{"id":294,"date":"2019-10-10T22:16:51","date_gmt":"2019-10-10T16:46:51","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=294"},"modified":"2019-10-10T22:16:51","modified_gmt":"2019-10-10T16:46:51","slug":"evaluation-of-antidiabetic-drugs","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/evaluation-of-antidiabetic-drugs\/","title":{"rendered":"Evaluation of Antidiabetic Drugs"},"content":{"rendered":"\n
Evaluation of Diabetes<\/em><\/strong><\/p>\n\n\n\n \u00a0<\/em><\/strong> Insulin – Discovered by Banting& Best<\/em><\/strong> <\/p>\n\n\n\n Need for new drugs<\/p>\n\n\n\n Purpose: <\/strong>the effect of the drug on insulin, glucagon & somatostatin secretion without interference from other organ systems. <\/p>\n\n\n\n Procedure<\/strong>: Pancreas of Wistar rats isolated and perfused with PSS and glucose. Test compound in different concentrations added to perfusate, f\/b glucose. The perfusate is collected every minute for 30 min to measure the level of the hormones.<\/p>\n\n\n\n Variable<\/strong>: Values of each hormone, for each minute, are plotted versus time. The effect of test compounds on hormones in response to elevated glucose is compared with the control.<\/p>\n\n\n\n Purpose: <\/strong>To study their dynamic response between various metabolic states<\/p>\n\n\n\n Procedure<\/strong>: Islets isolated from Wistar rats by collagenase method, perfused with PSS & glucose. For 2-18 min, increasing concentrations of test compound added f\/b simultaneous increase in glucose concentrations.<\/p>\n\n\n\n Variable<\/strong>: measure the level of insulin.<\/p>\n\n\n\n Procedure<\/strong>: Insulin-producing tumor cells are used (RIN-m, INS-1 cells) \u00e0<\/p>\n\n\n\n These are incubated with [3H] glibenclamide or [3<\/sup>H] glimepiride (or any appropriate makers e.g for Incretin receptors) which bind to specific receptors. \u00e0 Then test drugs are added <\/p>\n\n\n\n Variable<\/strong>: displacement of the labeled marker by test drug is noted by liquid scintillation counters.<\/p>\n\n\n\n Purpose: <\/strong>to study the effect of the drug on net glucose production and lactate utilization by the liver. <\/p>\n\n\n\n Procedure<\/strong>: Liver of Wistar rats isolated and perfused with PSS & Na- L- Lactate for 5min. The test compounds are added in increasing concentrations to the perfusate medium. The system is run for 2 hrs and samples are collected at intervals.<\/p>\n\n\n\n Variable<\/strong>: Net glucose production from lactate & net lactate utilization is determined from the effluate.<\/p>\n\n\n\n The values are plotted against time before and after the addition of test compounds<\/p>\n\n\n\n Experimental models are developed with the purpose of enhancing understanding of the pathophysiological mechanisms of diseases that affect humans. <\/p>\n\n\n\n Regardless of the classification, the resulting metabolic abnormalities that characterize diabetes contribute greatly to the clinical complications, and the major clinical strategy is aimed at restoring metabolic balance. However, a major concern in testing potential and successful interventions in humans is that due to the natural history of T2D, it takes years for the complications to develop. <\/p>\n\n\n\n Advantages<\/p>\n\n\n\n Disadvantages-<\/strong><\/strong><\/p>\n\n\n\n To be relevant, an animal model should mirror the pathophysiology and natural history of diabetes or the model should develop complications of diabetes with an etiology similar to that of the human condition. They only mirror specific conditions as seen in humans.<\/strong><\/p>\n\n\n\n PRINCIPLE:<\/strong> I<\/p>\n\n\n\n In chemically induced models of type 1 diabetes, a high percentage\nof the endogenous beta cells are destroyed, and thus, there is little\nendogenous insulin production, leading to hyperglycemia and weight loss.