INTRODUCTION:

From various biomedical fields diabetes is getting much more attention, specialy molecular basis to study the cure for it. Modern revisions possibly will deliver implements for the use of numerous genes as targets for risk impost, therapeutic approaches and prophecy of complications [1]. Type I diabetes is Insulin dependent diabetes mellitus and Type II refers to Insulin non-dependentdiabetes mellitus.ADA (American Diabetes Association) and WHO (World Health Organization) says on no account established cure has yet been found diabetes [2,3,4]. Nevertheless, treatment modalities embrace control of obesity as a prime drive with lifestyle amendments, oral hypoglycemic agents, and insulin sensitizers like biguanides like metformin.These are the agents that reduce insulin resistance, which are still recommended for first line content of a prescription particularly for obese patients [5].

Apart from obesity many authors proposes the contribution of stress on blood glucose levels [6]. Therefore some authors suggest that strategies like shielding β-cell function and improving insulin sympathy should work fine. These two are the mechanisms which can hit the bull's eye. Weight burden forfeiture and physical commotion with some medications, are thought to be improve both insulin secretion and sensitivity [8]. As traditional drug therapies has failed to protect from the diabetic complications which took place though controlled blood glucose levels dramatically [7]. Many research papers fantastically elaborate the detailed mechanism of various molecular pathways responsible for the diabetic complications, which includes Activation of Protein Kinase-C, Hexosamine Pathway, Polyol Pathway [9] & formation of Advance Glycation End Products [10]. Liver disease causes major deaths in diabetes. In Verona Diabetes Study which was based on population Liver cirrhosis was the fourth principal basis of death and calculated as 4.4% for diabetes-related deaths [11]. Mainly diabetic liver damage takes account of cirrhosis, hepatocellular carcinoma, abnormal liver enzymes, NAFLD (Non-alcoholic fatty liver disease) and acute liver failure. The management of diabetes mellitus in patients with liver damage is ideally thorny due to liver-related alterations in drug metabolism, impending interactions between the drugs, and formation of hepatotoxicity.[12]. Further researchers specify that diabetes is well associated to liver anomalies, like abnormal glycogen deposition, fibrosis, hepatocellular carcinomas (HCCs), viral hepatitis and acute liver disease. Moreover, undue build-up of fat in the liver may deteriorate insulin resistance and lead to unembellished metabolic dysfunction. Due to uncontrolled hyperglycemia with fatty liver causes destruction of the hepatocytes and subsidize the risk of increased mortality and morbidity in diabetics. In diabetes mellitus there is high rate of comorbidities and poor diagnosis of liver cirrhosis. Prognosis of diabetes in patients with early stage cirrhosis is challenging as these patients may contemporary false negative fasting glucose or Glycated hemoglobin (HbA1c) results, thus mimicking normal glucose tolerance (NGT). Hence, there is intense need for prognosis of the early stages of diabetes mellitus in patients with cirrhosis. Regrettably, there are very less evidences verified to make endorsements for management in the early stages of cirrhosis in diabetic patients. [13]. In ancient Ayurveda we can see the similar signs of the aliments. For these kind of ailments rejuvenation therapy that is Rasayana therapy is suggested. To evaluate such rock-hard proclamations we decided to choose the herbal Isolates in combination with well-established antihyperglycemic agents. Curcumin is isolated from Haridra which is potent molecule but has limitation as poor absorbance. To counter poise this we took NanoCurcumin which has excellent absorbency due to its particle size.[14] Allicin is another super lead compound which must be studied for its magical effects. Many authors have claimed Allicin for its Lipid lowering and Antidiabetic actions.[39-43] Ginger is one of most used Rasayana herb which has wide array of actions. Herewe have chosen the super critical fluid extract of Ginger that is Zingiber Officinale. Ginger covers Antidiabetic, Antihypertensive as well as immune boosting activity which will be helpful in various diabetic complications. [15] Different animal models claim different mechanisms which are quite comparable to several diabetic conditions of patient. Here we would like to test and evaluate comparative status of various marketed and herbal drugs in lowering of blood glucose levels and management of diabetic liver mutilation.which will be caused due to oxidative stress triggered by Streptozotocininduced diabetes in rats by inhibiting the Polyol pathway associated with the protein of enzyme poly ADP ribose polymerase (PARP) and Protein Kinase C (PKC) expression, as evidenced by both an increase in plasma antioxidant enzyme levels and glycogen biosynthesis enzyme activity within the liver.

