GENETICS OF TYPE II DIABETES MELLITUS AND OBESITY
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A mutation in the beta-3-adrenergic receptor gene (Trp64Arg), common in many ethnic populations, has an association with early onset of non-insulin dependent diabetes mellitus, elevated insulin levels, increased body mass index, and other features of the insulin resistance syndrome. To better characterize the physiology of these alterations, we will study the differences in glucose metabolism, body composition, and energy expenditure in: 1) individuals with two copies of the normal allele; 2) individuals with two copies of the variant allele; and 3) individuals who are heterozygous for the variant receptor. We will determine the body composition using CT scans for visceral fat measurements, anthropomorphic measurements, and DEXA scans to determine fat mass. Glucose tolerance will be determined using IV glucose tolerance tests to measure acute insulin response to glucose (AIRg) (insulin secreted in the first 10 minutes after a standardized glucose bolus), insulin sensitivity index (Si), and insulin disposition index (Si x AIRg) using Minimal Model analysis. Energy expenditure will be determined using indirect calorimetry and doubly- labeled water method, and compared among the three groups. Individual measurements will be collated into a database and quantitative traits will be compared among the three groups by analysis of variance, and where appropriate, analysis of covariance. Genotyping of study participants began in the summer of 1995. The first individual was studies in the summer of 1996. Since that time, we have genotyped over 2400 individuals, and have enrolled 47 into the GCRC physiologic studies. Of these, 18 subjects are homozygous for the mutation, 13 of whom have enrolled in the GCRC protocol. We will need to recruit approximately 2500 more individuals in order to attain our goal of studying 25 homozygotes. The study is now fully funded by the American Diabetes Association through December, 2000. The GCRC-approved project is expected to be completed by the summer of 2000. Preliminary analysis reveals a significant association (p<0.05) with lower AIRg and non- significant trends toward lower S1 and disposition index in those homozygous for the variant allele. We have also found strong associations of the variant allele with low resting metabolic rates and higher than normal thermic effect of feeding. These data suggest that individuals homozygous for the Arg64 allele secrete less insulin in response to a glucose bolus, perhaps due to decreased lipolysis and delivery of free fatty acids to pancreatic B-cells, or altered sympathetic nervous system signaling.
The Old Order Amish of Lancaster County, Pennsylvania initially numbered in the hundreds, and are now a population of over 200. This population is a well-defined, genetically homogeneous Caucasian population with very large sibships, a high degree of consanguinity, and well documented genealogies. The goal of this study is to recruit and phenotypically characterize large multiplex pedigrees with noninsulin dependent diabetes mellitus (NIDDM) for a genome-wide search for susceptibility genes for this heterogeneous and polygenic disorder. To date, over a thousand subjects have been studied. These individuals are from 80 two- and three-generation families constituting one extended pedigree and over 2000 sib pairs. Of the first consecutive 258 subjects recruited, 16.2% had diabetes if they had a first degree relative with diabetes, compared to only 6.5% if there was no first degree relative with diabetes (RR 2.5; p
