Graeme Bell, Ph.D.

Molecular Genetics of Diabetes Mellitus; Molecular Biology of Insulin Secretion

Research Summary

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 ß-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 ß-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 ß-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 ß-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 Papers

Johnson JD, Han Z, Otani K, Ye H, Zhang Y, Wu H, Horikawa Y, Misler S, Bell GI & Polonsky KS (2004). RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J. Biol. Chem. 279:24794-24802.

Ng MC, So WY, Cox NJ, Lam VK, Cockram CS, Critchley JA, Bell GI & Chan JC (2004). Genome-wide scan for type diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. Diabetes 53:1609-1613.

Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR. (2004) Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713-2718.

Ng MCY, So W-Y, Lam VKL, Cockram CS, Bell GI, Cox NJ & Chan JCN (2004). Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. Diabetes 53:2676-2683.

Sagen JV, Ræder H, Hathout E, Shehadeh N, Gudmundsson K, Bævre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Søvik O & Njølstad PR (2004). Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2. Patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713-2718.

Grasberger H, Ye H, Mashima H & Bell GI (2005). Dual promoter structure of ZFP106: regulation by myogenin and nuclear respiratory factor-1. Gene 344:143-159. Epub 2004 Nov 19.

Iwasaki N, Horikawa Y, Tsuchiya T, Kitamura Y, Nakamura T, Tanizawa Y, Oka Y, Hara K, Kadowaki T, Awata T, Honda M, Yamashita K, Oda N, Yu L, Yamada N, Ogata M, Kamatani N, Iwamoto Y, del Bosque-Plata L, Hayes MG, Cox NJ & Bell GI (2005). Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population. J. Hum. Genet. 50:92-98. Epub 2005 Feb 5.

Wang CZ, Wang Y, Di A, Magnuson MA, Ye H, Roe MW, Nelson DJ, Bell GI & Philipson LH (2005). 5-Amino-imidazole carboxamide riboside acutely potentiates glucose-stimulated insulin secretion from mouse pancreatic islets by KATP channel-dependent and independent pathways. Biochem. Biophys. Res. Commun. 330:1073-1079.

Grasberger H & Bell GI (2005). Subcellular recruitment by TSG118 and TSPYL implicates a role for zinc finger protein 106 in a novel developmental pathway. Int. J. Biochem. Cell Biol. 37:1421-1437.

Xie JT, Mehendale SR, Li X, Quigg R, Wang X, Wang CZ, Wu A, Aung HH, Rue PA, Bell GI & Yuan CS (2005). Anti-diabetic effect of ginsenoside Re in ob/ob mice. Biochim. Biophys. Acta 1740:319-325 [Epub 2004 Nov 5].

Gunawardana SC, Hara M, Bell GI, Head WS, Magnuson MA & Piston DW (2005). Imaging beta cell development in real-time using pancreatic explants from mice with green fluorescent protein-labeled pancreatic beta cells. In Vitro Cell. Dev. Biol. – Animal 41:7-11.

Park SY, Wang X, Chen Z, Powers A.C, Magnuson MA, Head WS, Piston DW & Bell GI (2005) Optical imaging of pancreatic beta cells in living mice expressing a mouse insulin I promoter-firefly luciferase transgene. Genesis 43:80-86 [Epub ahead of print].

Ng MC, Miyake K, So WY, Poon EW, Lam VK, Li JK, Cox NJ, Bell GI & Chan JC (2005) The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population. Diabetologia 48:2018-2024. Epub 2005 Aug 26.