MATERIAL AND METHODS:

Experimental Animals:

Wistar rats weighing 160-200 gm were selected. Animals of either sex were housed under standard laboratory conditions of temperature 22±30C and relative humidity of 44-56% with free access to standard pellet diet and water ad libitum. Has received ethical approval by the Institutional Animal Ethical Committee & number is CPCSEA/IAEC/2017/015.

Chemicals:

Marketed drugs were purchased from local market, Glucose diagnostic kit (Bio lab India), Nano Curcumin & Allicin were received as gift sample by Konark Herbals Pvt. Ltd & Alllusure, Allimax Pvt. Ltd. The Great Britain United Kingdom& Supercritical fluid extract of Zingiber Officinale was kindly provided by Nisarg Biotech Pvt. Ltd. Bangalore.

Induction of Diabetes:

Diabetes was induced in overnight fasted Wistar rats by single dose Intraperitoneal injection of freshly prepared STZ at 65 mg/kg body weight (b.w) dissolved in 0.01 M citrate buffer with pH 4.5 [16]. The nondiabetic control rats also received an injection of the citrate buffer. After 48 h STZ administration, retroorbiatal blood samples of the overnight fasted rats were collected to measure blood glucose levels. The rats that were found to have permanent Diabetes Mellitus (Fasting Blood Glucose (FBG)> 250 mg/dl were considered diabetic and used in the study.Animals were divided into ten groups of six rats in each as mentioned in Table No 1. All groups received respective treatment mentioned in the table.

Table 1: Selected Groups and Dose respectively.

Sr. No	Group & Drug	Drug Dose
1.	Group I: Normal (NC)	-
2.	Group II: Diabetic Control (DC)	-
3.	Group II: Metformin (M)	100 mg/kg PO
4.	Group III: Metformin + Glibenclamide (GM)	100+0.6=106 mg/kg, P.O.
5.	Group IV: Metformin + Sitagliptine(JM)	120 mg/kg metformin P.O.+ 11.67 mg/kg Sitagliptin P.O.
6.	Group V: Metformin + Glimepride (GLM)	Metformin 120 mg/kg, + Glimepiride 1 mg/kg, P.O.
7.	Group VI: Metformin + Pioglitazone + Glimepride (Tri)	120 mg/kg Metformin 1.25 mg/kg Pioglitazone 0.7 mg/kg Glimepiride P.O.
8.	Group VII: Metformin + NanoCurcumin (MC)	100 mg/kg P.O. + 50 mg/kg P.O.
9.	Group VIII: Metformin + Allicin (MA)	100 mg/kg P.O. +16mg/kg i.p.
10.	Group IX: Metformin + Ginger CO2 Extract (MG100)	100 mg/kg P.O. + 100 mg/kg P.O.

Collection of blood and determination of biochemical parameters:

Rats were treated for 6 weeks. Blood samples were collected from tail vein in 0, 1, 2, 3, 4, 5, and 6weeks after the administration of and blood glucose levelswere determined by using GOD/POD. At the completion of the treatments, the animals were fasted overnight and then blood samples were drawn from their retro-orbital plexus. Immediately after blood samples collection, serum was isolatedby centrifugation at 3000 rpm for 10 min by using Remi Lab Centrifuge and then analyzed for variousbiochemical parameters. The serum samples were stored at −80°C in afreezer until they were analyzed. Glycated Hemoglobin concentration was determined, Serum cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, Alkaline phosphatase (ALP) and Alanine transaminase (ALT) {formerly called serum glutamate-pyruvate transaminase (SGPT) or serum glutamic-pyruvic transaminase (SGPT)}, Aspartate transaminase (AST){formerly known as Serum Glutamic Oxaloacetic transaminase (GOT, SGOT) levels were measured by previously described methods [17] using diagnostic kits (Biolab Diagnostics (I) Pvt. Ltd.) by auto analyzer.

