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.
Role of BH3-only molecules Bim and Puma in beta-cell death in Pdx1 deficiency.
(2014 Aug) Diabetes
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Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.
(2014 Jun) JAMA
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Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder.
(2014 May) Pediatr Diabetes
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Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
(2014 Mar) Nat Genet
. 2014 Mar;46(3):234-44. doi: 10.1038/ng.2897. Epub 2014 Feb 9. 24509480
Genetic complexity in a Drosophila model of diabetes-associated misfolded human proinsulin.
(2014 Feb) Genetics
. 2014 Feb;196(2):539-55. doi: 10.1534/genetics.113.157602. Epub 2013 Nov 26. 24281154
Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin.
(2014 Feb) Genetics
. 2014 Feb;196(2):557-67. doi: 10.1534/genetics.113.157800. Epub 2013 Nov 26. 24281155
Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications.
(2014 Jan) Diabetes Care
. 2014 Jan;37(1):202-9. doi: 10.2337/dc13-0410. Epub 2013 Sep 11. 24026547
Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.
(2013) PLoS One
. 2013 Jun 6;8(6):e65777. doi: 10.1371/journal.pone.0065777. Print 2013. 23762423
In vitro scan for enhancers at the TCF7L2 locus.
(2013 Jan) Diabetologia
. 2013 Jan;56(1):121-5. doi: 10.1007/s00125-012-2730-y. Epub 2012 Sep 26. 23011354
An in vivo cis-regulatory screen at the type 2 diabetes associated TCF7L2 locus identifies multiple tissue-specific enhancers.
(2012) PLoS One
. 2012;7(5):e36501. doi: 10.1371/journal.pone.0036501. Epub 2012 May 10. 22590553
Exome sequencing and genetic testing for MODY.
(2012) PLoS One
. 2012;7(5):e38050. doi: 10.1371/journal.pone.0038050. Epub 2012 May 25. 22662265
Three Strikes and You're Cured.
(2012 May) Sci Transl Med
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Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice.
(1998 Sep) J Biol Chem
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A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.
(1998 Jul) Nat Genet
. 1998 Jul;19(3):292-6. 9662408
Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.
Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY.
(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.
(1997 Oct) Diabetes
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Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1)
(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)
(1996 Dec) Nature
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A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.
(1996 Jun) Nat Genet
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