Transgenic hyperinsulinemia: A mouse model of insulin resistance and glucose intolerance without obesity

Abstract

Type II diabetes represents the most common form of diabetes in humans and is a major cause of morbidity and mortality.! In any individual patient, the primary metabolic abnormality initiating this disease process remains elusive, in spite of extensive study of the human condition and multiple animal models.2-5 Most of these models share several features with human type II diabetes, including glucose intolerance associated with hyperinsulinemia, insulin resistance, and obesity. We describe here transgenic mice that represent a novel model of early type II diabetes. They share many physiologic characteristics with other rodent models of type II diabetes, but they are not obese. They are not the result of a poorly defined mutation that may cause extensive abnormalities beyond those seen in glucose homeostasis, and they are not the result of surgical or pharmacologic manipulation. The metabolic abnormalities seen in these transgenics result from the introduction of multiple copies of the normal human insulin gene into their genome. The production of these transgenics has been previously described.6 Briefly, an 8.8 kilobase (kb) human genomic DNA fragment was introduced by pronuclear microinjection. This DNA fragment includes the entire human preproinsulin gene plus ~2 kb of 5' flanking sequences and >5 kb of 3' genomic sequence. This 5' region contains all the known cis-acting elements that regulate the insulin gene.1-!! The two homozygous transgenic lines analyzed in our study were derived from two independent founder animals, and carry 8 and 32 copies of the human insulin gene, respectively. These copies of the human gene are stably integrated and transmitted to offspring in an autosomal dominant fashion, implying that insertion occurred in each founder at a single site, with the multiple copies of the transgene inherited as a single genetic unit. Expression of the human gene was confirmed at both the RNA and protein levels, and correct tissue specificity of expression has been maintained.6 These transgenics were found to be chronically hyperinsulinemic, with total plasma insulin levels roughly correlating with insulin gene copy number, suggesting a gene dosage effect. In these animals, hyperinsulinemia is the primary event, resulting from the introduction of additional insulin genes. The data presented here demonstrate that hyperinsulinemia itself can result in physiologic abnormalities typical of early stages of type II diabetes.