Viruses and diabetes.
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Diabetes Mellitus, Type 1↗
Biomedical subjects
K W Taylor
Publications and source records attributed to K W Taylor.
The role of viruses in human diabetes.
Viruses have long been considered a major environmental factor in the aetiology of Type I (insulin-dependent) diabetes mellitus and recent work has greatly confirmed and extended this role. In addition to the enteroviruses, there are several other viruses which, from time to time, have been considered potential causal agents for human diabetes. With the exception of rubella, their role is not clear. The relation of enteroviruses with Type I diabetes has only been properly clarified by the use of new technologies, especially those based on polymerase chain reaction methods to identify them in blood. It is now evident from studies in several countries that enterovirus infection accompanies or precedes the onset of diabetes in many children. It is less certain whether this is true for older persons or for other types of diabetes. Enterovirus infection in pregnancy has also been suggested to cause diabetes in children. The infection with enteroviruses seems to be linked to the induction of islet-cell autoantibodies as well as to the expression of interferon-alpha. Both of these events are connected with islet-cell destruction. It has become increasingly important to establish the nature of the infecting virus in the early stages of diabetes. It seems likely that a number of viruses of the coxsackie or echovirus type are involved, although the nature of the nucleotide sequences responsible for diabetogenicity remains elusive.
Diabetes Mellitus, Type 1↗
Enterovirus variants in the serum of children at the onset of Type 1 diabetes mellitus.
AIMS: This study was designed to assess further the possible links between enterovirus infection and Type 1 diabetes mellitus (DM). METHODS: Sera from 110 children in the age range 0-15 years was obtained shortly after the diagnosis of Type 1 DM, in paediatric centres throughout the UK. They were tested for the presence of enteroviral sequences by the polymerase chain reaction (PCR) of the 5' nontranslated region (5' NTR). One hundred and eighty-two controls tested were matched for age, geographical location and time of year. RESULTS: A significantly greater number of diabetic children (27% vs. 4.9%, P <0.005) had evidence of enteroviral RNA sequences. Proportionally, more younger children were enterovirus PCR positive, thus eight out of 20 children aged < or =2 years were enterovirus PCR positive. Sequence analysis showed that there was considerable variation in the sequences detected, although all appeared to be of the coxsackie/echovirus type. CONCLUSION: This study re-emphasizes that a link exists between enteroviral infection and the onset of Type 1 DM, particularly at a very early age, and suggests that these viruses are aetiologically important in diabetes in a significant proportion of children.
Adolescent↗
Simultaneous onset of type 1 diabetes mellitus in identical infant twins with enterovirus infection.
This report describes classical Type 1 insulin deficient diabetes mellitus (DM) arising in twins aged 14 months, both of whom had evidence of enterovirus infection. The diagnosis of Type 1 DM was made in the second twin within 12 days of the first. Enterovirus infection was detected in each twin at diagnosis by polymerase chain reaction (PCR). Both twins were negative for enterovirus by PCR 5 months following diagnosis, although both were then positive for islet cell antibodies. Sequencing of the amplicons produced by PCR suggested that the viruses from each twin were not the same but that they were both variants related to echovirus 6.
Age of Onset↗
Conference report: CIBA Foundation meeting on enteroviruses and early childhood diabetes.
A symposium held at the CIBA Foundation in April 1996 discussed recent research on the relationship between enteroviruses and the onset of insulin-dependent (Type 1) diabetes mellitus. New data were presented and discussed concerning the frequency of viral infection in the probands and mothers of children with diabetes and the immune responses associated with candidate viruses. Further evidence was presented but yet more is needed to look at the role of viruses in the pathogenesis of IDDM and the mechanisms by which it might occur.
Child, Preschool↗
Coxsackie B virus infection and onset of childhood diabetes.
Infection with Coxsackie B viruses has been linked to insulin-dependent diabetes mellitus. Nine of 14 serum samples (64%) taken from children at the onset of diabetes were positive for enterovirus RNA by PCR. All of the children were under age six, and five were under age three. By contrast, enterovirus sequences were detected in only two of 45 serum samples from appropriate comparison children (4%). Sequences from six of the positive patients showed strong homology with Coxsackie B3 and B4 viruses, and there were some common patterns among the sequences from infected diabetic children. This is evidence for a role for enteroviruses in childhood diabetes.
