The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity

Abstract

In millions of people, obesity leads to type 2 diabetes (T2D; also known as non-insulin-dependent diabetes mellitus). During the early stages of juvenile obesity, the increase of insulin secretion in proportion to accumulated fat balances insulin resistance and protects patients from hyperglycaemia. After several decades, however,beta-cell function deteriorates and T2D develops in approximately 20% of obese patients. In modern societies, obesity has thus become the leading risk factor for T2D (ref. 5). The factors that predispose obese patients to alteration of insulin secretion upon gaining weight remain unknown. To determine which genetic factors predispose obese patients to beta-cell dysfunction, and possibly T2D, we studied single-nucleotide polymorphisms (SNPs) in the region of the insulin gene (INS) among 615 obese children. We found that, in the early phase of obesity, alleles of the INS variable number of tandem repeat (VNTR) locus are associated with different effects of body fatness on insulin secretion. Young obese patients homozygous for class I VNTR alleles secrete more insulin than those with other genotypes.

Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

“…As the present study includes a large number of individuals of ethnically homogenous origin, the estimated genotype distributions, both among Type 2 diabetic patients, and among NGT subjects, can be expected to reflect distribution of the class I and class III alleles in Danish Caucasians with considerable precision. Other studies with participants of Northern European origin have reported a genotype distribution similar to the one reported in the present study [2,3].…”

“…However, a significant effect of the class III allele on insulin sensitivity was seen in only one of the examined study groups and in the combined analysis, and thus, as the authors conclude, this could be a chance finding from numerous statistical tests made in the study. In a study of obese children it was shown that the class I allele was associated with increased fasting insulin levels, indicating increased insulin sensitivity among carriers of the class III allele [2]. Moreover, the INS-VNTR genotype was shown to have a strong influence on the correlation between insulin levels and BMI, indicating that a potential association between fasting insulin levels and the INS-VNTR depends on the degree of obesity.…”

“…Fourthly, variation of the INS-VNTR has been associated with increased and decreased birthweight [12,13]. And finally, it has been suggested, in a study of obese children [2], that variation of the INS-VNTR affects fasting serum insulin levels, while a recent study reported an effect of the class III allele on increased BMI and decreased insulin sensitivity in three Caucasian cohorts comprising a total of 1184 children and 1099 parents [3].…”

“…The class I (26-63 repeats) and the class III (141-209 repeats) alleles have reported frequencies among Caucasians of between 0.67-0.72 and 0.28-0.33 respectively, while the intermediary class II (64-140 repeats) allele is rare among Caucasians [1,2,3].…”

Markers of insulin resistance are associated with fatness and fitness in school-aged children: the European Youth Heart Study

“…This can be explained by the fact the insulin resistance may increase before children display impaired glucose tolerance. In the very early stages of insulin resistance, the pancreas may compensate for this metabolic disturbance by excreting higher quantities of insulin [38].…”