Graeme Bell, Ph.D.


Research Description

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

A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.
Mercader JM et al.
(2017 Nov) Diabetes. 2017 Nov;66(11):2903-2914. doi: 10.2337/db17-0187. Epub 2017 Aug 24. 28838971 (Full Text)

Multi-ethnic Meta-analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea Related Quantitative Trait Locus in Men.
Chen H et al.
(2017 Oct) Am J Respir Cell Mol Biol. 2017 Oct 27. doi: 10.1165/rcmb.2017-0237OC. 29077507

In vivo measurement and biological characterisation of the diabetes-associated mutant insulin p.R46Q (GlnB22-insulin).
Stoy J, Olsen J, Park SY, Gregersen S, Hjorringgaard CU, Bell GI
(2017 Aug) Diabetologia. 2017 Aug;60(8):1423-1431. doi: 10.1007/s00125-017-4295-2. Epub 2017 May 6. 28478482

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
Manning A et al.
(2017 Jul) Diabetes. 2017 Jul;66(7):2019-2032. doi: 10.2337/db16-1329. Epub 2017 Mar 24. 28341696 (Full Text)

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans.
Cade BE et al.
(2016 Oct) Am J Respir Crit Care Med. 2016 Oct 1;194(7):886-897. 26977737 (Full Text)

Analysis of protein-coding genetic variation in 60,706 humans.
Lek M et al.
(2016 Aug) Nature. 2016 Aug 18;536(7616):285-91. doi: 10.1038/nature19057. 27535533 (Full Text)

The genetic architecture of type 2 diabetes.
Fuchsberger C et al.
(2016 Aug) Nature. 2016 Aug 4;536(7614):41-47. doi: 10.1038/nature18642. Epub 2016 Jul 11. 27398621 (Full Text)

Beyond type 2 diabetes, obesity and hypertension: an axis including sleep apnea, left ventricular hypertrophy, endothelial dysfunction, and aortic stiffness among Mexican Americans in Starr County, Texas.
Hanis CL, Redline S, Cade BE, Bell GI, Cox NJ, Below JE, Brown EL, Aguilar D
(2016 Jun) Cardiovasc Diabetol. 2016 Jun 8;15:86. doi: 10.1186/s12933-016-0405-6. 27266869 (Full Text)

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.
Horikoshi M et al.
(2016 May) Hum Mol Genet. 2016 May 15;25(10):2070-2081. Epub 2016 Feb 23. 26911676 (Full Text)

A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data.
Kim YJ, Lee J, Kim BJ, Park T
(2015 Dec) BMC Genomics. 2015 Dec 29;16:1109. doi: 10.1186/s12864-015-2192-y. 26715385 (Full Text)

Genome-Wide Association Study of Staphylococcus aureus Carriage in a Community-Based Sample of Mexican-Americans in Starr County, Texas.
Brown EL, Below JE, Fischer RS, Essigmann HT, Hu H, Huff C, Robinson DA, Petty LE, Aguilar D, Bell GI, Hanis CL
(2015) PLoS One. 2015 Nov 16;10(11):e0142130. doi: 10.1371/journal.pone.0142130. eCollection 2015. 26569114 (Full Text)

Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications.
Naylor RN, John PM, Winn AN, Carmody D, Greeley SA, Philipson LH, Bell GI, Huang ES
(2014) Diabetes Care. 2014;37(1):202-9. doi: 10.2337/dc13-0410. Epub 2013 Sep 11. 24026547 (Full Text)

Role of BH3-only molecules Bim and Puma in beta-cell death in Pdx1 deficiency.
Ren D, Sun J, Wang C, Ye H, Mao L, Cheng EH, Bell GI, Polonsky KS
(2014 Aug) Diabetes. 2014 Aug;63(8):2744-50. doi: 10.2337/db13-1513. Epub 2014 Mar 21. 24658302 (Full Text)

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.
Estrada K et al.
(2014 Jun) JAMA. 2014 Jun 11;311(22):2305-14. doi: 10.1001/jama.2014.6511. 24915262 (Full Text)

Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder.
Shalev SA, Tenenbaum-Rakover Y, Horovitz Y, Paz VP, Ye H, Carmody D, Highland HM, Boerwinkle E, Hanis CL, Muzny DM, Gibbs RA, Bell GI, Philipson LH, Greeley SA
(2014 May) Pediatr Diabetes. 2014 May;15(3):252-6. doi: 10.1111/pedi.12086. Epub 2013 Oct 21. 24138066 (Full Text)

