Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States.

AIMS: To determine the risk, hazard rate and factors affecting progression to diabetes in monozygotic twins of patients with Type I (insulin-dependent) diabetes mellitus. METHODS: Prospective analysis was done of two cohorts of non-diabetic monozygotic twins of patients with Type I diabetes from Great Britain (n = 134) and the United States (n = 53). RESULTS: The diabetes-free survival analysis was similar between both cohorts (p = 0.6). The combined survival analysis (n = 187, median follow-up = 17.7 years, range = 0.01-57) at 40 years of discordance estimated a 39% probability of diabetes for the initially discordant twin. Survival analysis with left truncation of data estimated that probability to be 50%. For twins who became concordant (n = 47), the median discordance time was 4.2 years (range 0.4 to 39), exceeding 15 years in 23.4%. Twins of probands diagnosed at 24 years of age or younger had a 38% probability of diabetes by 30 years of discordance, compared with 6% for twins of probands diagnosed after 24 years of age (p = 0.004). The twins of probands diagnosed before 15 years of age had the highest diabetes hazard rate in the first discordance year, decreasing thereafter. By survival analysis, diabetes risk was higher in twins who were heterozygous for DR3-DQ2 and DR4-DQ8 than in twins with neither DR3-DQ2 nor DR4-DQ8 (p < 0.05). CONCLUSION/INTERPRETATION: Monozygotic twins of patients with Type I diabetes from two different countries had similar rates of progression to diabetes. Whereas most twins did not develop diabetes, 25% of the twins who progressed did so after more than 14 years of discordance. An age-related heterogeneity was observed, with higher progression to diabetes for twins of patients diagnosed at a younger age.

Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis.

To determine the concordance rate for Type II (non-insulin-dependent) diabetes mellitus in monozygotic twin pairs, initially ascertained discordant for diabetes, we carried out a prospective study on 44 non-diabetic subjects, each of whom had a sibling twin with diabetes (21 men, 23 women, median age 55 years, interquartile range 47-65). The subjects were referred as discordant for Type II diabetes. The twin pairs were part of the British Diabetic Twin Study and ascertained between May 1968 and January 1998. These subjects underwent an OGTT at time of referral and periodically thereafter. The mean follow-up was 8 years (range 0-18 years) and data were collected until January 1996. The percentage of twins who developed Type II diabetes was assessed by standard actuarial life-table methods and the pairwise concordance rate, that is the proportion of concordant pairs over the sum of concordant and discordant pairs, was calculated. The observed rates of concordance for Type II diabetes at 1, 5, 10, and 15 years follow-up were 17, 33, 57, and 76%, respectively. The concordance rate for any abnormality of glucose metabolism (either Type II diabetes or impaired glucose tolerance) at 15 years follow-up was 96%. The concordance rate for Type II diabetes in monozygotic twins is very high even in twins initially ascertained discordant for diabetes.

Importance of persistent cellular and humoral immune changes before diabetes develops: prospective study of identical twins.

OBJECTIVES: To determine the pattern of cellular and humoral immune changes associated with insulin dependent diabetes before diabetes develops. DESIGN: Prospective study over 10 years of 25 non-diabetic identical twins of patients with insulin dependent diabetes. The non-diabetic twins were followed up either till they developed diabetes or to the end of the study. SETTING: Teaching hospital. SUBJECTS: 25 non-diabetic identical cotwins of patients with diabetes; 46 controls of the same sex and similar age tested over the same period. Of the 25 twins (total follow up 144 patient years), 10 developed diabetes (prediabetic twins); the remainder were followed up for a mean of 7.7 years. MAIN OUTCOME MEASURES: Results of glucose tolerance tests or fasting blood glucose concentrations at each sample point. Measurements of activated T lymphocytes, expressing the HLA-DR antigen, islet cell antibodies, and insulin autoantibodies in samples. RESULTS: All 10 prediabetic twins had both cellular and humoral changes initially and in most samples before diabetes was diagnosed (activated T lymphocytes in 39/40, islet cell antibodies in 45/47, and insulin autoantibodies to islet cells and insulin were detected infrequently (in 8/54, 6/69, and 0/69 samples, respectively). The combination of cellular and humoral (islet cell antibodies or insulin autoantibodies) immune changes were detected in all 10 of the prediabetic twins but in only one of the 15 non-diabetic twins (P < 0.001). The positive predictive value in this cohort of increased percentages of activated T cells and the presence of antibodies to islet cells or insulin on two consecutive occasions was 100%. CONCLUSION: Most of the twins had cellular or humoral immune changes at some stage. A combination of cellular and humoral immune changes and their tendency to persist is highly predictive of insulin dependent diabetes and distinguishes twins who develop diabetes from those who do not.

