We studied the molecular characteristics of three naturally occurring variants in the human apolipoprotein B (apoB) signal peptide, their frequencies in non-insulin-dependent diabetic and random populations, and their association with several measures of lipid and carbohydrate metabolism. In a random sample of 197 French whites, there were two common alleles, 5'beta SP-24 and 5'beta SP-27, with frequencies of 0.35 and 0.65, respectively. In a random sample of 181 Mexican Americans, there was an additional allele, 5'beta SP-29, with a frequency of 0.03. DNA sequence analysis indicated that the signal peptide alleles consisted of the following: 5'beta SP-29 encoded 29 amino acids in the signal peptide containing two copies of the sequence CTG GCG CTG encoding Leu-Ala-Leu and a consecutive run of eight Leu-encoding codons; 5'beta SP-27 encoded 27 amino acids with a run of only six Leu codons; 5'beta SP-24 encoded 24 amino acids and contained a single copy of CTG GCG CTG and a run of six Leu codons. In the sample of French whites, average apoAI and glucose levels were significantly different among signal peptide genotypes. 5'beta SP-24/24 homozygotes had higher apoAI levels than the two other signal peptide genotypes (1.59 vs. 1.42 g/L, respectively). Heterozygous 5'beta SP-24/27 individuals had the highest glucose levels. In the random sample of Mexican Americans, average glucose levels were also significantly different among signal peptide genotypes. However, the rank order of average glucose levels was not the same between the two samples.(ABSTRACT TRUNCATED AT 250 WORDS)