Chapter 15 : The Possible Role of Enteroviruses in Diabetes Mellitus

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Insulin-dependent diabetes mellitus (IDDM) is the most common severe chronic childhood illness, affecting an estimated 123,000 children in the United States. Picornaviruses have long been examined for their role as the primary etiologic agent in the pathogenesis of IDDM. Encephalomyocarditis virus (EMCV), a murine picornavirus, produces acute lytic infection of pancreatic β cells and diabetes whose severity correlates with the degree of β-cell lysis. An alternative innocent bystander theory proposes that local inflammation in the peri-insular tissue may induce molecules on the surface of β-cells that enteroviruses could use as cellular receptors. Well-established models of persistent viral infection leading to IDDM include reovirus type 1-induced diabetes and lymphocytic choriomeningitis virus (LCMV)-induced diabetes in mice as well as congenital rubella syndrome (CRS) in humans. Much of what is known concerning tropism of enteroviruses to the human pancreas has been learned from autopsy studies of newborns and infants who died of fulminant enteroviral infection. A large prospective study of young children monitored for concurrent development of enteroviral infections and β-cell autoimmunity is needed to test the hypothesis that symptomatic and/or serologically detectable enteroviral infection is associated with development of IDDM or β-cell autoimmunity. At present, it is not known, whether a single pathogenic mechanism is responsible for diabetes induced by various picornaviruses or whether diabetes can result from a spectrum of picornavirus-induced lesions, e.g., acute β-cell lysis, chronic autoimmunity, or insulin secretion defect. The rate of spontaneous mutation for enteroviruses is as high as 10 .

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 1

Molecular homology between GAD and coxsackievirus P2-C. Solid lines enclose identical amino acid residues. Dashed lines enclose residues with similar charges, polarities, or hydrophobicities. Reproduced from the ( ), by copyright permission of the American Society for Clinical Investigation.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 2

Incidences of IDDM (thin line) and enteroviral meningitis (EVM) (heavy line) in Wielkopolska, Poland, (a) Children aged 0 through 4 years; (b) children aged 5 through 9 years; (c) children aged 10 through 14 years.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 3

Incidence of IDDM (thin line) and enteroviral meningitis (EVM) (thick line) in Wielkopolska, Poland, 1980 through 1988. The IDDM curve reflects 3-month moving averages. The dominant serotypes of enteroviruses cultured from or determined serologically in the meningitis cases are shown. E, echovirus; B5, CVB5.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 4

Incidence of IDDM in the age group 0 through 14 years in Norway, Colorado, and Poland in 1978 through 1980, showing significant geographic differences in incidence rates.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 5

Age distribution of enteroviral meningitis in Norway, Colorado, and Poland. The high incidence of enteroviral meningitis in the age group 0 through 14 years in Poland (low IDDM risk) compared to those in Colorado (moderate IDDM risk) and Norway (high IDDM .risk) supports the polio model of IDDM etiology.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 6

Age distribution of enteroviral meningitis inWielkopolska, Poland. There was no evidence for a change in distribution during the epidemic year (1982) compared to that in the nonepidemic years (1979 through 1981 and 1983).

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Image of FIGURE 7

Incidence of IDDM and enteroviral meningitis (AM) in Colorado, 1978 through 1988. The incidence of IDDM paralleled that of enteroviral meningitis in lower-income Hispanics but not in higher-income non-Hispanic white children.

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Associations between HLA phenotype and elevated CVB IgM levels in newly diagnosed IDDM patients

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15
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Problems in relating viruses to IDDM etiology

Citation: Rewers M, Atkinson M. 1995. The Possible Role of Enteroviruses in Diabetes Mellitus, p 353-385. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch15

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