Base Sequence↗
The effects of islet cell surface antibodies on the metabolic function of mouse islet B cells in vitro.
Immunoglobulin (Ig) fractions from the plasma of a group of newly diagnosed insulin-dependent diabetes mellitus (type 1) patients and set of control subjects were assessed for their effects on isolated mouse islet function. It was found that Igs from type 1 patients caused a significant inhibitory effect on insulin secretion when incubated with mouse islets as compared with controls (25.6 +/- 2.9 pg islet-1 h-1 vs 44.7 +/- 7.7 pg islet-1 h-1, P < 0.05). The plasma samples from which the Igs were obtained were then tested for the presence of antibodies to the mouse islet cell surface (ICSA). Four of the nine patients were positive for ICSA, and plasma samples from eight control subjects were all negative. ICSA-positive samples appeared to have the greatest inhibitory effect on insulin secretion when compared with their respective controls (53.3 +/- 7.0 pg insulin islet -1 min-1 vs 30.9 +/- 3.7 pg insulin islet -1 min-1, (P < 0.05). In contrast, it was also found that ICSA-positive Ig fractions had no significant effect on glucose oxidation when co-incubated with mouse islets as compared with the controls (11.3 +/- 2.3 pmol islet-1 h-1 vs 11.2 +/- 2.9 pmol islet-1 h-1). These studies suggest that Igs from newly diagnosed type 1 patients containing ICSA may impair insulin secretion from isolated mouse islets by mechanisms which do not involve the inhibition of B-cell glucose metabolism.
Adolescent↗
The spectrum and angular distribution of x rays scattered from a water phantom.
To calculate the response of an image receptor to the x rays emerging from a scattering medium, it is necessary to know the x-ray spectrum and intensity as a function of the angle of incidence on the receptor. To permit this calculation for any x-ray spectrum incident on a medium, these functions must be known for monoenergetic x rays. For monoenergetic x rays in the range 20-70 keV we have measured with a high-purity germanium detector the spectrum and intensity of x rays emitted from a water phantom at angles of 0 degree-50 degrees to the direction of the primary beam. The spectrum and intensity of emitted x rays have also been calculated by the Monte Carlo method. At small exit angles, most of the x rays have energies close to the incident energy. As the exit angle increases, the fraction of multiply scattered x rays increases. At very large exit angles, the dominant feature of the spectrum is the peak due to these multiply scattered x rays. For small scattering angles the Monte Carlo calculations are in good agreement with the measurements over the range of energies. For large scattering angeles the scattered photon fluence predicted by Monte Carlo modeling is consistently lower than the measurement in the region just below the full energy peak. The cause of the discrepancies is not fully understood, but cannot be accounted for by Compton broadening alone. An alternate approach to model incoherent scattering is proposed.
Humans↗
Complete nucleotide sequence of a beta-cell tropic variant of coxsackievirus B4.
A mouse pancreas-adapted variant of coxsackievirus B4 (P-CB4) has been shown to replicate in, and cause an excessive release of insulin from, pancreatic beta cells cultured in vitro. The prototype CB4 strain (JVB Benschoten), from which the adapted variant was derived, although able to replicate in cultured islets does not cause a similar release of insulin from the beta cells. The pancreas-adapted virus has also been shown to cause host cell protein synthesis shut-off in beta cells and to inhibit (pro)insulin biosynthesis. These metabolic changes occur in the absence of cytolytic damage [Szopa et al.: Bioscience Reports 5:63-69, 1985 and Cell Biochemistry and Function 4:181-187, 1986]. To investigate the genetic basis for this beta cell tropism, the complete nucleotide sequence of P-CB4 has been determined and compared to that of the previously published sequence of the prototype CB4 strain (JVB Benschoten) [Jenkins et al.: Journal of General Virology 68:1835-1848, 1987]. Twenty-five nucleotide sequence differences were observed. Of these, six occur in the 5' noncoding region of the genome and 19 in the coding region (resulting in seven amino acid changes). The possible significance of these changes in relation to the beta cell tropism of the pancreas-adapted virus is discussed.
