Diabetes susceptibility genes, part 5: Animal models of diabetes

21/4/05. Fernando Gibson and Philippe Froguel

Previously in their five-part series on the search for diabetes susceptibility genes, Fernando Gibson and Philippe Froguel discussed candidate gene studies and genome-wide searches. In the final part, they examine studies of animal models of diabetes.

The third approach to the identification of diabetes-related genes, and arguably the most tractable route, has been to study animal models of diabetes.

The non-obese diabetic (NOD) mouse strain has long been studied as an excellent model of type 1 diabetes because it spontaneously develops a disease that is very similar to the human condition.

Breeding this strain with a diabetes-resistant mouse strain has allowed major histocompatibility complex (MHC) genes to be transferred from one strain to the other, and vice versa. Many insights into the general role of the MHC in type 1 diabetes (see part 2) have come from the construction of such 'congenic' strains.

A wide range of rodent models of type 2 diabetes have being submitted to genetic analysis in an effort to deliver novel susceptibility genes for study in humans. Two of the most studied rodent models are: the Goto Kakizaki (GK) rat, which was produced by recurrent selective inbreeding of non-diabetic (Wistar) rats with high plasma levels of glucose; and the New Zealand Obese (NZO) mouse, a strain selected for its predisposition to obesity-induced type 2 diabetes that mirrors human type 2 diabetes.

Several of the rodent susceptibility loci identified by genome-scans of the progeny of these strains are in the same order - 'syntenic' - with human type 2 diabetes susceptibility loci (during mammalian evolution, small blocks of the same genes have been preserved in the same linear order across species).

For example, the Niddm1 and Niddm2 loci identified in the GK rat are syntenic with established human type 2 diabetes loci at chromosomes 10q and 1q, respectively. Powerful mouse and rat genome databases have been established that curate and integrate this linkage data with the rodent genomic sequence data. Thus, it is now very straightforward to obtain a complete listing of genes and polymorphic markers under a linkage peak.

The continuing worldwide increase in the prevalence of diabetes is one of the most serious human health problems of the early 21st century. Identifying genes that influence susceptibility to diabetes is vital to promote a better understanding of the molecular mechanisms underlying disease pathogenesis. This, in turn, will lead to the development of improved antidiabetic preventative and therapeutic procedures.

The substantial advances in diabetes gene identification of the past decade, together with the emergence of the 'omics' technologies - transcriptomics (transcriptional profiling) proteomics (protein profiling) and metabonomics (metabolite profiling) - provide confidence that diabetes genes will continue to be identified at an increasing rate.

Until very recently, linkage analysis in disease-affected families was the only genome-wide method for diabetes gene-hunters. Now, with the increasingly comprehensive catalogue of heritable variation in the human genome, and the availability of cheaper high-throughput genotyping technologies, researchers are turning their attention to genome-wide association studies. Indeed, the first faltering attempts to perform genome-wide association analyses for type 2 diabetes have already been reported.

However, identifying diabetes susceptibility alleles is just one of the challenges for the years to come. We need to understanding how diabetes risk is influenced by the complex interaction of these alleles with each other and with the environmental exposures encountered during life: in the womb, in childhood, and as adults. And we need to establish how best to translate this understanding into concrete health benefits for humans.

Dr Fernando Gibson, a Wellcome Trust University Award Fellow, and Professor Philippe Froguel are in the Section of Genomic Medicine, Imperial College London.

Home > Genes and the body > Genes and disease > Features > Diabetes susceptibility genes, part 5: Animal models of diabetes

Diabetes susceptibility genes, part 5: Animal models of diabetes

Related links