LINKAGE ANALYSIS OF ACUTE INSULIN-SECRETION WITH GLUT2 AND GLUCOKINASE IN PIMA-INDIANS AND THE IDENTIFICATION OF A MISSENSE MUTATION IN GLUT2

The acute insulin response (AIR), a measure of pancreatic beat-cell fu nction, aggregates in families and is a predictor for the development of non-insulin-dependent diabetes mellitus (NIDDM) in insulin-resistan t Pima Indians. To assess the genetic components of AIR and NIDDM, pol ymorphic dinucleotide repeat regions in two candidate genes, the liver /islet glucose transporter gene (GLUT2) and the glucokinase gene, were evaluated. Sib-pair linkage analyses were performed to determine if l inkage exists between these marker loci and measurements of AIR and NI DDM. No linkage was found between glucokinase and either AIR or NIDDM. Robust sib-pair linkage analyses suggest linkage between GLUT2 and ac ute insulin response (P = 0.04), but no linkage was observed with NIDD M. The coding region of the GLUT2 gene was screened for mutations usin g polymerase chain reaction-single-strand conformation polymorphism an alysis. A single base change was identified in exon 3 in -5% of the st udy population, and it constitutes the first reported mutation in the human GLUT2 gene. This base change resulted in an amino acid substitut ion (Thr110 --> Ile110) in the second membrane-spanning region of the GLUT2 protein. No significant association was noted between AIR and th e presence or absence of the mutation. Thus, this mutation in GLUT2 is unlikely the cause of a low AIR in Pima Indians.