D. J. Becker

The Pittsburgh Insulin-dependent Diabetes Mellitus (IDDM) Morbidity and Mortality Study: Mortality Results

A follow-up study of 1966 patients with insulin-dependent diabetes mellitus (IDDM) who were diagnosed at Childrens Hospital of Pittsburgh (CHP) between 1950 and 1981 has been completed. The mean age of the population at follow-up was 21.2 yr with a mean duration of IDDM of 12.9 yr. Nine percent of the patients were deceased, a sevenfold excess in mortality compared with the U.S. population. The relative increase in mortality was greater for females than males and greater for blacks than whites. Before age 20, the primary excess in mortality was at onset of IDDM, or within 6 mo after onset, and was due to acute diabetic complications. After age 20, the annual mortality risk was approximately 2%, which was more than 20 times greater than for the U. S. population. Renal disease was responsible for the majority of these deaths. There was a reduced risk of dying for diabetic patients who were diagnosed between 1966 and 1971 compared with patients diagnosed during earlier years.

Correlates of Insulin Antibodies in Newly Diagnosed Children with Insulin-dependent Diabetes Before Insulin Therapy

Insulin antibodies, as measured by plasma radiolabeled insulin-binding capacity, were determined in 124 newly diagnosed insulin-dependent diabetic (IDDM) children before and after 1, 3, and 5 days of insulin therapy. Controls were 35 nondiabetic children with plasma insulin binding capacity of 1.0 ± 0.7%. The patients were divided into three groups according to their plasma insulin-binding capacity. Group 1 (N = 79) had binding within two standard deviations (SD) of the control mean, group 2 (N = 20) had insulin binding 2–6 SD above controls, and group 3 (N = 25) showed insulin-binding capacity of more than 6 SD above the control mean. After exogenous insulin therapy, plasma 125I-insulin-binding capacity dropped significantly in both groups 2 and 3, concurrent with significant increases in plasma insulin levels. The three groups differed from each other in that patients in group 3 were significantly younger thanin the other groups and clinically seemed to be more severely dehydrated, as reflected in their higher levels of serum urea nitrogen, plasma glucose, potassium, and elevated pulse rate. The three groups did not differ in respect to sex, HLA-DR antigens, Coxsackie-B antibody titers, islet cell cytoplasmic antibodies, immunoglobulin level, and C-peptide levels. Only two of 446 siblings of IDDM children showed elevated insulin binding, one of whom developed IDDM 6 wk later. The presence of an insulin-binding substance probably representing insulin antibodies in some cases of newly diagnosed IDDM suggests that autoimmunity in this disorder is not limited to the B-cell membrane and cytoplasm and lends further support to the heterogeneity Of IDDM.

Insulin-dependent diabetes mellitus mortality. The risk of cigarette smoking.

The relation between cigarette smoking and mortality was examined prospectively in a population of adult insulin-dependent diabetes mellitus (IDDM) patients. In 1981, information on smoking history and other health and lifestyle factors was obtained by questionnaire from 93% of the 723 patients included in the Childrens Hospital of Pittsburgh IDDM registry who were diagnosed between 1950 and 1964. Vital status as of January 1, 1988 was ascertained for 98% of the 548 patients who participated in the baseline survey and were alive as of January 1, 1982. Fifty-four cases died during the 6-year follow-up (32 male, 22 female). Proportional hazards analysis revealed that heavy smoking was a significant independent predictor of all-cause mortality among females but not males. The excess mortality in female diabetics was explained primarily by a marked excess risk of coronary heart disease mortality in smokers. These data strongly suggest that cigarette smoking, especially among diabetic females, should be avoided in order to improve longevity.

