Treatment Proposals on Type 2 Diabetes Mellitus - Research Proposal Example

?Research Proposal Introduction: Type 2 Diabetes mellitus is one of the global predominant diseases. Vitamin D and its receptors are present in almost 30 types of tissues (pancreas, myocardium and lymphocytes, etc.,) showing its importance to the human body. Vitamin D is found to regulate the insulin secretion along with the calcium ions. Vitamin D deficiency results in the imbalance of the parathyroid hormone in the body and results in the increase in the calcium level and the increase of calcium inhibits the insulin activity. The reduction of insulin activity removes the glucose transporter in the urine samples out of the body. This concludes that glucose level monitoring and the Vitamin D level monitoring is very important for the type 2 Diabetes patients.1 When the Vitamin D binds to the vitamin D receptor (VDR), a heterodimer is formed. This hetereodimer then binds to the DNA and initiates many cofactors leading to the increase in the transcription of the genes that are responsible for the production of the proteins that control the calcium homeostasis. Vitamin D regulates the insulin receptor gene expression at the genetic level. The mRNA that codes for insulin receptor gene is produced at large numbers by increasing the expression level. The increase in the insulin receptor will increase the binding of the insulin and makes the GLUT4 transporter gene translocation from the intracellular level to the plasma membrane. 2 This increase in flux increases the glucose metabolism and thus controls the type 2 Diabetes mellitus in humans.GLUT 4 contain the phosphate at the basal state. The phosphorylation of GLUT4 is mediated by the cyclic cAMP- dependent protein kinase inhibiting the glucose transport.2 Scientific Background: A study was carried out in the year 1993, to identify the genes that are responsible for the regulatory domain of the GLUT4 in the adipose tissue. The transcriptional regulation of the gene was studied in the murine C2C12 skeletal muscle cell line. Transient transfection of the 5’ and 3’ deletions of the GLUT4 5’ flanking DNA has identified a region of 281 base pairs present at the myotube-specific expression. 3 The total RNA was isolated and used for Northern Blot analysis and hybridization was carried out. This gene was then inserted into the luciferase EcoRI- DraI fragment plasmid and further analysis was carried out. 3 The GLUT4 mRNA was found to be dependent on the thyroid hormone. This region was also found between the -517 and -237 region. This 281 base pair region is found to play a major role in understanding the mechanism that controls the GLUT4 gene expression in the skeletal muscle. All these experiments were carried out in the rat model.3 The vitamin D deficiency is found to be associated with the impaired insulin secretion. When Vitamin D is supplied at sufficient level then it binds to the vitamin D receptors (VDRs) present in the pancreatic beta cells. VRD gene is present in the Chromosome 12-cen-q12. When allelic variations are done in the VDR receptor gene then glucose absorbance rate also varies. The genomic DNA was extracted from the four healthy individuals and the four SNPS at the intron 8 and Exon 9 was examined with the controls. 4 The peripheral blood samples were analyzed for the given SNPS at the VDR gene using the polymerase chain reaction and then by the restriction fragment length polymorphism (RFLP). The restriction sites looked for were TaqI, ApaI, BsmI and Tru91SNP. 4 It was found that the genotypes were similar in both the patients and control. This concluded that VDR is not the major gene for the Type 2 Diabetes mellitus. Hence further research is necessary for finding the responsible gene for Type 3 Diabetes mellitus.4 The vitamin D is not only the factor that is responsible for the insulin resistance. There are other factors too. The 25- hydroxyl vitamin D (25(OH)-D) is found to be inversely proportional to the insulin resistance and the (25( OH)-D) concentration is determined in the serum for the analysis. The association between the (25(OH)-D) and the insulin secretion based on food consumption was also tested and found to have no relationship. Further work is carried out to look for the relationship between the oral glucose tolerance test and the (25(OH)-D). 5 Further studies proved that there is no association between these two. As this hypothesis is found to be controversary to the concept that vitamin D and insulin resistance and type 2 Diabetes are related, this was found to be related to the compensatory hyperinsulinemia.5 The studies of the Mini-Finland Health study and the Finnish mobile clinic health examination survey has revealed that T2DM risk in men were reduced by the higher (25(OH)-D). They have also found that this result is not applicable to the women. They have also found that glucose level at different stages (fasting, normal, and exercising) contributes to the analysis very much.6 Methodology: The protocol designed based on the above reviews is as follows: The patients having Type 2 diabetes mellitus are selected with a wide range in age, disease condition and both genders. The peripheral blood glucose level and the excretion of the GLUT4 protein in the urine sample are monitored by giving Vitamin D at different concentrations. From the Richardson’s study, the methodology adopted for the identification of the region responsible for the GLUT4 gene expression can be used for mRNA studies. Conclusion: The literature review conducted by Alvarez and Ashraf clearly states that many factors needed to be confirmed to have relationship with the Type 2 Diabetes mellitus. They have also concluded that the link between Vitamin D and Type 2 diabetes need to be established by further studies. The uses of Biomarkers such as luciferase gene are able to predict the relationship between the genes that are responsible for the secretion of the protein glucose transporter and T2DM. The pathophysiological mechanisms of the relationship between the vitamin D, Type 2 Diabetes and GLUT4 remain unexplained. Hence research must be carried out to find out the concept behind them. Studies have also confirmed that VDR gene is not responsible for the Type 2 Diabetes. We propose to do an intensive research to identify the relationship between the GLUT4, Vitamin D and T2DM. References: 1. Meerza, D., Naseem, I and Ahmed, J, “Can Vitamin D be a potential treatment for Type 2 Diabetes mellitus?”, Diabetes and Metabolic syndrome: Clinical Research and Reviews, 4, 2010, pp.245-248. 2. Schurmann, A., Mieskes, G., and Joost, HJ., “Phosphorylation of Adipose/ muscle- type glucose transporter (GLUT4) and its relationship to glucose transport acitviity”, Biochemical Journal, 285, 1992, pp.223- 228. 3. Richardson, J. M., and Pessin, J. E., “Identification of the skeletal muscle- specific Regulatory Domain in the Rat GLUT4/ Muscle Fat gene”, Journal of Biological Chemistry, 268, 28, 1993, pp.21021-21027. 4. Ye, W., Reis, A. F., Laforgue, D.D., Chentelot, C.B., Timsit, J and Velho, G. “Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset”, European Journal of Endocrinology, 145, 2001, pp.181-186. 5. Ou, H. Y., Karnchanasorn, R., Lee, L. Z and Chiu, K. C, “Interaction of BMI with Vitamin D and insulin sensitivity”, European Journal of Clinical investigation. 2011. 6. Pittas, A. G., Lau, J., Hu, F. B and Dawson-Hughes, B., “The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis,” Journal of Clinical Endocrinology and Metabolism, 92, 6, 2007, pp. 2017–2029. Read More