The identification of genetic markers for non-insulin dependent diabetes (NIDDM) would permit a full evaluation of the role of non-genetic factors in the expression of that common disease, and thus the possible prevention of inherited diabetes and its complications. This proposal is to examine the genetic predisposition to NIDDM by application of the tools of molecular genetics to Caucasian pedigrees ascertained through an NIDDM or gestational diabetic proband with one affected sibling. Pedigree members will be screened for diabetes and glucose intolerance by standard 75 gm oral glucose tolerance test. Inherited patterns of insulin levels and insulin secretion will be examined to identify phenotypic markers of genetic heterogeneity, and lymphoblastoid cell lines will be established and DNA prepared. These pedigrees will be examined for defects of the insulin receptor gene, the insulin gene, and the glucose transporter gene by using previously identified DNA polymorphisms or polymorphisms to be identified for each locus to test for linkage to diabetes. Where linkage is identified, haplotypes defined by these polymorphisms will be used to examine the role of environmental factors and obesity in predisposed individuals not expressing NIDDM. The putatively defective genes will be characterized at the molecular level by cloning and sequencing. This analysis will provide an estimate of the role of these genes in greater than 5% of pedigrees with inherited diabetes. The clinical data will be subjected to segregation analysis to identify subgroups with uniform mode of inheritance and phenotypic markers, which would be suitable for a general mapping approach using random polymorphic DNA markers if no major predisposing gene is discovered with the candidate approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK039311-05
Application #
3463139
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1988-05-01
Project End
1993-04-30
Budget Start
1992-08-12
Budget End
1993-04-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Elbein, Steven C; Gamazon, Eric R; Das, Swapan K et al. (2012) Genetic risk factors for type 2 diabetes: a trans-regulatory genetic architecture? Am J Hum Genet 91:466-77
Rasouli, Neda; Kern, Philip A; Elbein, Steven C et al. (2012) Improved insulin sensitivity after treatment with PPAR? and PPAR? ligands is mediated by genetically modulated transcripts. Pharmacogenet Genomics 22:484-97
Ma, Lijun; Mondal, Ashis K; Murea, Mariana et al. (2011) The effect of ACACB cis-variants on gene expression and metabolic traits. PLoS One 6:e23860
Elbein, Steven C; Kern, Philip A; Rasouli, Neda et al. (2011) Global gene expression profiles of subcutaneous adipose and muscle from glucose-tolerant, insulin-sensitive, and insulin-resistant individuals matched for BMI. Diabetes 60:1019-29
Sharma, Neeraj K; Langberg, Kurt A; Mondal, Ashis K et al. (2011) Type 2 diabetes (T2D) associated polymorphisms regulate expression of adjacent transcripts in transformed lymphocytes, adipose, and muscle from Caucasian and African-American subjects. J Clin Endocrinol Metab 96:E394-403
Mondal, Ashis K; Das, Swapan K; Baldini, Giulia et al. (2010) Genotype and tissue-specific effects on alternative splicing of the transcription factor 7-like 2 gene in humans. J Clin Endocrinol Metab 95:1450-7
Das, Swapan K; Sharma, Neeraj K; Elbein, Steven C (2010) Analysis of osteocalcin as a candidate gene for type 2 diabetes (T2D) and intermediate traits in Caucasians and African Americans. Dis Markers 28:281-6
Das, Swapan K; Mondal, Ashis K; Elbein, Steven C (2010) Distinct gene expression profiles characterize cellular responses to palmitate and oleate. J Lipid Res 51:2121-31
Elbein, Steven C (2009) Genetics factors contributing to type 2 diabetes across ethnicities. J Diabetes Sci Technol 3:685-9
Wang, Hua; Hays, Nicholas P; Das, Swapan K et al. (2009) Phenotypic and molecular evaluation of a chromosome 1q region with linkage and association to type 2 diabetes in humans. J Clin Endocrinol Metab 94:1401-8

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