HLA Heterogeneity of Insulin-dependent Diabetes Mellitus at Diagnosis: The Pittsburgh IDDM Study

Although some previous studies have suggested that insulin-dependent diabetes mellitus (IDDM) is a heterogeneous condition with variant forms being associated with HLA-DR types, the evidence, thus far, is conflicting. To address this issue, we have examined the presenting characteristics of a consecutive admission series of 200 newly diagnosed cases of IDDM from the Childrens Hospital of Pittsburgh. Because HLA-DR frequencies vary by race, data are presented only for the 172 white cases with complete HLA-DR typing. HLADR3 was found more frequently among male cases and DR4 among female cases (P < 0.005). Generally, patients with DR4 presented with a severer clinical picture, being more likely to have impaired consciousness and significant dehydration. In addition, patients with DR4 were more likely to be acidotic, ketotic, and to more frequently report a recent viral infection. This latter finding was supported by a greater frequency of antibodies to Coxsackie-B viruses in the DR4 cases at presentation. These results therefore suggest that there is considerable heterogeneity in IDDM, at least in presenting characteristics, according to HLA-DR type.

Height at diagnosis of insulin dependent diabetes in patients and their non-diabetic family members.

Height at the onset of insulin dependent diabetes mellitus was evaluated in 200 newly diagnosed children, 187 non-diabetic siblings, and 169 parents. Diabetic children 5-9 years of age at diagnosis were consistently taller than the national average. Non-diabetic siblings of the same age were also tall. Diabetic children aged 14 or over at diagnosis were short, while their siblings and parents were of normal height. Diabetic children positive for islet cell antibodies were taller than those without islet cell antibodies. No association between height and HLA antigens was found. Non-diabetic siblings at high risk for the disease were closer in height to the diabetic children than were the lower risk, non-diabetic siblings. Siblings, particularly those under 10, were also significantly more obese than the general population. Deviations in growth in patients with insulin dependent diabetes mellitus appear to be related to age at diagnosis and a factor(s) not related to parental height.

Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

Aims/hypothesis. High frequencies of T-cell receptor (TCR) Vβ7+ T cells were detected among the lymphocytes isolated from pancreatic islets of children at the onset of Type I (insulin-dependent) diabetes mellitus. We assessed whether a preferential expression of certain TCR Vβ gene families could also be detected among the peripheral blood mononuclear cells from diabetic patients. Methods. T-cell receptor repertoires were evaluated by using a semi-quantitative RT-PCR-based technique and confirmed by FACS analysis in peripheral blood mononuclear cells from diabetic patients before, at and after onset of the disease. These patients were also tested for exposure to enteroviruses by RT-PCR and by measuring titres of enterovirus-specific antibodies of the IgA, IgG, and IgM classes. Results. T-cell receptor Vβ7 gene family values were higher in recently-diagnosed diabetic patients (10.5 % ± 3.7) than in age-matched non-diabetic control subjects (5.1 % ± 1.6) (p < 0.001). In a time-course analysis of people who developed diabetes during clinical monitoring (i. e., converters), T-cell receptor Vβ7 gene expression showed values consistently above 10 % (p < 0.0005). Long-standing diabetic patients showed lower percentage of Vβ7 expression compared to values measured at disease onset. In the longitudinal study of the converters, multiple acute enterovirus infections were also detected. These infections appeared to be temporally related to increased percentage of Vβ7 gene transcripts. Conclusion/interpretation. The deviation in the T-cell receptor Vβ repertoire among circulating T cells from diabetic patients seems to re-emphasize the importance of enterovirus infections in accelerating the progression of Type I diabetes. [Diabetologia (2000) 43: 1484–1497]

Characterizing sudden death and dead-in-bed syndrome in Type 1 diabetes: analysis from two childhood-onset Type 1 diabetes registries

Diabet. Med. 28, 293–300 (2011)