Altered islet beta-cell function before the onset of type 1 (insulin-dependent) diabetes mellitus.

To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 non-diabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followed-up prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2 +/- 2.0 vs 1.8 +/- 1.8 nmol/l; p less than 0.05); but lower glucose clearance (1.0 +/- 0.5 vs 1.9 +/- 0.7 %/min; p less than 0.05), first phase insulin response at 0.5 g/kg (21.1 +/- 23.2 vs 143 +/- 50 nmol/l; p less than 0.0001), and total insulin responses at 0.1 g/kg (p less than 0.05) and 0.5 g/kg (p less than 0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R2) than control subjects (p less than 0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R2 and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R2 and subnormal first phase insulin response were 67% and 58% respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.

Decreased growth velocity before IDDM onset.

Diabetes can retard growth. Growth was studied prospectively in 12 nondiabetic identical twins aged less than 14 yr and in their co-twins with insulin-dependent diabetes mellitus (IDDM) to determine whether changes in growth occur before the onset of IDDM. Seven of the 12 nondiabetic twins subsequently developed IDDM; the remainder are now unlikely to become diabetic. A significantly reduced growth velocity was observed more frequently in the nondiabetic twins (7 of 12) than in their diabetic co-twins (1 of 12; P = 0.03). Of the 7 nondiabetic twins who were prediabetic, 6 had a reduction in growth velocity to below the 3rd percentile before the onset of diabetes compared with 1 of their diabetic co-twins (P = 0.03). However, only 1 of the 5 nondiabetic twins who did not develop diabetes showed a reduction in growth velocity. The nadir of growth in the twins who developed diabetes occurred a mean of 1.2 yr before diagnosis (range 0.3-2.3 yr). All 7 of the prediabetic twins had islet cell antibodies when first seen, and 3 had them before they showed either decreased growth velocity or impaired glucose tolerance. In 4 prediabetic twins, the decreased growth preceded impaired glucose tolerance. The prediabetic twins tested had lower testosterone or estradiol levels at the time they showed decreased growth than their diabetic twins. We conclude that decreased growth velocity is an early sensitive marker of IDDM.

A critique of pancreas transplantation.

There are three possible indications for pancreas transplantation 1. to correct the diabetic state; 2. to cure or ameliorate the complications of diabetes or to delay or diminish their deterioration; 3. to prevent the complications. The diabetes we are considering here is type 1 or insulin-dependent diabetes, a disorder in which there is more or less complete insulin deficiency. No one has suggested pancreas transplantation for type 2, non-insulin dependent diabetes. This article questions the rationale of pancreas transplantation. It maintains that the value of the procedure has not been established.

Transfer from animal insulins to semisynthetic human insulin: a study in four centres.

The effects of transfer from animal insulin to semisynthetic human insulin on glycaemic control, insulin dose and anti-insulin antibodies were investigated in a total of 108 patients at four centres in a double-blind controlled study of eight months duration. Six months after transfer from porcine to human insulin there was a mean (+/- SE) increase in pre-breakfast blood glucose of 1.1 +/- 0.6 mmol l-1 (vs a reduction of 1.6 +/- 0.7 mmol l-1 in controls) (p less than 0.01), and a mean increase of pre-lunch blood glucose of 0.9 +/- 0.7 mmol l-1 (vs a reduction of 1.14 +/- 0.7 mmol l-1 in controls) (p less than 0.05). Six months after transfer from bovine to human insulin, there were no significant changes in blood glucose. Glycated haemoglobin showed no significant change six months after transfer from either bovine or porcine to human insulin. Hypoglycaemic symptoms, the total daily insulin dose, and the ratio of short- to intermediate-acting insulin did not change significantly after transfer from either bovine or porcine to human insulin. Transfer from bovine to human insulin resulted in a significant decline in anti-human insulin antibodies (mean (range): 50.5(14.8-125)% of initial levels), vs controls (113(43.4-234)% of initial levels; p = 0.034), and a non-significant decline in anti-bovine insulin antibodies (52.2(25.8-111)% vs 81.7(42.5-128)%; p = 0.082).

