Evaluating Role of Cholagogue and Choleretic Drugs in the Management of NIDDM Related to Post Cholecystectomy-A Pilot Clinical Trial

Undoubtedly diabetes is related to hyperglycemia but diabetic patients may also suffer severe complications due to disturbed physiological and biochemical processes associated with the disturbed bile acids production and microfloral composition1–6. Use of bile acids in diabetes treatment is now a day encouraging because it is found to improve glycemia as well the ameliorate complications. A long waited major improvement would be the discovery of treatments for diabetes that avoid and even replace the absolute requirement for injected insulin. Recent studies in a rat model of Type 1 diabetes show that a multi-therapeutic approach incorporating bile acids and probiotics, as adjunct therapy, exerted better control over glycemia and resulted in ameliorating complications, than when each treatment was administered alone7,8. Accordingly, improving diabetes complications, reducing prevalence and restoring normal physiological patterns Abstract

should significantly optimise diabetes treatment and the quality of life of diabetic patients.
In the past, bile acids were considered to have three basic physiological functions 9 However, recent studies have expanded the role of bile acids to include endocrine signaling to regulate glucose, lipid and their own homeostasis and influence energy expenditure and gut microfloral composition.
Hepatic fat accumulation is a well-recognized complication of diabetes with a reported frequency of 40-70 %. Impaired gall bladder contraction was found amongst patients of diabetes mellitus with autonomic neuropathy. The mechanism responsible for cholecystoparesis is attributed to vagal neuropathy. Incomplete gall bladder emptying leads to sequestration of cholesterol and nidus formation. Patients of diabetes mellitus had statistically significant larger fasting gall bladder volumes and these values were highly significant amongst patients with autonomic neuropathy. 2. Patients of diabetes mellitus and statistically significant larger post fatty meal gall bladder volume and these values were highly significant in patients with autonomic neuropathy 11 .

Relation between Disturbed Bile Salt Concentration and Diabetes
The amino acid taurine, which is used by hepatocytes in bile acid conjugation and bile salts formation, has many other physiological functions including the regulation of intracellular osmolarity, cardiomyocytes functions, and as an antioxidant. A hypoglycemic effect of taurine, directly or through synergizing the effect of insulin, has also been reported 12 . Conjugated bile acids include glycine and taurine conjugates, both existing in constant ratio. Glycine conjugated bile acids are less soluble and are harder to excrete compared with taurine conjugated bile acids. This result in bile accumulation noticed in diabetic subjects 13 . In diabetic patients, who have increased lipid metabolism, the percentage of taurocholic acid in bile is decreased indicating an altered biosynthesis of taurine 14 . Conjugated bile acids (bile salts) can form micelles that solubilise and transport lipids across biological membranes. Bile acids as absorption promoters have the potential to aid intestinal, ocular, nasal, pulmonary and rectal absorption of insulin. Bile acids are hypoglycemic agents on their own and thus can be used as adjunct therapy in treating Diabetes.
Therefore it is clear that disturbed composition as well as secretion of bile causes improper absorption of insulin and impaired elimination of cholesterol and digestion of dietary protein. This leads to Steatohepatitis and secondary Insulin resistance. Thus impaired bile secretion with improper composition causes fatty liver, dyslipidemia and hyperglycemia.
According to Ayurveda the pathogenesis of Prameha starts with the vitiation of Meda by Kapha followed by Mamsa and other dushya and then only vitiation of Mutra to manifest as Prameha. This signifies that according to Ayurveda Hyperglycemia preceded by Dyslipidiemias. The role of Meda (fat/adipose tissues) is of great importance in the pathogenesis of Prameha. Its role is not as Dushya (disturbed functioning of the dhatus), but something more than that. According to Charaka Samhita, Vapavahana and Vrikka are the Srotomula of Meda dhatu. It is important to elaborate the term Vapavahana in the context of Prameha as the vitiated dhatu causes vitiation of Srotas and viceversa. Vapavahan signifies an organ responsible for circulation/storage of Vasa/ Meda. It can be correlated with Gall Bladder. The next important pathological hallmark in the pathogenesis of Prameha is Bahudrava Shleshma (Kapha that contains too much liquid) that joins and affects Meda, causing it to become Abaddha (unobstructed or fluid). Bahudrava means that Kapha loses its natural properties and get vitiated; it is worth full to mention here that this derangement may be acquired (due to faulty dietary habits and life style) or congenital, whatever may be the cause this vitiated Kapha is unable to perform its normal functions. Describing the physical properties of Kapha it is mentioned that it is unctuous in touch and look like ghrta (oil). Thus it can be said that Kapha in body represents lipid components of the body and vitiated Kapha can be correlated with dyslipidemia.
Role of dyslipidemia and metabolic abnormalities in the pathogenesis of diabetes is very obvious and well elaborated in modern medicine. Among the metabolic abnormalities that commonly accompany diabetes are disturbances in the production and clearance of plasma lipoproteins. Moreover, development of dyslipidemia may be a harbinger of future diabetes. A characteristic pattern, termed diabetic dyslipidemia, consists of low High Density Lipoprotein (HDL), increased triglycerides, and postprandial lipemia. This pattern is most frequently seen in type 2 diabetes and may be a treatable risk factor for subsequent cardiovascular disease [15][16][17] . Thus Ayurveda says that disturbed secretion of bile by Gall Bladder causes improper lipid metabolism that secondarily leads to Diabetes.
The contemporary hypoglycemic drugs gives good glycemic control in newly diagnosed cases but in chronic cases there is no alternative than using Insulin due to which the term NIIDM is not use these days. Increasing the dose or synergistically administration of one or more neither hypoglycemic drugs nor control the glucose level neither prevents complications. A patient of Diabetes with fatty liver, Dyslipidemia and autonomic neuropathy can't be only manage by hypoglycemic drugs only and therefore with the progression of disease and manifestation of complications its management become more and more difficult. The established Ayurvedic antidiabetic drugs like Vijaysara (ICMR study) showed that it has no effect on Cholesterol, LDL, VLDL and ALT, AST.
Therefore we plan to carry out a clinical trial to evaluate the effect of Cholagogue and Choleretic drugs in the management of type-2 Diabetes and simultaneous assess its effect on liver function and lipid profile. This clinical study will helpful in establishing a safe, cost effective, well tolerated and multitargeted drug which is effective to manage hyperglycemia, fatty liver and dyslipidemia concurrently with evidences.
In the present study we have chosen four drugs which are found to have Cholagogue and Choleretic effect in experimental studies. These drugs are -Kutaki, Bhringaraj, Bhumanlaki and Kalmegha.
Research studies have shown that Picrorhiza kurroa has a dose-dependent (1.5-12 mg/kg x 7) choleretic effect; it also possessed a marked anticholestatic effect against paracetamol-and ethynylestradiol-induced cholestasis 18 .
It antagonized the changes in bile volume as well as the contents (bile salts and bile acids). It has also reported to have hypoglycemic activity 19 . Bhumyamalki is reported for having potent hepatoprotective, immunostimulating, antiinflammatory, antiviral, antioxidant, cholagogue, adaptogenic and membrane stabilizing properties, which are constitutive qualities for any hepatoprotective drugs to act against viral hepatitis 20,21 . These activities have been attributed to its anticholestatic action, reduction in free radicals and reduction in cell protein necrosis as well as immune suppression and glutathione depletion reduction potential. Phyllanthus niruri is also claimed to have anti-diabetic effect 22 . Previous research studies showed that Eclipta alba has significant Cholagogue hepatoprotective activity against paracetmol induced rat. The antiheptotoxic activity of the leaf extract of Eclipta alba were compared with the standard hepatoprotective agent silymarin 23 . Eclipta alba is also reported to have hypoglycemic activity 24 . Kalmegha is known as King of Bitter and is reported to have a wide range of medicinal and pharmacological actions. Previous studies showed the Choleretic effect of Andrographolide obtained from Andrographic panniculata in rats 25 . It also has antioxidant and hepatoprotective effect 26 .

