Mouse Models and the Genetics of Diabetes

Abstract

In humans, both type 1 and type 2 diabetes exemplify genetically heterogeneous complex diseases in which epigenetic factors contribute to underlying genetic susceptibility. Extended human pedigrees often show inheritance of both diabetes types. A common pathophysiological denominator in both disease forms is pancreatic ␤-cell exposure to proinflammatory cytokines. Hence, it is intuitive that systemically expressed genes regulating ␤-cell ability to withstand chronic diabetogenic stress may represent a component of shared susceptibility to both major disease forms. In this review, the authors assemble evidence from genetic experiments using animal models developing clearly distinct diabetes syndromes to inquire whether some degree of overlap in genes contributing susceptibility can be demonstrated. The conclusion is that although overlap exists in the pathophysiological insults leading to ␤-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct. Diabetes 54 (Suppl. 2):S151-S158, 2005 T he complex of genes in the HLA locus (IDDM1) contributing the major component of human susceptibility to autoimmune type 1 diabetes clearly provides a starting point for comparison for overlap with major susceptibility contributors to classic type 2 diabetes. Indications of humoral immunity against pancreatic ␤-cell autoantigens in 10 -30% of patients deemed clinically to have type 2 diabetes led to the concept that these patients exhibit latent autoimmune diabetes in adults (LADA), or "type 1.5" diabetes (1). Many LADA patients exhibit decreased frequency of the highest risk HLA class I and class II alleles and increased frequency of HLA alleles conferring strong protection against juvenile-onset type 1 diabetes (1). Although most type 2 diabetes cases clearly are not autoimmune in causation, and thus, specific HLA alleles are not identified as major type 2 diabetes susceptibility contributors, the LADA cases raise the possibility that a subset of non-HLA susceptibility may be shared. Under such circumstances, the absence of the high-risk HLA alleles results in a more slowly progressive disease that only presents in adulthood when pathophysiological stresses on ␤-cells, including obesity and insulin resistance shared in common with patients with classic type 2 diabetes, become prevalent.Polymorphisms in the upstream regulatory region of the insulin gene currently represent the strongest non-HLA locus linked to human type 1 diabetes susceptibility (IDDM2) (2). The pathogenic mechanism has not been associated with insulin processing, secretion, or action, but rather with the ability to express intrathymically and elicit T-cell tolerance to this major type 1 diabetes autoantigen (3,4). Alleles associated with resistance to type 1 diabetes, on the other hand, have been associated with polycystic ovarian syndrome (5), an insulin resistance syndrome that often leads to type 2 diabetes. Because type 2 diabetes often culminates in insulin deficiency attributed to ␤-cell failure associated with chron...

Immune Cell–Derived C3 Is Required for Autoimmune Diabetes Induced by Multiple Low Doses of Streptozotocin

“…Whether C3 and/or its activation cleavage products, C3a, C3b, or C3dg are involved in the pathogenesis of diabetes in NOD mice is an issue that remains to be tested. However, the generation of C3 −/− NOD mice is improbable because both C3 and the diabetes-susceptible H-2K d genes are located on chromosome 17 (17,18). …”

“…We chose the MLDS model over the NOD model because C3 and the diabetes susceptibility genes in the NOD strain are closely linked on chromosome 17 (17,18), thus impairing our ability to produce C3-deficient NOD animals. Streptozotocin (STZ), a toxin that binds to the GLUT2 receptor on pancreatic β-cells, has been used for decades to induce diabetes in rodent models (19).…”

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“…As a corollary, the lack of relationship between glycosylated hemoglobin and other parameters suggests that this index might be a less sensitive indicator of diabetic complications affecting cardiovascular regulatory mechanisms, in particular, changes in heart rate variability and blood pressure variability. A clinical advantage of this approach might be that indirect autonomic monitoring could furnish a surrogate outcome to assess not only early cardiovascular damage but also the beneficial effects of therapy, such as provided by respiratory and exercise training, 26 on autonomic dysregulation or therapies targeting more directly endothelial function, 27 such as with angiotensin-converting enzyme inhibitors. An additional clinical observation regards the significant increase in SAP observed in these young T1DM patients, particularly apparent in the adolescent subgroup.…”

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