STATISTICAL ANALYSIS:

The data was statistically analyzed by using Prism version 6.01. Results are presented as mean ± SEM. (n=6), data analyzed by one-way ANOVA followed by Dunnett’s test. (Dunnett’s test is used when we compare one group {usually the control treatment} with the other groups.)Level of significance at P<0.05 probability level.(Differences were considered significant when P≤0.05.) The results were expressed as Mean ± SD/SEM. Mean values were considered statistically signiﬁcant when *p< 0.05, **p< 0.01 and ***p < 0.001. [33] When compared with diabetic control group. Comparisons were made between normal control to diabetic control using student t-test (# p<0.05, ## p < 0.01, ### p < 0.001).

RESULT:

Fig.1. Effect of Fasting Blood glucose levels.

After injection of Streptozotocin animals showed the significant rise of blood glucose levels ## p < 0.01. All the groups prominently showed significant activity in terms of the reduction of fasting blood glucose levels.

Fig. 2. Effect on Glycation of Hemoglobin termed as HbA1C.

Results are presented as mean ± SEM. (n=6), data analyzed by one-way ANOVA followed by Dunnett’s test.

In diabetic control group there was high levels of glyacated hemoglobin. All the groups showed significant activity. Metformin, Glibenclamide + Metformin, Sitagliptin + Metformin,Metformin + Pioglitazone + glimepiride,Metformin + Ginger CO2 Extract Groups have shown significant activity (*p< 0.05). Metformin + glimepirides, Metformin + NanoCurcumin, and Metformin + Allicin had shown highly significant activity( **p < 0.01).

Fig. 3. Effect on Diabetic Hyperlipidemia.

Diabetes induced Hyperlipidemia was severely induced in diabetic animals. In terms of Serum Total cholesterol group of Glibenclamide+ Metformin, showed significant reduction (*p<0.05). Whereas Metformin + Glimepiride, Metformin +Pioglitazone + Glimepiride, Metformin + Ginger CO2 Extract, Metformin + Nano Curcumin, and Metformin + Allicin had shown highly significant activity (**p<0.01). Serum total Triglycerides were seen significantly at high value in diabetic group.Glibenclamide + Metformin, Metformin + Glimepiride, and Metformin + Pioglitazone + Glimepiride groups showed significant reduction (*p < 0.05). Metformin + Ginger CO2 Extract, Metformin + NanoCurcumin, and Metformin + Allicin had shown highly significant activity (**p < 0.01).

High density Lipoprotein was significantly reduced in diabetic rats. Sitagliptin + Metformin, Metformin + Pioglitazone + Glimepiride, and Metformin + Ginger CO2 Extract groups showed significant increase in HDL (*p<0.05). Metformin + NanoCurcumin, and Metformin + Allicin had shown highly significant activity in terms of restoring HDL values(**p<0.01). Low density lipoprotein (LDL) was significantly increased in diabetic rats(## p < 0.01). Sitagliptin + Metformin, Metformin + Glimepiridegroups showed significant decrease in LDL (*p<0.05). Metformin + Pioglitazone + Glimepiride, Metformin + NanoCurcumin, Metformin + Allicin and Metformin + Ginger CO2 Extract groups showed highly significant activity (**p < 0.01).

Fig. 4. Effect on Alkaline Phosphate (ALP), Aspartate Aminotransferase (AST), Alanine Aminotransferase levels (ALT). Activity levels.

Alkaline Phosphate levels were increased in diabetic groups and in Sitagliptin + Metformin and Metformin + Glimepiride,Metformin + Allicin and Metformin + Ginger CO2 Extract showed significant reduction in the same (*p<0.05). Metformin + NanoCurcumin group showed highly significant reduction in ALP activity (**p<0.01). Aspartate Aminotransferase levels were increased in diabetic groups and in and Metformin + Glibenclamide, Metformin + Allicin and Metformin + Ginger CO2 Extract showed significant reduction in the same (*p<0.05). Sitagliptin + Metformin and Metformin + NanoCurcumin groups showed highly significant reduction in AST activity (**p<0.01).Alanine Aminotransferase levels were increased in diabetic groups and in Sitagliptin + Metformin and Metformin + Glibeclamide and Metformin + Ginger CO2 Extract showed significant reduction in the same (*p<0.05). Only Metformin + Allicin, Metformin + NanoCurcumin groups showed highly significant reduction in ALT activity (**p< 0.01).