Impaired glucose tolerance precedes but does not predict insulin-dependent diabetes mellitus: a study of identical twins.

Non-diabetic identical twins of insulin-dependent diabetic patients were studied within five years of the diagnosis of their index twin in order to determine whether changes in intermediary metabolism precede the onset of insulin-dependent diabetes mellitus. Two studies were performed: a cross-sectional study of 12 non-diabetic twins and a prospective study of a separate group of 41 non-diabetic twins. Of the 12 twins tested in the cross-sectional study six developed insulin-dependent diabetes and six did not; the six who developed diabetes were given an oral glucose load a mean of 10 months before diagnosis; they then had normal fasting blood glucose levels but worse glucose tolerance than control subjects (120 min post-load (mean +/- SD) blood glucose 8.5 +/- 3.5 vs 4.9 +/- 0.9 mmol/l respectively, p less than 0.05). However, blood lactate, pyruvate, alanine, glycerol, 3-hydroxybutyrate and serum insulin levels were similar. In contrast, the six twins in this cross-sectional study who did not develop diabetes and are now unlikely to do so, as a group, had no significant changes compared with the control subjects though one had impaired glucose tolerance. To determine the predictive value of impaired glucose tolerance a separate group of 41 non-diabetic twins was studied prospectively for 8 to 22 years having a total of 147 glucose tolerance tests in this period; in this group six developed diabetes. Eight of the 41 had impaired glucose tolerance; impaired glucose tolerance was found in four of the six who developed diabetes as compared with only four of the 35 who did not (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Are thyrogastric autoantibodies associated with an increased susceptibility to developing type 1 (insulin-dependent) diabetes? A study in identical twins.

To examine whether the presence of thyrogastric autoantibodies is associated with an increased susceptibility towards developing type 1 diabetes we have tested for thyroid (microsomal and thyroglobulin) and gastric-parietal cell antibodies in 86 pairs of identical twins, 47 discordant and 39 concordant for type 1 diabetes. Autoantibodies were detected in both twins of a pair in 35 and in neither twin in 45 pairs. In only 6 pairs (3 discordant) was there a discrepancy in the antibody results between co-twins. The frequency of antibodies was similar in twin pairs discordant, (21/44, 48%), and concordant, (14/36, 39%), for diabetes. Thyrogastric antibodies were not more frequent in pairs that were female, diagnosed above the age of 20, or had HLA DR3 as opposed to DR4. We conclude that thyrogastric autoantibodies are common in both type 1 diabetic patients and their non-diabetic identical twins. Their presence appears to be genetically determined but does not increase the susceptibility of developing diabetes. The presence of autoantibodies does not appear to indicate a separate aetiological type of diabetes.

B-cell responses to intravenous glucose and glucagon in non-diabetic twins of patients with type 1 (insulin-dependent) diabetes mellitus.

The B-cells of patients with recently diagnosed Type 1 (insulin-dependent) diabetes may have no response to glucose when the response to glucagon is present but attenuated. This observation suggests that the recognition of glucose is more severely affected than that for non-glucose stimulants. To determine whether a similar selective decrease in glucose response was present before the onset of diabetes we studied two groups of non-diabetic identical twins of patients with recently diagnosed Type 1 diabetes: one group with complement-fixing islet cell antibodies who were at high risk of developing diabetes (four of the five have already developed diabetes) and a group without such antibodies at low risk of developing diabetes. In addition, a group of patients with chronic pancreatitis were studied to control for non-specific damage to the B-cell. Responses to i.v. glucose and i.v. glucagon were compared. Patients with chronic pancreatitis has similar responses to both glucose and glucagon and the responses did not differ from control subjects. The B-cells of the immune positive group showed evidence of pathology because the insulin and C-peptide responses to both stimuli were reduced when compared to either their control subjects or the immune negative twin group. However, the B-cell response to both glucose and glucagon in the immune positive twins was similar. Because the B-cell response to glucose was not less than that to glucagon, a selective destruction of the glucose recognition system cannot be a characteristic of all twins throughout the period before they develop Type 1 diabetes.

