Erythrocyte sodium-lithium countertransport and blood pressure in identical twin pairs discordant for insulin dependent diabetes.

OBJECTIVE: To investigate whether insulin dependent diabetes is responsible for the abnormal behaviour of the carrier in sodium-lithium countertransport and whether the diabetic state is associated with rise in blood pressure. DESIGN: Case-control study. SETTING: London teaching hospital. SUBJECTS: 44 twin pairs discordant for insulin dependent diabetes living in United Kingdom and 44 healthy control subjects matched for age, sex, and body mass index. None of the twin pairs or the controls had evidence of microalbuminuria. MAIN OUTCOME MEASURES: Sodium-lithium countertransport activity in erythrocytes and arterial blood pressure. RESULTS: The mean (95% confidence interval) sodium-lithium countertransport activity (mmol Li per litre of red blood cells per h) of the diabetic twins (0.291 (0.244 to 0.338)) was similar to that of their non-diabetic cotwins (0.247 (0.204 to 0.290)); both values were significantly higher than that of the controls (0.187 (0.157 to 0.216); p < 0.05). In addition, systolic blood pressure was higher in those twins with diabetes (127 (122 to 133) mm Hg) than in the non-diabetic cotwins (122 (117 to 127) mm Hg; p < 0.01). There were no significant differences in mean diastolic blood pressure between any of the groups studied. CONCLUSIONS: The raised erythrocyte sodium-lithium countertransport activity in the diabetic twins compared with the controls seems to be inherited rather than a consequence of overt diabetes. The higher systolic blood pressure in diabetic twins than non-diabetic cotwins indicates that insulin dependent diabetes does exert a small influence on systolic blood pressure.

Effect of insulin-dependent diabetes mellitus on lipids and lipoproteins: a study of identical twins.

1. Forty-five identical twin pairs, discordant for insulin-dependent diabetes mellitus, were studied with respect to their serum lipid (high-density lipoprotein, low-density lipoprotein, total cholesterol and triacyl-glycerol) and apoprotein [apoprotein A-I, apoprotein B and lipoprotein (a)] concentrations and apoprotein (a) phenotypes. The twins were compared with an age- and sex-matched non-diabetic control group. 2. A significantly higher value was found only for high-density lipoprotein cholesterol in the diabetic twins of the female twin pairs. 3. Highly significant correlations existed between the twin pairs for all lipids and lipoproteins measured, particularly lipoprotein (a), for which identical apoprotein (a) isoforms were also found. 4. Correlations existed between the non-diabetic twins and the control subjects for high-density lipoprotein cholesterol and apoprotein A-I, probably due to the rigorous matching of control subjects. 5. The similarity between values for lipids and lipoproteins in the non-diabetic twins and control subjects suggested no effect of a genetic susceptibility to insulin-dependent diabetes mellitus. The differences in lipoproteins we describe for the identical twins discordant for insulin-dependent diabetes mellitus, in whom there was no evidence of a raised urinary albumin excretion rate, does not appear to explain the excess mortality from cardiovascular disease reported in patients with this disease.

Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, non-obese diabetic mice and HLA-DQ transgenic mice.

Glutamic acid decarboxylase (GAD65) has been implicated as a targeted self antigen in the immune destruction of pancreatic beta cells. T cell responses to GAD65 peptides have been detected in both patients with type I diabetes and in the non-obese diabetic (NOD) mouse. To establish which GAD65 epitopes are important in the immunopathogenesis of disease we initially compared T cell responses to GAD65 epitopes in conditions of disease susceptibility and protection. T cell responses to GAD65 peptides were measured in monozygotic twin pairs selected on the basis of disease discordance and T cell recognition of immunogenic regions of GAD65. Peptides of interest were then used to immunize susceptible NOD mice and H2-E transgenic NOD mice which are protected from diabetes. A differential response to the epitope GAD65 521-535 discriminated diabetic from non-diabetic human twins as well as susceptible from protected mice. This epitope as well as GAD 505-519 induces T cell responses despite binding the type I diabetes associated HLA-DQA1*0301/DQB1*0302 product with low affinity. Since DQ-restricted T cell responses are difficult to study in humans, HLA-DQ8 transgenic mice were then used: GAD epitopes 521-535 and 505-519 induced responses in DQ8 transgenic mice and T cell lines were established. Long-term T cell lines against GAD 505-519 were HLA-DQ restricted, and responded to peptide with a strong IFN-gamma and IL-10 response. The findings implicate GAD 521-535 as a possible target peptide in pathogenesis and are compatible with a model whereby self-reactive T cells specific for low-affinity peptide-MHC complexes may escape thymic negative selection.