This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Considerable evidence supports the existence of several susceptibility genes for type 2 diabetes (T2DM) on chromosome 1q21-q23. Association of variants near the liver pyruvate kinase gene (PKLR) with T2DM has been replicated in several Caucasian populations, but the region of association is broad and includes at least 6 expressed genes. This proposal will test the hypothesis that noncoding variants in this region alter expression of one or more genes and result in increased hepatic glucose production among individuals carrying the susceptible haplotype. A multifaceted approach is proposed, that will first define the region of association in both Caucasian and African American subjects using single nucleotide polymorphisms (Aim 1). Within this region, variation in all coding, conserved, and putative regulatory regions will be screened for variation in 24 Caucasian and 24 African American individuals. Evidence for duplications and rearrangements altering gene copy number will be sought (Aim 2).
Aim 3 will test for differences in expression levels by genotype for all amenable genes in this region in subcutaneous fat, muscle, and immortalized lymphocytes, and will test for differences in allelic expression where common variants in transcribed sequences are found.
Aim 4 will test 10 individuals homozygous for each haplotype to determine insulin secretion, insulin sensitivity by euglycemic clamp, and hepatic glucose production. Fat and muscle will be obtained to correlate phenotype with expression profiles of genes in this region. These studies may identify the specific nucleotide variant leading to T2DM, or alternatively will identify the pathway and genes that increase susceptibility in this region.
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