<\/p>\n\n\n\n Alloxan produces a triphasic response. New\nformulations of insulin can be tested in this model.<\/p>\n\n\n\n Blood glucose levels show triphasic response with hyperglycemia for 1 hour f\/b hypoglycemia that lasts for 6hours & stable hyperglycemia after 48hours.<\/p>\n\n\n\n Treatments that may prevent beta-cell death\ncan be tested in this model.<\/p>\n\n\n\n These are useful in understanding the Pathophysiology\nof DM1 and studying immunomodulatory interventions.<\/p>\n\n\n\n Encephalomyocarditis virus, Coxsackie\nvirus.<\/p>\n\n\n\n PANCREATECTOMY:<\/strong><\/strong><\/p>\n\n\n\n Type 2 diabetes is characterized by insulin resistance and the inability\nof the beta cell to sufficiently compensate.<\/p>\n\n\n\n Therefore, animal models of type 2\ndiabetes tend to include models of insulin resistance and\/or models of beta-cell\nfailure. Many animal models of type 2 diabetes are obese, reflecting the human\ncondition where obesity is closely linked to type 2 diabetes development. <\/p>\n\n\n\n These models can be used for studying\ntreatments to improve insulin resistance and treatments to improve \u03b2- cell function.<\/p>\n\n\n\n These are more accurate models of\nhuman DM2. <\/p>\n\n\n\n High-fat feeding:<\/strong> <\/p>\n\n\n\n Non- obese models\nof type 2 diabetes<\/strong><\/p>\n\n\n\nIn-vitro:<\/strong><\/h2>\n\n\n\n
Effect on pancreas:<\/strong><\/h3>\n\n\n\n
The isolated pancreas of rats:<\/strong> <\/h4>\n\n\n\n
Isolated pancreatic islets: <\/strong><\/h4>\n\n\n\n
Receptor binding studies:<\/strong> <\/h4>\n\n\n\n
Effect on the liver: <\/strong><\/h3>\n\n\n\n
Perfusion of isolated rat liver:<\/strong> <\/h4>\n\n\n\n
In-vivo:<\/strong><\/h2>\n\n\n\n
Type 1 DM:<\/strong> <\/h3>\n\n\n\n
Chemically induced type 1 DM:<\/strong> <\/h4>\n\n\n\n
\n Possible uses of the model:<\/strong>\n <\/td> <\/td><\/tr> \n Single-dose models\n <\/td> \n New formulations of insulin\n <\/td><\/tr> \n Multiple STZ dose model\n <\/td> \n Treatments that may prevent beta cell death\n <\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n <\/td> NOD mouse <\/strong> (Non- obese diabetic)<\/strong> <\/td> BB rats<\/strong> <\/td> LEW.1AR1\/iddm rats<\/strong> <\/td><\/tr> Age at onset of diabetes<\/strong> <\/td> Insulitis at 3- 4 wks f\/b overt diabetes at 10-14 wks up to 6 mo) <\/td> Insulitis and insulin deficiency at 8- 16 wks <\/td> Insulitis for at least a week prior to onset at 8- 9 wks <\/td><\/tr> Insulin deficiency<\/strong> <\/td> Mild <\/td> Severe, require insulin for survival <\/td> Severe <\/td><\/tr> Gender effect<\/strong> <\/td> M < F <\/td> M = F <\/td> M = F <\/td><\/tr> Associated autoimmune diseases<\/strong> <\/td> Sialadenitis, thyroiditis <\/td> Thyroiditis <\/td> Organs free of infiltration <\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n \n Virus<\/strong>\n <\/td> \n Peculiarities of disease<\/strong>\n <\/td><\/tr> D- a variant of encephalomyocarditis virus (EMC- D)<\/strong> <\/td> Selectively infects and destroys pancreatic \u03b2- cells in adult male ICR- Swiss mice<\/strong> Adult male C3H\/ HeJ mice <\/strong>are resistant Pretreatment with cyclosporine- A :<\/strong> Increased severity and incidence of diabetes in ICR- Swiss mice and induction of diabetes in C3H\/ HeJ mice <\/td><\/tr> Diabetogenic strain (E2) of coxsackievirus B4 <\/strong>[Coxsackie virus-> CD I mice (C for C)] <\/td> CD 1 mice- <\/strong>Islet cell destruction was associated with chronic islet cell inflammation, the elevation of islet cell antibody, the prolonged presence of viral DNA in the pancreas <\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n Type\n2 DM:<\/strong><\/h3>\n\n\n\n