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How Preclinical Gene Models Push Advance Anti Diabetic Research?

How Preclinical Gene Models Push Advance Anti Diabetic Research?

Ants always eat sweet food but none of them haven’t diabetes?- This could be the longing and despondent statement of any of the more than 300 million individuals worldwide affected by diabetes.

Diabetes is debatably the most critical health care concern that has ignited a global crisis on the fiscal and physical status of all nations of the world. With its intricate association with obesity, hypertension, cardiovascular diseases, cancers, Kidney and Eye disease, Stroke, Alzheimer?s disease and so on, it has become a giant octopus that ruthlessly extends it claws to drill dents in the socio-economic welfare and quality of life. Recently, with the ever increasing incidence of diabetes in children as well, it has become imperative for the health care sector to speed up research on diabetes and identify drug targets that in the long run would emerge as a possible cure for the presently incurable, but manageable disease.

#1 How does diabetic research progress?

Virtually every medical achievement of the last century has depended directly or indirectly on research with animals.?

The truth and weight of this statement can be realized from the Nobel Prize winning isolation of insulin from the pancreas of dogs. Eventually mice became the most preferred animal models that have significantly contributed to the progress in diabetes research as well as in research regarding other diseases. This is because the genome of mice and humans are 90% identical. The striking anatomical, genetic and physiological similarity, cost effectiveness, generation time and life span make them a highly efficient tool in the field of drug development.

#2 What are the most widely used Animal models for diabetes?

In research involving animals, scientists attempt to induce the identical disease features into the mice. In case of the diabetes, the mice are rendered completely devoid of insulin by treating them with chemicals like streptozotocin and alloxan that destroy pancreas, the production house of insulin. Injecting streptozotocin releases toxic levels of nitric oxide that cause DNA damage of the insulin secreting pancreatic beta cells and subsequently kills them. On the other hand, alloxan treatment releases highly reactive and toxic ?free radicals? that ameliorate the pancreas and induce experimental diabetes

#3 Are the currently used models of diabetes research robust?

The applicability of the results of drug testing done on mice models to humans depends on whether the diabetes induced in mice exactly resembles that of the diabetes occurring in humans. So naturally, the question of whether the alloxan and streptozotocin induced diabetes is similar to the human equivalent of diabetes arises. The answer to this question is unfortunately No! Following are disadvantages of using alloxan and streptozotocin induced mice.

  • Hyperglycemia develops due to the killing of insulin producing beta cells of pancreas. However, another major pathogenic feature of diabetes is insulin resistance- the inability of liver, muscle and other cells to properly use the secreted insulin. This core feature of type 2 diabetes mellitus is not captured by these animal models.
  • The FDA has directed that streptozotocin induced diabetes model should not be used in preclinical studies involving drug targets aimed at the immune system in type 1 diabetes. This is because type 1 diabetes involves the autoimmune destruction of pancreatic beta cells which is not reflected in the streptozotocin model of diabetes.
  • Diabetes induced by chemicals is reversible because of the development of insulinoma and spontaneous beta cell regeneration which poses a big problem during long term studies
  • The results of experiments done on chemically induced diabetes models show high variability in terms of hyperglycemia development
  • There is a high incidence of liver and kidney tumors in these animals
  • The dose and time of streptozotocin required to induce diabetes is still not standardized
  • A high degree of lethality is found in case of alloxan induced diabetes mellitus.

#4 What alternatives does preclinical research provide?

Hence an animal model with pathologic features resembling type 2 diabetes is highly important. A proven strategy superior to chemically induced models to study both type 1 and type 2 diabetes is the use of genetic mouse models.The following genetic animal models are invaluable in pre-clinical diabetes research.

NOD (Non-obese diabetic) mice: These mice have the characteristic features of autoimmune type 1 diabetes like the infiltration of pancreatic cells by leukocytes and insulitis development. These mice are produced by mutating the CTLA-4 gene that play an important role in suppressing the immune response of the T cells. Without a functional CTLA gene T cells attack the insulin producing cells resulting in type 1 diabetes. This mice could provide important data on the pathogenesis of type 1 diabetes.

ob/ob mice: Developed by introducing a mutation in the leptin gene, these mice are a highly useful model to study type 2 diabetes as they display hyperphagia, hyperinsulinemia, hyperglycemia, hyperlipidaemia, insulin resistance and so on that mimic a type 2 diabetic individual.

db/db mice: These mice harbor a mutation in the leptin receptor gene and are the best model to study obesity induced insulin resistance as they display increased body weight, insulin resistance, hyperphagia, hyperinsulinemia, hyperlipidemia and so on.

The Zucker rats (fa/fa): These are excellent rat models in obesity research which demonstrate hyperlipidaemia and hypertension apart from increased body weight. Additional features like hypertrophy and hyperplasia of the adipose tissue shown by these rats makes them outstanding models for obesity and diabetes research.

Apart from these sophisticated invivo animal models, cutting edge biomedical research could be done with the additional support of invitro and ex-vivo models. Interesting research questions on diabetes associated complications can be addressed using high end facilities designed for thrombosis, orthopaedic, vascular and macular degeneration research. Further liver, adipocyte, PBMC cell lines facilitate the invitro confirmation of the results of animal experiments in diabetes and vice versa. Other cell lines like chondrocytes, glial cells, spleenocytes, and Caco2 could be used to study a variety of other metabolic disorders. The world of animal research is expanding in leaps and bounds every day and the successful outcome of a Diabetic NCE is highly dependent on the use of genetically engineered animal models.

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