Aim and Objective
• To assess the effect of PEPA compound in the management of Type-2 Diabetes Mellitus.

Exclusion Criteria
• Patients already diagnosed to be suffering from the severe complications of Diabetes Mellitus viz.,

Study Groups
This was a pilot study to evaluate the efficacy of polyherbal compound in management of T2 Diabetes mellitus and therefore only 15 patients were enrolled in the study and allocated in a single group.

Study Duration
The study was conducted at the O.P.D and I.P.D. wing of Chaudhary Brahm Prakash Ayurveda Charak Sansathan, Khera Dabur, New Delhi between March 2015 to September 2015.
• Aavilamutrata (discoloration of urine/ change in consistency of urine)

Objective Parameters
• Fasting blood sugar • Postprandial blood sugar

Observation and Result
The   Oral medicine group provided highly significant (p<0.001) reduction in blood sugar level fasting and post prandial. While provided significant result in fasting sugar while highly significant reduction in postprandial level.

Discussion
According to the concept of Ayurveda there are two types of Prameha (diabetes) Avarana janya madhumeha and dhatu kshya janya madhumeha, it supports the receptor theory of modern medicine. Addition of Ayurvedic medicaments as supportive therapy to the NIDDM patients decrease the requirement of exogenous insulin thus ultimately helping in reducing adverse effects   caused by insulin therapy. Acharya Sushruta described Apathya nimittaja Prameha which is nearer to type 2 diabetes. It emphasizes on diabetes-insulin toxicityhyper insulinemia-obesity. On the other hand Ayurveda also give a due emphasis to Prameha-sthaulya (Sthula Pramehi)-importance of Meda (lipids) among 10 dushyas etc. Moreover, Sushruta advocates Medoroga chikitsa (obesity) in Prameha chikitsa highlighting closeness between sthaulya ( obesity) and Prameha( diabetes). Though Prameha is more than diabetes as it covers obesity-diabetes-metabolic syndrome all together but the concept given by in old Indian Medical treatise for management of Prameha is well applicable for diabetes also. Basically body rely upon its own endogenous synthesis and if anything supplement from outer source it not only reject it but also stops its own production. So it is more useful to potentiate body own production by strengthening its own powerhouse i.e., liver which may be either by burning excessive fat deposited in its cells (through exercise) or by rejuvenating it by using cholagogue and cholerectic drugs.

Conclusion
This is a very preliminary type clinical study and thus not able to give any definitive conclusion but then also it proves to be a footstep guiding those who are interested to search new dimension for the management of diabetes.