Now showing items 1-6 of 6
| Abstract: | In the present study a detailed investigation on the alterations of dopamine and its receptors in the brain regions of streptozotocin induced diabetic and insulin induced hypoglycaemic rats were carried out. Glutamate receptor, NMDARI gene expression in the hypoglycaemic and hyperglycaemic brain was also studied. EEG recording in hypoglycaemic and hyperglycaemic will be carried out to measure brain activity. in vitro studies on glucose uptake and insulin secretion, with and without specific antagonists were carried out to confirm the specific receptor subtypes - DA D1, DA D2 and NMDA involved in the functional regulation during hyperglycaemic and hypoglycaemic brain damage. The molecular studies on the brain damage through dopaminergic and glutamergic receptors will elucidate the therapeutic role in the corrective measures of the damage to the brain during hypoglycaemia and hyperglycaemia. This has importance in the management of diabetes and antidiabetic treatment for better intellectual functioning of the individual. |
| Description: | Department of Biotechnology, Cochin University of Science and Technology |
| URI: | http://dyuthi.cusat.ac.in/purl/2806 |
| Files | Size |
|---|---|
| Dyuthi-T0827.pdf | (7.861Mb) |
| Description: | Department of Biotechnology, Cochin University of Science and Technology |
| URI: | http://dyuthi.cusat.ac.in/xmlui/purl/1983 |
| Files | Size |
|---|---|
| Dyuthi-T0412.pdf | (2.497Mb) |
| Abstract: | Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycemia with disturbances in carbohydrate, protein and lipid metabolism resulting from defects in insulin secretion, insulin action or both. Currently there are 387 million people with diabetes worldwide and is expected to affect 592 million people by 2035. Insulin resistance in peripheral tissues and pancreatic beta cell dysfunction are the major challenges in the pathophysiology of diabetes. Diabetic secondary complications (like liver cirrhosis, retinopathy, microvascular and macrovascular complications) arise from persistent hyperglycemia and dyslipidemia can be disabling or even life threatening. Current medications are effective for control and management of hyperglycemia but undesirable effects, inefficiency against secondary complications and high cost are still serious issues in the present prognosis of this disorder. Hence the search for more effective and safer therapeutic agents of natural origin has been found to be highly demanding and attract attention in the present drug discovery research. The data available from Ayurveda on various medicinal plants for treatment of diabetes can efficiently yield potential new lead as antidiabetic agents. For wider acceptability and popularity of herbal remedies available in Ayurveda scientific validation by the elucidation of mechanism of action is very much essential. Modern biological techniques are available now to elucidate the biochemical basis of the effectiveness of these medicinal plants. Keeping this idea the research programme under this thesis has been planned to evaluate the molecular mechanism responsible for the antidiabetic property of Symplocos cochinchinensis, the main ingredient of Nishakathakadi Kashayam, a wellknown Ayurvedic antidiabetic preparation. A general introduction of diabetes, its pathophysiology, secondary complications and current treatment options, innovative solutions based on phytomedicine etc has been described in Chapter 1. The effect of Symplocos cochinchinensis (SC), on various in vitro biochemical targets relevant to diabetes is depicted in Chapter 2 including the preparation of plant extract. Since diabetes is a multifactorial disease, ethanolic extract of the bark of SC (SCE) and its fractions (hexane, dichloromethane, ethyl acetate and 90 % ethanol) were evaluated by in vitro methods against multiple targets such as control of postprandial hyperglycemia, insulin resistance, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B) and dipeptidyl peptidase-IV (DPPxxi IV). Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition, insulin dependent glucose uptake (3 fold increase) in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F and reduced triglyceride accumulation in 3T3-L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence of bioactives (beta-sitosterol, phloretin 2’glucoside, oleanolic acid) in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test (OGTT) to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. Chapter 3 highlights the beneficial effects of hydroethanol extract of Symplocos cochinchinensis (SCE) against hyperglycemia associated secondary complications in streptozotocin (60 mg/kg body weight) induced diabetic rat model. Proper sanction had been obtained for all the animal experiments from CSIR-CDRI institutional animal ethics committee. The experimental groups consist of normal control (NC), N + SCE 500 mg/kg bwd, diabetic control (DC), D + metformin 100 mg/kg bwd, D + SCE 250 and D + SCE 500. SCEs and metformin were administered daily for 21 days and sacrificed on day 22. Oral glucose tolerance test, plasma insulin, % HbA1c, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein etc. were analysed. Aldose reductase (AR) activity in the eye lens was also checked. On day 21, DC rats showed significantly abnormal glucose response, HOMA-IR, % HbA1c, decreased activity of antioxidant enzymes and GSH, elevated AR activity, hepatic and renal oxidative stress markers compared to NC. DC rats also exhibited increased level of plasma urea and creatinine. Treatment with SCE protected from the deleterious alterations of biochemical parameters in a dose dependent manner including histopathological alterations in pancreas. SCE 500 exhibited significant glucose lowering effect and decreased HOMA-IR, % HbA1c, lens AR activity, and hepatic, renal oxidative stress and function markers compared to DC group. Considerable amount of liver and muscle glycogen was replenished by SCE treatment in