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
Mahajan A et al.
(2014 Mar) Nat Genet. 2014 Mar;46(3):234-44. doi: 10.1038/ng.2897. Epub 2014 Feb 9. 24509480 (Full Text)

Genetic complexity in a Drosophila model of diabetes-associated misfolded human proinsulin.
Park SY, Ludwig MZ, Tamarina NA, He BZ, Carl SH, Dickerson DA, Barse L, Arun B, Williams CL, Miles CM, Philipson LH, Steiner DF, Bell GI, Kreitman M
(2014 Feb) Genetics. 2014 Feb;196(2):539-55. doi: 10.1534/genetics.113.157602. Epub 2013 Nov 26. 24281154 (Full Text)

Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin.
He BZ, Ludwig MZ, Dickerson DA, Barse L, Arun B, Vilhjalmsson BJ, Jiang P, Park SY, Tamarina NA, Selleck SB, Wittkopp PJ, Bell GI, Kreitman M
(2014 Feb) Genetics. 2014 Feb;196(2):557-67. doi: 10.1534/genetics.113.157800. Epub 2013 Nov 26. 24281155 (Full Text)

Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.
Yin H, Park SY, Wang XJ, Misawa R, Grossman EJ, Tao J, Zhong R, Witkowski P, Bell GI, Chong AS
(2013) PLoS One. 2013 Jun 6;8(6):e65777. doi: 10.1371/journal.pone.0065777. Print 2013. 23762423 (Full Text)

In vitro scan for enhancers at the TCF7L2 locus.
Savic D, Park SY, Bailey KA, Bell GI, Nobrega MA
(2013 Jan) Diabetologia. 2013 Jan;56(1):121-5. doi: 10.1007/s00125-012-2730-y. Epub 2012 Sep 26. 23011354 (Full Text)

An in vivo cis-regulatory screen at the type 2 diabetes associated TCF7L2 locus identifies multiple tissue-specific enhancers.
Savic D, Bell GI, Nobrega MA
(2012) PLoS One. 2012;7(5):e36501. doi: 10.1371/journal.pone.0036501. Epub 2012 May 10. 22590553 (Full Text)

Exome sequencing and genetic testing for MODY.
Johansson S, Irgens H, Chudasama KK, Molnes J, Aerts J, Roque FS, Jonassen I, Levy S, Lima K, Knappskog PM, Bell GI, Molven A, Njolstad PR
(2012) PLoS One. 2012;7(5):e38050. doi: 10.1371/journal.pone.0038050. Epub 2012 May 25. 22662265 (Full Text)

Three Strikes and You're Cured.
Chong AS, Bell GI
(2012 May) Sci Transl Med. 2012 May 9;4(133):133fs12. doi: 10.1126/scitranslmed.3004020. 22572878

Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice.
Dukes ID, Sreenan S, Roe MW, Levisetti M, Zhou YP, Ostrega D, Bell GI, Pontoglio M, Yaniv M, Philipson L, Polonsky KS
(1998 Sep) J Biol Chem. 1998 Sep 18;273(38):24457-64. 9733737

A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.
Concannon P, Gogolin-Ewens KJ, Hinds DA, Wapelhorst B, Morrison VA, Stirling B, Mitra M, Farmer J, Williams SR, Cox NJ, Bell GI, Risch N, Spielman RS
(1998 Jul) Nat Genet. 1998 Jul;19(3):292-6. 9662408

Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.
Pontoglio M, Sreenan S, Roe M, Pugh W, Ostrega D, Doyen A, Pick AJ, Baldwin A, Velho G, Froguel P, Levisetti M, Bonner-Weir S, Bell GI, Yaniv M, Polonsky KS
(1998 May) J Clin Invest. 1998 May 15;101(10):2215-22. 9593777 (Full Text)

Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY.
Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell GI
(1997 Dec) Nat Genet. 1997 Dec;17(4):384-5. 9398836

Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY.
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 GI
(1997 Oct) Diabetes. 1997 Oct;46(10):1652-7. 9313765

Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1)
Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI
(1996 Dec) Nature. 1996 Dec 5;384(6608):458-60. 8945471

Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3)
Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI, et al.
(1996 Dec) Nature. 1996 Dec 5;384(6608):455-8. 8945470

A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.
Hanis CL et al.
(1996 Jun) Nat Genet. 1996 Jun;13(2):161-6. 8640221