Islet-cell antibodies as predictors of the later development of type 1 (insulin-dependent) diabetes. A study in identical twins.

To determine the value of islet-cell antibodies, both complement-fixing and non-complement-fixing, in predicting the later development of Type 1 (insulin-dependent) diabetes, we studied different groups of identical twins. Twelve twins have developed diabetes and 11 of these had non-complement-fixing islet-cell antibodies before diagnosis, and eight out of nine tested had complement-fixing islet-cell antibodies. Of the twins who have remained non-diabetic for many years and are now unlikely to develop diabetes, twelve have had non-complement-fixing islet-cell antibodies at some stage but only four have ever had complement-fixing antibodies. In 29 non-diabetic co-twins tested within 5 years of the diagnosis of diabetes in the affected twin the presence of islet-cell antibodies, especially complement-fixing, predicted the progression to frank diabetes with a high specificity (100%), sensitivity (88%) and predictive value (100%). In pairs remaining discordant the antibodies were found more frequently in the diabetic than the non-diabetic twin. We conclude that the presence of islet-cell antibodies is not genetically determined and can occur without progression to diabetes. However, the presence of islet-cell antibodies, especially complement-fixing, in non-diabetic twins tested soon after the diagnosis of their co-twin, indicates a high risk for the development of diabetes.

Comparison of skewness coefficient, coefficient of variation, and Gini coefficient as inequality measures within populations.

The moment skewness coefficient, coefficient of variation and Gini coefficient are contrasted as statistical measures of inequality among members of plant populations. Constructed examples, real data examples, and distributional considerations are used to illustrate pertinent properties of these statistics to assess inequality. All three statistics possess some undesirable properties but these properties are shown to be often unimportant with real data. If the underlying distribution of the variable follows the often assumed two-parameter lognormal model, it is shown that all three statistics are likely to be highly and positively correlated. In contrast, for distributions which are not two-parameter lognormally distributed, and when the distribution is not concentrated near zero, the coefficient of variation and Gini coefficient, which are sensitive to small shifts in the mean, are often of little practical use in ordering the equality of populations. The coefficent of variation is more sensitive to individuals in the right-hand tail of a distribution than is the Gini coefficient. Therefore, the coefficient of variation may often be recommended over the Gini coefficient if a measure of relative precision is selected to assess inequality. The skewness coeficient is suggested when the distribution is either three-parameter lognormally distributed (or close to such), or when a measure of relative precision is not indicated.

Alterations in T-lymphocyte subpopulations in type I diabetes. Exploration of genetic influence in identical twins.

To evaluate factors influencing the alteration in subsets of T-lymphocytes, we studied 24 pairs of identical twins discordant for insulin-dependent (type I) diabetes mellitus. Subsets were assessed by monoclonal antibodies and a pure preparation of peripheral blood mononuclear cells obtained by centrifugation of heparinized whole blood with a Ficoll/Triosil gradient. In 12 pairs studied within 5 yr of diagnosis, we observed a reduction in the percentage of cells reacting with OKT8 (recognizing the CD8 antigen present on the suppressor/cytotoxic subset) (P less than .05), but a similar level was detected in their nondiabetic cotwins. In 12 pairs studied greater than 5 yr after the diagnosis and in whom the nondiabetic twin is less likely to develop diabetes, the percentage of cells reacting with OKT8 was reduced in both the diabetic (P less than .05) and the nondiabetic (P less than .01) twins. Reductions were also seen with OKT3 (recognizing the CD3 antigen present on the total T-lymphocyte population) and OKT4 (recognizing the CD4 antigen present on the helper/inducer subset), but only in the diabetic twins from the group with longer discordance. We conclude that a reduced percentage of suppressor/cytotoxic cells is associated with type I diabetes, but the reduction appears to be genetically determined. Total T-lymphocytes are also reduced but mainly in the helper/inducer subset and only in diabetic patients of long duration. Such a reduction cannot therefore be primarily genetically determined.