DISCUSSION:

Diabetes is a complex disorder and only blood glucose levels monitoring will not serve the purpose. Many diabetic people suffer from hepatic dysfunctioning. Many researchers have focused a light beam on it. [18] Effective decrease in Fasting blood glucose level is prime requirement of the antidiabetic agents but due to newer concepts and molecular research ideal antidiabetic agent must talk head to head about diabetic complications. [19] Here we have tried to club the modern Allopathywith ancient Ayurveda. Rasayana Chikitsa helps to prevent degenerative disorders and diseases of senility. As Rasayana herbs are more prominent to heal the degenerative diseases they also sharpens memory, mental acuity and intelligence, boosts immunity, acts as anti-aging, rejuvenation and anabolic, Improves metabolism, Feeling of general well-being and provides complexion.Maintain health and promotes longevity of life.Increases vigor and vitality. [20] Metformin is the first line of treatment drug from the class of biguanides. [21] Its mechanism of action may be by active stimulation of (AMPK) AMP-activated protein kinase and inhibition of complex I which is in the mitochondrial respiratory chain, by increaisng levels of cAMP (cyclic adenosine monophosphate) along with decreased activation of PKA(protein kinase-A).[22] Sitagliptin inhibits dipeptidyl peptidase-4 (DPP-4) (DPPIV) Enzyme which inhibits gluconeogenesis and improves insulin secretion.DPP4 breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released when we take food. Sitagliptin Prevents breakdown of GLP-1 and GIP, which can suppress the release of glucagon by the alpha cells of the pancreas and increases the secretion of insulin.[23] Glibenclamide causes insulin release by cell membrane depolarization, opening voltage-dependent calcium channels. In beta cell of pancreas it inhibits the (KATP) ATP-sensitive potassium channels inhibitory regulatory (SUR1) subunit sulfonylurea receptor1[24]. Glimepiride is a secretogouge whch decreases blood glucose levels by pancreatic beta cells stimulation to release the insulin.[25] Pioglitazone typically stimulates the nuclear receptor PPAR-γ (peroxisome proliferator-activated receptor gamma) by means of which It modulates the transcription of the various genes tangled in the regulation of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. As a result itdecreases insulin resistance in the liver and peripheral tissues, decreases gluconeogenesis in the liver, and reduces quantity of glucose and glycated hemoglobin in the bloodstream.[26]. Curcumin reduces blood glucose levels, due to its ability to inhibit formation of MCP, IL-6, TNF-α (inflammatory cytokines) either directly or through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Prostaglandin E2 (PGE2). By adding, its valuable effects on inflammation arevalidated by initiation of AMPK and inhibition of Mitogen-Activated Protein Kinase (MAPK).[27] Harikesh Dubey et. al. in their study shown that Allicin is active in the dealing with diabetes induced hypertensionover a mechanism that suggests selective opening of SUR2.[6]-gingerol and Shagols are major constituents of supercritical fluid extract of ginger which causes amplified glucose uptake by promotion of (GLUT4) translocation by means of AMPK activation in L6 myocytes and canblock the upsurgeof fasting blood glucose level and improved glucose intolerance. Myoung Jin Son et. al. demonstrated for the first time that gingerol and shagolsregulatesliverenzyme gene expression which arelinked to glucose metabolism, andcauses reduction in glucose production and an increase in glycogen synthesis, these changes contributing to the anti-hyperglycemic effect of ginger.[28] In our study we observed that all the groups showed highly significant blood glucose lowering activity. Only major difference is seen with respect to aggressive reduction and gradual reduction. It might be due to Antihyperglycemic and Hypoglycemic nature of molecules. Drastic up and downs in blood glucose levels can be observed by HbA1C value. It gives you chart whether you have successfully managed diabetes or not.[29] in our findings all the groups were significant in reduction of HbA1C but Glimepiride + Metformin, Metformin+Nano Curcumin, Metformin + Allicin combinations were highly significant as depicted in results.

