical symptoms viz. polyuria and polydipsia. Diabe 250 formulation treated animals had a smooth and even fur coat as opposed to coarse fur coat in hyperglycemic control group. However there was no protection against polyphagia throughout the study period. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation in diabetic nephropathy.
Effect of Diabe 250 formulation in STZ induced diabetic nephropathy in C57BL/6 mice. The results clearly indicated dose dependent promising anti-diabetic activity of Diabe 250 formulation at the tested dose level and treatment period in multiple low dose of STZ induced diabetes model. Considerable inhibition in elevation of glycated hemoglobin indicates the regression of diabetic severity. Biochemical data at the end of treatment period suggests the utility of Diabe 250 formulation treatment in diabetes induced complications. Two month of diabetic stabilization in experimental model leads to further biochemical changes that lead to several complications. Four week treatment of Diabe 250 formulation at high dose (500 mg/kg) evidence of remarkable inhibition of circulating glucose level and urinary microalbumin strongly exhibits the significance of Diabe 250 formulation in diabetes induced nephropathy. There was no change in glomerular number and nodular lesions and tubules, blood vessels and interstitium were found to be within normal limit in all assigned groups. The glomerular (G) loops have thin basement membranes normal complement of cells and the mesangial matrix is sparse. Tubular (T) basement membranes are within normal limits and tubular epithelium does not show any damage. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation in diabetic atherosclerosis.
Effect of Diabe 250 formulation in STZ induced diabetic atherosclerosis in C57BL/6 mice. The results obtained from the STZ induced diabetes followed by athrogenic diet induced atherosclerosis animal model strongly demonstrated that, 28 days oral administration of 500 mg/kg of Diabe 250 formulation has potential role in reducing the levels of biomarkers that leads to the formation of atherosclerosis. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation in combination with standard drug metformin.
Effect of Diabe 250 formulation in combination with standard drug metformin in STZ induced diabetes mellitus in wistar rats. Findings of this study strongly demonstrated the anti-diabetic activity of Diabe 250 formulation in combination with suboptimal dose of metformin. The combination of Diabe 250 formulation at 250 mg/kg and 500 mg/kg with suboptimal dose of metformin i.e. 250 mg/kg showed additive anti-diabetic activity as compared to individual treatments. Interestingly, 21 days treatment of high dose of Diabe 250 formulation with suboptimal dose of metformin demonstrated greater anti-diabetic activity as compared to optimal dose of metformin. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation in combination with standard drug glibenclamide.
Effect of Diabe 250 formulation in combination with standard drug glibenclamide in STZ induced diabetes mellitus in wistar rats. Findings of this study strongly demonstrated the role of Diabe 250 formulation in the potentiation of anti-diabetic effect of suboptimal dose of glibenclamide i.e. 1 mg/kg. Result clearly indicated the anti-diabetic effect of combination treatment of high dose of Diabe 250 formulation and sub optimal dose of glibenclamide was comparable to anti-diabetic effect of optimal dose of glibenclamide. Hence it can be concluded that, the combination of sub optimal dose (1 mg/kg) of glibeclamide with Diabe 250 formulation 500 mg/kg shows superior results as compared to individual treatment of glibenclamide (1 mg/kg) and Diabe 250 formulation 500 mg/kg. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation in combination with standard drug insulin.
Effect of Diabe 250 formulation in combination with standard drug insulin in STZ induced diabetes mellitus in wistar rats. Findings of this study strongly demonstrated the role of Diabe 250 formulation in the potentiation of anti-diabetic effect of suboptimal dose of insulin. Low dose of Diabe 250 formulation in combination offered superior results. The combination of suboptimal dose of insulin i.e. 1 μg/kg with Diabe 250 formulation at 500 mg/kg shows better results as compared to individual treatment of both insulin (1μg/kg) and Diabe 250 formulation (500 mg/kg). In addition to this the combination of suboptimal dose of insulin i.e. 1 μg/kg with Diabe 250 formulation 250 mg/kg showed enhanced result as compared to individual treatment of both insulin (1 μg/kg) and DB14201 (250 mg/kg). Interestingly, result clearly indicated the anti-diabetic effect of combination treatment of low dose of Diabe 250 formulation and sub optimal dose of insulin was comparable to anti-diabetic effect of optimal dose of insulin (5 μg/kg). (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation on prevention of diabetes mellitus.
Effect of Diabe 250 formulation on prevention of development of STZ induced diabetes mellitus in wistar rats. Findings of this study strongly demonstrated that Diabe 250 formulation treatment have prominent role in the prevention of STZ induced diabetes mellitus. Result clearly indicated the prophylactic as well as therapeutic potential of Diabe 250 formulation in this experimental model. Diabe 250 formulation at the dose of 500 mg/kg was found to be more promising. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effect of Diabe 250 formulation on uncontrolled diabetes.
