Many different viruses belonging to several genera have the potential to damage beta cells. The mechanisms they employ are varied, and infection may result in either a direct destruction of islets and rapid insulin deficiency, or in a more gradual loss of functioning islets with the onset of diabetes many years later. Several case histories involving extensive cytolysis of beta cells can be directly linked to viral infection, whilst an example of diabetes occurring many years after viral infection is found in individuals who had a congenital infection with rubella virus. Here, the virus induces an autoimmune reaction against beta cells. Autoimmune phenomena have also been observed in islets following infections with viruses other than rubella, and thus activation of autoimmune mechanisms leading to beta-cell destruction may be a relatively frequent occurrence. Recent evidence shows that picornaviruses are not exclusively lytic, and can induce more subtle, long-term changes in beta cells, which may be important in the aetiology of diabetes. The exact mechanisms involved are not known, but it is clear that several viruses can directly inhibit insulin synthesis and induce the expression of other proteins such as interferons, and the HLA antigens. Strain differences in viruses are important since not all variants are tropic for the beta cells. Several laboratories are in the process of identifying the genetic determinants of tropism and diabetogenicity, especially amongst the Coxsackie B (CB) virus group. The sequence of one such diabetogenic CB4 strain virus has been determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Infections with Coxsackie viruses (especially Coxsackie B4) are thought to be involved in the pathogenesis of diabetes. Many interdependent variables determine the outcome of an infection with a Coxsackie virus, one of them being the tropism of the virus for a specific tissue. The extent to which Beta cell tropic variants of Coxsackie B4 virus occur naturally was assessed. Human isolates of this virus were tested in an in vitro system in which elevated insulin release from infected islets incubated at a non-stimulatory (2 mmol/l) glucose concentration appears to be related to viral attack. Using this technique, 8/24 isolates tested, impaired secretory function in mouse islets. Some strains of Coxsackie B4 virus, therefore, will directly infect mouse islets in vitro leading to changes in islet cell function. In conclusion, these findings confirm that variants of Coxsackie B4 virus with the potential to damage Beta cells occur quite frequently in the natural population. In certain circumstances the damage they inflict on Beta cells may cause destruction of these cells, or precipitate overt diabetes.

The long-term effects of Coxsackie B4 (CB4) infection of mice on pancreatic islet function were investigated. Mice were inoculated with various strains of CB4 virus and 2, 3 and 6 months later islet insulin synthesis and release from isolated islets were measured. Insulin release at basal glucose concentration (2 mmol l-1) was higher in islets from mice inoculated with pancreas-adapted CB4 strains than in control islets or those from mice inoculated with tissue culture-adapted CB4. Thus, two strains of pancreas-adapted virus (P11 and P12) increased basal insulin release by 72% compared with control islets (p less than 0.05) 1 month after inoculation. Another strain (P13) increased insulin release by 421% at 3 months post-inoculation (p less than 0.01) and by 192% at 6 months (p less than 0.05) compared with control islets. The rate of total protein synthesis in islets from P11-inoculated mice 1 month later was 61% lower than in control islets at basal glucose levels (p less than 0.001), and was 25% lower at 20 mmol l-1 glucose (p less than 0.01). There were no significant changes in protein synthesis in islets from infected mice at 3 or 6 months. The abnormal insulin release occurred with minimal changes in random blood glucose concentrations. Histologically the islets were unchanged and there were no detectable islet cell antibodies. These results show that CB4 infection may lead to a persistent metabolic dysfunction in islets with minimal changes in blood glucose levels.