diabetic animals. Although metformin showed better effect, the activity of SCE was very much comparable with this drug. xxii The possible molecular mechanism behind the protective property of S. cochinchinensis against the insulin resistance in peripheral tissue as well as dyslipidemia in in vivo high fructose saturated fat diet model is described in Chapter 4. Initially animal were fed a high fructose saturated fat (HFS) diet for a period of 8 weeks to develop insulin resistance and dyslipidemia. The normal diet control (ND), ND + SCE 500 mg/kg bwd, high fructose saturated fat diet control (HFS), HFS + metformin 100 mg/kg bwd, HFS + SCE 250 and HFS + SCE 500 were the experimental groups. SCEs and metformin were administered daily for the next 3 weeks and sacrificed at the end of 11th week. At the end of week 11, HFS rats showed significantly abnormal glucose and insulin tolerance, HOMA-IR, % HbA1c, adiponectin, lipid profile, liver glycolytic and gluconeogenic enzyme activities, liver and muscle triglyceride accumulation compared to ND. HFS rats also exhibited increased level of plasma inflammatory cytokines, upregulated mRNA level of gluconeogenic and lipogenic genes in liver. HFS exhibited the increased expression of GLUT-2 in liver and decreased expression of GLUT-4 in muscle and adipose. SCE treatment also preserved the architecture of pancreas, liver, and kidney tissues. Treatment with SCE reversed the alterations of biochemical parameters, improved insulin sensitivity by modifying gene expression in liver, muscle and adipose tissues. Overall results suggest that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with antiglycation and antioxidant activities. |
| URI: | http://dyuthi.cusat.ac.in/purl/4961 |
| Files | Size |
|---|---|
| Dyuthi-T2037.pdf | (8.011Mb) |
| Abstract: | The incidence of diabetes is rapidly increasing and by 2030 an expected 592 million individuals are projected to be affected (WHO report). Hyperglycaemic condition is recognized as the causal link between diabetes and its complications. The chronic hyperglycemia resulting from diabetes brings about a rise in oxidative stress due to overproduction of reactive oxygen species (ROS) as a result of glucose auto oxidation and protein glycosylation. Generation of ROS leads to oxidative damage of the structural components (such as lipids, DNA and proteins) of cells and potentiate diabetes related complications. Oxidative insult in cells is also created by the impairment in functioning of endogenous antioxidant enzymes because of their non enzymatic glycosylation and oxidation. The prolonged exposure of oxidative stress may cause insulin resistance by triggering an alteration in cellular redox balance. Several lines of evidence suggest that oxidative stress occurs in diabetes and could have a role in the development of insulin resistance. The cause and cellular mechanism responsible for this abnormality is not fully understand despite of intense investigative efforts. However it is unknown whether it is the cause or consequence of diabetes. Despite strong experimental evidence indicating that oxidative stress may determine the onset and progression of late-diabetic complications, controversy exists between the cause and associative relationship between oxidative stress and diabetes mellitus. Disruption of glucose homeostasis is a characteristic feature of Non-insulin dependent diabetes mellitus (NIDDM) and is associated with some complications including cardiovascular disease and renal failure. Glucose transport, the rate limiting step in glucose metabolism, can be activated in peripheral tissues by two distinct pathways. One stimulated by insulin through IRS-1/PI3K, Preface Page 2 the other by muscle contraction/exercise through the activation of AMPK. Both pathways also increase the phosphorylation and activity of MAPK family components of which p38 MAPK participates in the full activation of GLUT4.Insulin exerts its biological effect upon binding with the insulin receptor (IR) thereby activating the downstream signaling that lead to enhanced glucose uptake. In skeletal muscle, it potentiates glucose transport through PI3K mediated or non-PI3K mediated pathways. Alterations or defects in its signal transduction pathway was found in diabetic patients associated with decreased levels of IRb, IRS-1, and PI3K. In the insulin signaling, PI3K is a key molecule and inhibition of PI3K completely abolish insulin stimulated uptake. Akt or Pkb is an important downstream target of insulin stimulated glucose transport and metabolism.Impairment in fuel metabolism occurs in obesity, and this impairment is a leading pathogenic factor in type 2 diabetes. The insulin resistance associated with type 2 diabetes is most profound at the level of skeletal muscle as this is the primary site of glucose and fatty acid utilization. Therefore, an understanding of how to activate AMPK in skeletal muscle would offer significant pharmacologic benefits in the treatment of type 2 diabetes. Metformin and the thiazolidinedione drugs exert the effects via activation of AMPK. Activation of AMPK occurs in response to exercise, an activity known to have significant benefit for type 2 diabetics. AMPK serves as sensor of energy status whose activity is triggered in response to changes in nutritional status in order to modulate tissue-specific metabolic pathways |
| URI: | http://dyuthi.cusat.ac.in/purl/5151 |
| Files | Size |
|---|---|
| Dyuthi-T2185.pdf | (9.806Mb) |
| URI: | http://dyuthi.cusat.ac.in/purl/5226 |
| Files | Size |
|---|---|
| Dyuthi T-2261.pdf | (5.986Mb) |
| Description: | Department of Biotechnology, Cochin University of Science and Technology |
| URI: | http://dyuthi.cusat.ac.in/purl/2705 |
| Files | Size |
|---|---|
| Dyuthi-T0757.pdf | (12.27Mb) |
Now showing items 1-6 of 6
Dyuthi Digital Repository Copyright © 2007-2011 Cochin University of Science and Technology. Items in Dyuthi are protected by copyright, with all rights reserved, unless otherwise indicated.