Amongst all the groups treated with Diabe 250 formulation, the Combination of Metformin 250 mg/kg and Diabe 250 formulation 250 mg/kg showed maximum efficacy in lowering the blood glucose level as shown in figure 4e. However, Diabe 250 formulation -250 mg/kg showed maximum survival rate at the end of the study. The present study clearly demonstrated that Diabe 250 formulation 250 mg/kg offers maximum protection from mortality in case of uncontrolled diabetes. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Cardio-protective potential of Diabe 250 formulation.
Treatment with Diabe 250 formulation led to reduction in the levels of lipid peroxides at all doses as compared to control samples. SOD activity was found to be either comparable or elevated in Diabe 250 formulation treated groups. However the elevation in activity was most pronounced at low dose of 250 mg/kg. Catalase activity was also found to be elevated in all Diabe 250 formulation treated groups with highest elevation obtained at the low dose of 250 mg/kg as depicted in figure 4f. The results obtained from the present study, suggests that Diabe 250 formulation may possess antioxidative cardioprotective potential against the diseases associated with free radicals. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Studied mechanisms of pharmacological actions of Diabe 250:
α-glucosidase and α-amylase inhibitory activity of Diabe 250:
Intestinal α-glucosidase is a key enzyme for carbohydrate digestion and has been recognized as a therapeutic target for the modulation of postprandial hyperglycemia which is the earliest metabolic abnormality that occurs in type-2 diabetes mellitus. α-Amylase catalyses the hydrolysis of 1,4-glucosidic linkage of starch, glycogen and various oligosaccharides into simpler sugars which can be readily available for the intestinal absorption. Therefore, inhibition of α-amylase enzyme in the digestive tract of humans is being considered to be effective in controlling diabetes by decreasing the absorption of glucose from starch. Natural products are still the most available source of α-glucosidase and α-amylase inhibitor. Diabe 250 has demonstrated α-glucosidase inhibition at concentrations 50-1000 µg/mL. It was observed that at 1000 µg/mL, Diabe 250 showed strong inhibitory activity which was comparable to that of Acarbose (the standard drug). The enzyme inhibition with Diabe 250 tablet is in the range of 24.87−94.96 %. Similarly, Diabe 250 shows strong α-amylase inhibitory study at concentrations ranging from 50−1000 µg/m. At 1000 µg/mL, the formulation showed strong inhibitory activity than that of the standard employed (acarbose). (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
Effects of Diabe 250 on glucose uptake, TNF-α production and free fatty acids release by adipocytes and effect of insulin release by pancreatic-beta cells:
The plausible mechanism of action of Diabe 250 extract was evaluated based on key parameters viz. glucose uptake, TNF-α production and free fatty acids release by adipocytes and effect of insulin release by pancreatic-beta cells. Diabe 250 was found to be non-cytotoxic at concentrations from 0.1-600 μg/ml for 48 h on 3T3-L1 adipocytes and 0.1-100 μg/ml for 6 h on RIN-5F cells. The criteria for evaluation of non-cytotoxic concentrations are cell viability considered as ≥70 % as compared to control cells. Hence this concentration range was found to be non-cytotoxic and safe to use for the further evaluation of anti-diabetic potential of Diabe 250. The developed extract also demonstrated 68% - 133% increase in glucose uptake in 3T3-L1 adipocytes at concentrations from 0.1– 600 μg/ml as compared to untreated control cells after 24 h. A maximum of 133% increase in glucose uptake was recorded at 1 μg/ml concentration. The effect of Diabe 250 on cytokine release in 3T3-L1 preadipocytes was also studied. 3T3-L1 preadipocytes after stimulation with LPS (100 ng/ml) led to an increase in IL-6 release from 9.87 pg/ml (untreated control cells) to 28.76 pg/ml. Whereas, 3T3-L1 preadipocytes which are pretreated with Diabe 250 for 24 h at concentrations ranging from 1 μg/ml – 500 μg/ml demonstrated considerable inhibition in IL-6 release of 6.89 pg/ml – 16.41 pg/ml or 42.94 % to 76.04 % inhibition as compared to untreated control cells. The effect of Diabe 250 on adipolysis demonstrated that co-treatment of TNF α (10 ng/ml) and glucose (25 mM) led to an increase in glycerol release from 2.90 μg/ml (untreated control cells) to 19.84 μg/ml. Pretreatment with Diabe 250 for 24 h at concentrations from 1– 25 μg/ml of stimulated 3T3-L1 adipocytes led to inhibition of glycerol release from 19.84 - 1.37 μg/ml – 12.39 μg/ml or 37.57 % - 93.08 % as compared to untreated control cells. Hence, Diabe 250 (0.1– 25 μg/ml) demonstrated considerable inhibition of Glycerol release against TNF alpha and Glucose co-stimulated levels. Diabe 250 (0.1– 100 μg/ml) demonstrated 3.66 % - 458.40% increase in insulin release in RIN-5F cells after 6 h of treatment. A maximum of 458.40% increase in insulin release was recorded at concentration of 100 μg/ml. (ref: Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies. Journal of Ethnopharmacology. DOI: doi:10.1016/j.jep.2016.07.062)
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