Base Sequence↗
Diabetes mellitus due to viruses--some recent developments.
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)
Animals↗
Aqueous acidic degradation of the carbacephalosporin loracarbef.
The aqueous degradation of the carbacephalosporin loracarbef under moderately acidic conditions (pH range, 2.7-4.3) is described. Structures of a total of 10 compounds isolated by preparative reversed-phase HPLC have been proposed. Five of these 10 degradation compounds arose from hydrolysis of the beta-lactam ring followed by structural changes in the six-membered heterocyclic ring. Four compounds form from intermolecular reactions of loracarbef to form dimeric structures with peptide linkages. The remaining compound resulted from oxidation of the primary amine to a hydroxylamine. Pathways for the formation of these compounds from the parent loracarbef are proposed.
Cefaclor↗
Disturbance of mouse pancreatic beta-cell function following echo 4 virus infection.
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Animals↗
Differential effect of Coxsackie B4 virus on murine pancreatic islet preproinsulin mRNA and glyceraldehyde-3-phosphate dehydrogenase mRNA.
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Animals↗
Effects of a diabetogenic strain of encephalomyocarditis (EMC) virus on protein synthesis in mouse islets of Langerhans.
The effects of a diabetogenic strain of encephalomyocarditis (EMC) virus on total protein and insulin biosynthesis in mouse islets of Langerhans have been studied in tissue culture. In dispersed mouse islets, the rates of protein biosynthesis were assessed by measuring the incorporation of [3H]leucine into proteins. In infected dispersed islets incubated in 20 mM-glucose, both insulin and total protein biosynthesis were decreased at 6 h; only insulin biosynthesis was significantly decreased at 3 h. In whole islets, EMC virus brought about a decrease in glucose-stimulated protein and insulin biosynthesis as early as 2 h after infection without concomitant effects on insulin release. This inhibition of protein biosynthesis was still apparent at 20 h post-infection, at which time insulin release was found to be markedly elevated, and the islet insulin content was moderately decreased. At 44 h post-infection, glucose-induced insulin biosynthesis was preferentially inhibited. Infected islets at this later time point also displayed elevated levels of insulin release, and a marked loss of islet insulin content. When insulin mRNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels were assessed by dot-blot hybridization using appropriate cDNA probes, levels of insulin mRNA were shown to decrease steadily during the first 20 h of infection, in contrast with the levels of GAPDH mRNA. At 44 h post-infection, both types of mRNA were markedly decreased. It is suggested that there is an initial early 'shut-off' of protein synthesis without other detectable changes in islet function. This is followed by a phase where both insulin mRNA levels and insulin synthesis are dramatically decreased.
Animals↗
Coxsackie B4 viruses with the potential to damage beta cells of the islets are present in clinical isolates.
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.
Animals↗
Selective reduction of insulin mRNA in islets infected with encephalomyocarditis virus.
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Animals↗
Coxsackie B4 virus-induced changes in mouse pancreatic beta-cell mRNAs.
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Animals↗
Technique-dependent decrease in thyroid absorbed dose for dental radiography.
A LiF thermoluminescent dosimetry (TLD) system, calibrated in the tissue of interest with the beam used for experimentation, was employed to investigate dosages (muGy) to the thyroid region of an anthropomorphic phantom resultant from two dental complete-mouth radiographic procedures. Both techniques were compared in terms of dosages associated with combinations of lead apron and thyroid collar shielding while using a 70-kVp or 90-kVp x-ray beam for a 20-film complete-mouth series. Lead shielding significantly decreased the dose to the thyroid using both techniques (p less than 0.05). The use of the 90-kVp beam resulted in a significant reduction in the thyroid absorbed dose when using the bisecting angle technique (p less than 0.05) but caused a significant increase in the thyroid absorbed dose when the paralleling technique was used (p less than 0.05). The implementation of higher kilovoltage techniques in dental offices must therefore be dependent on the radiographic technique employed.
Humans↗