| Summary: | Type I diabetes is a multi-factorial disease resulting from the destruction of beta cells in
the islets of Langerhans of the pancreas, causing a serious derangement of glucose
metabolism that can be fatal in patients deprived of insulin treatment. Factors involved in
disease development include host genetic susceptibility genes, aberrant immune
reactions, and environmental agents such as viruses, drugs and diet. The pathogenesis of
virus-induced type I diabetes is not well-understood, and several mechanisms have been
proposed. It is known that only some strains of group B coxsackieviruses (CVBs) induce
glucose dysregulation in susceptible human patients and murine models; thus certain
intrinsic properties of diabetogenic strains must be responsible for causing beta cell
injury. The overall aim of this thesis was to characterize the viral factors that determine
the diabetogenicity of the CVB4 E2 strain, but are absent in the non-diabetogenic,
parental CVB4 JVB strain.
A diabetes-susceptible mouse strain, SJL/J, was infected with one of the two viruses, and
the pathogenic processes triggered by each virus infection in the pancreas were
compared. Histological analysis of sections of infected pancreas revealed that JVB
infection caused acute damage to the pancreas, which subsequently recovered and
regenerated new islet cells. On the other hand, E2 infection induced much more damage
to the exocrine pancreas, and no islet neogenesis was observed to occur. The E2 strain
was found to cause a higher degree of apoptosis of both islet and acinar cells, compared
to JVB virus. E2 viral titres in the pancreas, serum and other target organs were 10 to
100-fold higher than those produced by JVB virus, and infectious E2 viral particles were
present for a longer period of time. Also, E2 double-stranded RNA (dsRNA) persisted in
the pancreas until day 95 post-infection (p.i.), whereas JVB dsRNA was undetectable
after day 3. Examination of beta cell function showed that while islets of JVB-infected
mice resumed insulin production after day 3, the islets of E2-infected mice were found to
be insulin-deficient long after acute infection has been resolved. Endocrine cell damage
caused by E2 infection was found to be specific for beta cell insulin production, and did
not adversely affect proIAPP synthesis or alpha cell glucagon production up to day 35 p.i.
Glucose tolerance tests showed that JVB-infected mice were normoglycemic after day 10
p.i., whereas E2-infected ones were hypoglycemic from day 5 to 35. In summary, these
findings showed that the diabetogenic E2 strain is more virulent than the parental JVB
virus, and causes extensive exocrine tissue damage thereby preventing islet cell
neogenesis from occurring. The mice become extremely hypoglycemic despite a
complete absence of insulin production, due to the lack of pancreatic enzymes that the
exocrine pancreas normally supplies to enable digestion. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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