Regional cerebral blood flow during hypoglycaemia in children with IDDM

SummaryHypoglycaemia may cause transient cognitive impairment and neurological deficits that are frequently unilateral. The effect of mild hypoglycaemia (serum glucose level 3.4±0.1 mmol/l; mean±SEM) on regional cerebral blood flow and cerebrovascular resistance was studied in eight right-handed children with insulin-dependent diabetes mellitus (age 14.9±0.7 years; diabetes duration 7.4±1.1 years; six males) using the intravenous xenon-133 clearance method. Global mean cerebral grey and white matter blood flow, adjusted to mean pCO2 of cohort, showed a trend towards an increase from 54.7±3.5 ml·100 g−1·min−1 at baseline euglycaemia to 58.0±4.1 ml·100 g−1·min−1 during hypoglycaemia (p=0.075). Statistically significant changes were seen in global mean cerebral grey matter blood flow, as indexed by initial slope, which increased from 88.0±6.5 min−1 before hypoglycaemia to 96.3±7.2 min−1 during hypoglycaemia (p<0.05). Cerebral grey matter blood flow was significantly higher in the right hemisphere compared to the left during hypoglycaemia (p<0.01) but not at baseline euglycaemia. Measurements of global cerebrovascular resistance showed a borderline decrease from 1.64±0.11 to 1.54±0.11 mm Hg·ml−1·100 g−1·min−1 (p< 0.09). In conclusion, mild hypoglycaemia is associated with increases in cerebral blood flow which are greater in grey matter flow indices and in the right hemisphere. We speculate that asymmetrical cerebral blood flow changes may explain the frequent laterality of neurological deficits during severe hypoglycaemia.

Demonstration of a dawn phenomenon in normal adolescents.

To ascertain whether the dawn phenomenon occurs in normal adolescents and, if so, to determine its mechanism, we measured nocturnal plasma glucose, insulin, glucagon, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH) levels between 01.00 and 08.00 h in 10 healthy adolescents. The prehepatic insulin secretion rate was calculated based on C peptide levels. The metabolic clearance rate of insulin (MCRI) was calculated as the ratio of mean insulin secretion rate to mean insulin concentration. There was no change in plasma glucose, insulin, and glucagon between 01.00-04.00 and 05.00-08.00 h (paired t test). The MCRI was higher at 05.00-08.00 h compared to 01.00-04.00 h (9.30 +/- 1.50 vs. 4.87 +/- 1.11 ml.kg-1.min-1; p = 0.008). The prehepatic insulin secretion increased at 05.00-08.00 h relative to 01.00-04.00 h (1.1 +/- 0.2 vs. 0.6 +/- 0.1 pmol.kg-1.min-1; p = 0.013). Similarly, cortisol and ACTH levels were higher at 05.00-08.00 versus 01.00-04.00 h (323 +/- 33 vs. 102 +/- 22 nmol/l, p less than 0.001; 3.6 +/- 0.5 vs. 1.8 +/- 0.4 pmol/l, p = 0.006, respectively). Growth hormone was higher at 01.00-04.00 versus 05.00-08.00 h (7.6 +/- 1.2 and 3.0 +/- 0.9 microgram/l; p = 0.019). ACTH correlated with MCRI (r = 0.66; p = 0.002) and prehepatic insulin secretion (r = 0.75; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The development of type 1 (insulin-dependent) diabetes mellitus: Two contrasting presentations

SummaryGenetic, immunological and viral factors have been implicated in pathogenesis of Type 1 diabetes mellitus. The development of Type 1 diabetes in two siblings of patients with Type 1 diabetes studied as part of a large epidemiological study, is described. One case, a 13-year-old male not sharing either HLA haplotype with his diabetic sister, had virtually normal glucose tolerance 80 days before symptomatic presentation. He showed serological evidence of infection by Coxsackie CB4 (at diagnosis) and influenza A virus (soon after diagnosis). The other case, a 15-year-old male, had impaired glucose tolerance for over 500 days (i. e., since the diagnosis of diabetes in his HLA-identical brother) before symptomatic presentation which was not associated with serological evidence of acute viral infection. The former case was negative for islet cell antibody (cytoplasmic) when first seen though positive at diagnosis, while the latter was positive throughout. These two cases suggest contrasting interactions of the main pathogenetic factors associated with Type 1 diabetes.