Diabetic Hyperlipidemia or Diabetic Dyslipidemia is Elevated levels of blood lipids. Sundry studies expending tracer kinetics in hominids have established that hepatic production of apolipoprotein B (apoB), which is the major protein component of very low density lipoprotein (VLDL) and LDL is increased in diabetes. In diabetics there is a slower clearance of chylomicrons from the blood after dietary fat. The left over lipoproteins, in addition to LDL, are Atherogenic in nature. The various studies showed that subjects with a large variation in Total Cholesterol (TC) levels showed an increased risk for diabetics towards development of cardiovascular complications. The utmost communal outline of dyslipidemia in patients of diabetes is raised triglyceride levels and decreased (HDL) high Density Lipoprotein and increased cholesterol levels. Few of our groups have shown Antihyperlipidemic activity which will be very useful in correction of cardiovascular risk factor. [30] Aspartate Aminotransferase (AST or SGOT), Alanine Aminotransferase (ALT or SGPT), ALP are enzymes normally contained inside hepatic tissue. If the liver is bruised, these liver cells stumble the enzymesinto blood stream, raising the enzymatic levels in the blood and beckoning the liver damage.The truthful levels of these enzymes do not correlate wellwith the degree of liver damage or the prognosis (outlook). Thus, the exact levels of AST (SGOT), ALT (SGPT) and ALP cannot be used to define the gradation of liverdisease or predict the prospect. Serum glutamic pyruvic transaminase (SGPT) have a starring role in gluconeogenesis and seems to be more related to liver fat accumulation. Administration of highly significant groups to the diabetic rats significantly reduced the SGOT, SGPT, and ALP levels which represent the preventive action on liver damage in diabetic condition. ALP is homodimeric protein enzyme and released in blood stream when there is liver damage. Its release mechanism is still unclear till date. Disturbed liver enzymes are linked with glycemic control. Screening ofhepatic dysfunction in diabetics and consequent workup may lead to the documentation of hepatic co-morbidities and better management. In present study Curcumin and Allicin showed highly significant activity. Numerous studies had suggested link between plasma ALP levels towards adverse cardiovascular events which causes and cardiovascular mortality, jeopardy of death and of hospitalization, coronary heart disease risk, (MI) Myocardial infarction and stent thrombosis later to coronary angioplasty. Higher ALP levels can act as a prognostic indicator of dwindled survival in diabetic patients with acute myocardial infarction, possibly in association to decreased renal function and hepatic dysfunction.

Liver is often injured in the course of diabetes, as a magnitude of augmented stages of oxidative stress and dysregulation of immune function. [108] Histopathological Studies of groups showed that administration of Nanocurcumin Allicin and Supercritical fluid extract of Ginger to STZ induced diabetic animal’s revealed protective effect on tissue and cellular architecture, reemergence & cellular refurbishment, vascular congestion, recurrence of hepatocytes with pyknotic nucleimigrating from the sinusoidal lining layer as reasonable restoration and in some groups complete regeneration in the liver cells when compared to non-diabetic and diabetic control groups. Our findings indicate possible hepato-protective and Antidiabetic role of our new combinations.

CONCLUSION:

Herbal leads are better performers in terms of significant effect. Extensive and detail evaluation of phenomenon may conquer bad legacy of diabetes and may bring the next tomorrow in the patient’s life. Antidiabetic agents must be evaluated on the basis of healing diabetic complications too as only glucose reduction have timely ended with drastic diabetic complications. Doctors must diagnose for diabetic complications during systematic checkups and change in the treatment is substantial.

ACKNOWLEDGEMENT:

The authors are thankful to Dr. Pralhad Wangikar (Prado Preclinical Pvt. Ltd.) and Dr. S R Chaudhari, Principal SJVPM’S Rasiklal M Dhariwal Institute of Pharmaceutical Education and Research Chinchwad Pune for providing Infrastructure.

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Received on 12.05.2019 Modified on 16.06.2019

Research J. Pharm. and Tech 2019; 12(8): 3697-3702.

DOI: 10.5958/0974-360X.2019.00632.2