Deconstructing type 2 diabetes.

There is a natural temptation to extrapolate insights from these animal models to explain the pathophysiology of human diabetes. In some cases, the animal model closely resembles the human disease, as is the case with glucokinase knockout mice and MODY2. In contrast, insulin receptor knockout mice differ dramatically from patients with leprechaunism, the human disease resulting from absence of insulin receptors (9xElders, M., Schedewie, H., Olefsky, J., Givens, B., Char, F., Bier, D., Baldwin, D., Fiser, R., Seyedabadi, S., and Rubenstein, A. J. Natl. Med. Assoc. 1982; 74: 1195–1210PubMedSee all References, 20xTaylor, S.I. Diabetes. 1992; 41: 1473–1490Crossref | PubMedSee all References). While insulin receptor knockout mice develop a severe form of diabetes associated with marked hyperglycemia and ketoacidosis, patients with leprechaunism exhibit relatively mild hyperglycemia. Furthermore, intrauterine growth retardation, a key feature of the human disease, was not found in the knockout mouse. Why might the same mutation cause different phenotypes in different species? There may be differences in the genetic background; for example, parallel or redundant pathways may vary in importance in different species. Indeed, there can be striking differences in phenotype even when a specific mutation is introduced into different strains of mice. By mapping and ultimately cloning modifier genes that account for variations in phenotype, we will advance our understanding of polygenic diseases such as diabetes.The differences between insulin receptor knockout mice and the corresponding human disease invite the question: Are mice with tissue-specific insulin resistance good models for human disease?Insulin resistance in skeletal muscle. The phenotype of mice with insulin resistance at the level of muscle (16xMoller, D., Chang, P., Yaspelkis, B., Flier, J., Wallberg-Henriksson, H., and Ivy, J. Endocrinology. 1996; 137: 2397–2405PubMedSee all References, 6xBruning, J., Michael, M., Winnay, J., Hayashi, T., Horsch, D., Accili, D., Goodyear, L., and Kahn, C. Mol. Cell. 1998; 2: 559–569Abstract | Full Text | Full Text PDF | PubMedSee all References) closely resembles an early stage of human type 2 diabetes (DeFronzo 1997xDeFronzo, R. Diabetes Rev. 1997; 5: 177–269See all ReferencesDeFronzo 1997). Like “prediabetic” humans, these mice exhibit insulin resistance at the level of muscle, but maintain normal (or only minimally elevated) fasting plasma glucose levels. Unlike the animal models, the precise molecular cause of insulin resistance has not yet been elucidated in humans although it is known that there is a block at the level of glucose uptake/phosphorylation in muscle of patients with type 2 diabetes.Insulin resistance in pancreatic β cells. Because insulin resistance develops early in the natural history of type 2 diabetes, it has long been suspected that insulin resistance may play a causal role in the development of the defect in insulin secretion. Novel insights provided by βIRKO mice suggest a unified theory to explain the pathogenesis of type 2 diabetes. A genetic defect in the insulin action pathway may not only cause target cells to become insulin resistant, but also might directly cause β cell failure and insulin deficiency.However, Kulkarni et al. 1999xKulkarni, R., Bruning, J.C., Winnay, J., Postic, C., Magnuson, M., and Kahn, C. Cell. 1999; 96: 329–339Abstract | Full Text | Full Text PDF | PubMed | Scopus (770)See all ReferencesKulkarni et al. 1999 identified an important difference in phenotypes between βIRKO mice and human patients. Whereas insulin secretion is impaired in βIRKO mice, humans with mutations in the insulin receptor gene (e.g., patients with leprechaunism) exhibit striking hyperplasia of pancreatic islets and hypersecretion of insulin (Elders et al. 1982xElders, M., Schedewie, H., Olefsky, J., Givens, B., Char, F., Bier, D., Baldwin, D., Fiser, R., Seyedabadi, S., and Rubenstein, A. J. Natl. Med. Assoc. 1982; 74: 1195–1210PubMedSee all ReferencesElders et al. 1982). Furthermore, even in mice, a defect in insulin signaling does not necessarily cause deficiency in insulin secretion. Bruning et al. 1997xBruning, J.C., Winnay, J., Bonner-Weir, S., Taylor, S.I., Accili, D., and Kahn, C.R. Cell. 1997; 88: 561–572Abstract | Full Text | Full Text PDF | PubMed | Scopus (416)See all ReferencesBruning et al. 1997 engineered mice to become insulin resistant by introducing heterozygous null mutations into both the Insr gene and the Irs1 gene; these Insr+/−Irs1+/− mice developed striking hyperplasia of β cells. Interestingly, the phenotype of β cell hyperplasia observed in the Insr+/−Irs1+/− mice closely resembles the phenotype of patients with leprechaunism. Furthermore, Insr+/−Irs1+/− mice, like most patients with type 2 diabetes, exhibit generalized, partial insulin resistance rather than the total, tissue-specific insulin resistance of βIRKO mice. Thus, there appear to be complex interactions between insulin signaling and β cell function; depending upon the circumstances, insulin resistance may lead either to insulin deficiency (as in βIRKO mice) or to β cell hyperplasia plus hyperinsulinemia (as in humans with leprechaunism and Insr+/−Irs1+/− mice).Because type 2 diabetes is a complex heterogeneous disease with multiple genes contributing to the cause of this polygenic disorder, it is likely that these murine animal models will shed light on disease mechanisms that contribute to the pathophysiology of human diabetes. Defects in the insulin action pathway may be the cause of insulin deficiency in some patients, but there may also be patients in whom there are primary genetic defects that directly impair the machinery for insulin secretion. The approach of positional cloning, currently underway in several laboratories, holds great promise to resolve these controversies by directly identifying the genes that cause both insulin deficiency and insulin resistance.