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Type 1 diabetes mellitus (DM) results from the progressive destruction of pancreatic β-cells. Genetic factors are considered to be a major component for the development of type 1 DM (1,2). However, cumulative evidence suggests that environmental factors play an important role in the development of type 1 DM by influencing the penetrance of diabetes susceptibility genes. Such evidence includes the fact that the concordance rate for type 1 DM between monozygotic, genetically identical twins is less than 40% (2). The environmental factors thought to play a role in this disease include viral infections, certain dietary components, and toxins (3).

In this chapter, we briefly review viruses as one environmental factor, as well as the various pathogenic mechanisms by which viruses may act either to induce or prevent diabetes. For many years, viruses have been considered to be associated with the development of some cases of type 1 DM (3) (Table 37.1). There appears to be a seasonal variation in the onset of acute type 1 DM, with a peak in the autumn (4,5); diseases with seasonal incidences are often caused by viral infections. There also have been numerous anecdotal reports of a temporal association between viral infections and the development of diabetes in some patients (3). Viruses are involved in the pathogenesis of type 1 DM in at least two distinct ways: (a) by directly destroying insulin-producing pancreatic β-cells by cytolytic infection, and (b) by triggering or somehow contributing to β-cell–specific autoimmunity, leading to the development of type 1 DM (3). In addition, there is evidence that viruses can also protect against the development of diabetes in the spontaneously diabetic BioBreeding (BB) rat and nonobese diabetic (NOD) mouse (6,7).

Virus-Induced Diabetes Mellitus in Animals

Studies using experimental animal models of type 1 DM have provided valuable information indicating that viruses can cause type 1 DM. Several viruses have been clearly demonstrated to cause type 1 DM in animals, including encephalomyocarditis (EMC) virus (8), coxsackievirus B4 (9,10), and Kilham rat virus (KRV) (11). Other viruses, such as rubella virus (12,13), retrovirus (14,15), and bovine viral diarrhea-mucosal disease virus (BVD-MD) (16), are suspected of causing DM in hamsters and rabbits, NOD mice, and cattle, respectively.

Encephalomyocarditis Virus–Induced Diabetes Mellitus in Mice

EMC virus belongs to the picornavirus family. The form of the virus is a naked icosahedron, and the capsid is composed of a polyprotein, consisting of a single molecule of each of four polypeptides (VP1,2,3, and 4). The genome is a single linear molecule of single-stranded RNA of positive polarity. EMC virus–induced DM in mice is the best experimental animal model of DM brought on by a viral infection (8,17). Two different animal models have been established with respect to pathogenic mechanisms for EMC virus–induced diabetes (Fig. 37.1). The first model involves animals infected with a high dose [105 plaque-forming units (pfu)/mouse] of EMC virus, in which replication of the virus within the &#946;-cells play a major role in &#946;-cell destruction (Fig. 37.2). The second model involves animals infected with a low dose (<102 pfu/mouse) of EMC virus, in which macrophages that are recruited into the pancreatic islets after initial &#946;-cell destruction by EMC infection play a major role in the destruction of the remaining &#946;-cells (18,19).

Genetic Control of EMC Virus–Induced Diabetes: Susceptibility to EMC Virus–Induced Diabetes Mellitus Is Controlled Primarily by a Single Host Gene

Only some inbred strains of mice (SJL/J, SWR/J, DBA/1J, and DBA/2J) acquire DM when infected with the M-variant of EMC virus (EMC-M), whereas other strains (C57BL/6J, CBA/J, and AKR/J) are resistant (20). Susceptibility appears to be inherited as an autosomal-recessive trait, because the F1 cross between DM-prone SWR/J mice and DM-resistant