This laboratory is applying techniques of molecular biology and genetics to problems in medicine. Our major interests is non-insulin-dependent or Type 2 diabetes mellitus (NIDDM), a disorder or carbohydrate metabolism characterized by elevated blood glucose levels, which affects about 5% of the population in the United States. As with other common diseases of middle age such as cardiovascular disease and hypertension, genetic factors contribute to the development of NIDDM. Our working hypothesis is that a relatively small number, perhaps 5-10, of potentially identifiable major genes increase the risk of developing diabetes and that the individual's overall genetic background, together with environmental and lifestyle factors, influences the phenotypic expression of the major susceptibility genes.
In our genetic studies we are studying diabetes-prone families in which NIDDM has an early age-at-onset and a clear autosomal dominant mode of inheritance. These studies have resulted in the identification of two genes, one on chromosome 7 and another on chromosome 20, that are associated with early-onset NIDDM. The gene on chromosome 7 encodes the glycolic enzyme glucokinase which functions as the glucose sensor in the insulin-secreting _-cell to insulin so that higher blood glucose levels are required to stimulate insulin secretion. These mutations may be the cause of diabetes in 1-5% of all patients with NIDDM. They represent the most common cause of NIDDM identified to date.
Drawing on our understanding of the pathophysiology of NIDDM, we are also cloning and characterizing genes that might reasonably contribute to diabetes susceptibility. Since the pancreatic _-cell plays an important role in the pathogenesis of all forms of diabetes mellitus, we are particularly interested in studying genes in this cell type. We have partially sequenced over 1,200 randomly isolated cDNA clones from a human pancreatic islet cDNA library to determine the repertoire of genes expressed in normal adult human islets. About one-half of these clones represent known sequences and the remainder encode unknown proteins, some of which presumably endow the _-cell with its unique physiological properties. We are characterizing these novel gene products, as well as those encoding proteins of known function, in order to obtain an understanding of their roles in normal _-cell function and in the regulation of biosynthesis and secretion.
Finally, we have cloned the receptors for somatostatin and opioid peptides; this has led us into the area of neurobiology and the role of these receptors in the regulation of neuronal function.
Selected Publications
Hanis, C.L., Boerwinkle, E., Chakraborty, R., Ellsworth, D.L., Concannon, P., Stirling, B., Morrison, V.A., Wapelhorst, B., Spielman, R.S., Gogolin-Ewens, K.J., Shephard, J.M., Williams, S.R., Risch, N., Hinds, D., Iwasaki, N., Ogata, M., Omori, Y., Petzold, C., Rietzsch, H., Schröder, H.E., Schulze, J., Cox, N.J., Menzel, S., Boriraj, V.V., Chen, X., Lim, L.R., Lindner, T., Mereu, L.E., Wang, Y.Q., Xiang, K.S., Yamagata, K., Yang, Y., & Bell, G.I. (1996). A genome-wide search for human non-insulin-dependent (Type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genet. 13:161-167.
Yamagata, K., Oda, N., Kaisaki, P.J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R.D., Lathrop, M., Boriraj, V.V., Chen, X., Cox, N.J., Oda, Y., Yano, H., Le Beau, M.M., Yamada, S., Nishigori, H., Takeda, J., Fajans, S.S., Hattersley, A.T., Iwasaki, N., Hansen, T., Pedersen, O., Polonsky, K.S., Turner, R.C., Velho, G., Ch_vre J.C., Froguel, P. & Bell, G.I. (1996). Mutations in the hepatocyte nuclear factor-1a gene in maturity-onset diabetes of the young (MODY3). Nature 384:455-458.
Yamagata, K., Furuta, H., Oda, N., Kaisaki, P.J., Menzel, S., Cox, N.J., Fajans, S.S., Signorini, S., Stoffel, M. & Bell, G.I. (1996). Mutations in the hepatocyte nuclear factor-4a gene in maturity-onset diabetes of the young (MODY1). Nature 384:458-460.
Furuta, H., Iwasaki, N., Oda, N., Hinokio, Y., Horikawa, Y., Yamagata, K., Yano, N., Sugahiro, J., Ogata, M., Ohgawara, H., Omori, Y., Iwamoto, Y. & Bell, G.I. (1997). Organization and partial sequence of the hepatocyte nuclear factor-4a/MODY1 gene and identification of the missense mutation, R127W, in a Japanese family with MODY. Diabetes 46:1652-1657.
Horikawa, Y., Iwasaki, N., Hara, M., Furuta, H., Hinokio, Y., Cockburn, B.N., Lindner, T., Yamagata, Y., Ogata, M., Tomonaga, O., Kuroki, H., Kasahara, T., Iwamoto, Y. & Bell, G.I. (1997). Mutation in hepatocyte nuclear factor-1_ gene (TCF2) associated with MODY. Nature Genet. 17:384-385.
Pontoglio, M., Sreenan, S., Roe, M., Pugh, W., Ostrega, D., Doyen, A., Pick, A.J., Baldwin, A., Velho, G., Froguel, P., Levisetti, M., Bonner-Weir, S., Bell, G.I., Yaniv, M. & Polonsky, K.S. (1998). Defective insulin secretion in hepatocyte nuclear factor 1a-deficient mice. J. Clin. Invest. 101:2215-2222.
Concannon, P., Gogolin-Ewens, K.J., Hinds, D.A., Wapelhorst, B., Morrison, V.A., Stirling, B., Mitra, M., Farmer, J., Williams, S.R., Cox, N.J., Bell, G.I., Risch, N. & Spielman, R.S. (1998). A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 19:292-296.
Dukes, I.D., Sreenan, S., Roe, M.W., Levisetti, M., Zhou, Y.P. Ostrega, D., Bell, G.I., Pontoglio, M., Yaniv, M., Philipson, L. & Polonsky, K.S. (1998). Defective pancreatic _-cell glycolytic signaling in hepatocyte nuclear factor-1a-deficient mice. J. Biol. Chem. 273:24457-24464.
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