Druie E. Cavender

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.

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.

The Pittsburgh Insulin-Dependent Diabetes Mellitus (IDDM) study. HLA antigens and haplotypes as risk factors for the development of IDDM in IDDM patients and their siblings.

The relationships between HLA antigens, sex, age at diagnosis, season of onset and insulin-dependent diabetes mellitus (IDDM) were studied in a consecutive admissions series of newly-diagnosed IDDM patients at Childrens Hospital of Pittsburgh. In agreement with the findings of others, the strongest positive associations between IDDM and HLA antigens were seen with DR3 and DR4 (odds ratios (OR) of 3.5 and 4.4, respectively), while a very strong negative association was observed with DR2 (OR of 0.1). Male patients were significantly more likely than female patients to possess DR3 while female patients were significantly more likely to be DR4+. No consistent relationships were found between HLA antigens and either age at diagnosis or season of onset. Using a life table approach, the cumulative risk of IDDM by age 24 in HLA-identical siblings of IDDM patients was estimated to be 10.3%. This risk was significantly greater than the risks to either HLA-haploidentical siblings (2.2%) or to HLA-nonidentical siblings (1.0%), whose risks were not significantly different. B7 + HLA-identical siblings of patients appeared to be protected from the effects of HLA-identicality--their cumulative risk by age 24 was estimated to be only 2.3%.

Effects of Inflammatory Cytokines and Phorbol Esters on the Adhesion of U937 Cells, a Human Monocyte‐Like Cell Line, to Endothelial Cell Monolayers and Extracellular Matrix Proteins

The accumulation of mononuclear phagocytes at sites of chronic inflammation is dependent on an increase in the rate of extravasation of blood‐borne monocytes through the vascular endothelium into the connective tissue. Once the monocytes have emigrated into the connective tissue, they may differentiate into tissue macrophages, presumably following interactions with extracellular matrix proteins. To study these processes, we tested the effects of cytokines and phorbol esters on the adhesion of U937 cells, a human monocyte‐like cell line, to cultured endothelial cells (EC) and to matrix proteins. In the absence of cytokines, very few of the U937 cells adhered to EC (5% or less in most experiments). When EC were pretreated for optimal periods of time (4–8 hr) with recombinant interleukin‐1α (IL‐1α), IL‐1β, tumor necrosis factor‐α (TNFα), or lymphotoxin (LT; also known as TNF‐β), 35–85% of the U937 cells were able to bind. Interferon‐γ (IFN‐γ) and interleukin–2 (IL‐2) did not stimulate U937‐EC binding, even though IFN‐γ was shown to increase EC adhesiveness for T lymphocytes. Phorbol esters also greatly stimulated U937‐EC adhesion but, in this case, the increase was due to an action on the U937 cells. A monoclonal antibody (MAb), 60.3, against the CD11/CD18 family of leukocyte adhesion molecules partially inhibited the adhesion of untreated and phorbol ester‐treated U937 cells to noncytokine‐treated EC. However, that MAb had no effect on U937 cell binding to TNF‐α‐treated EC. Thus U937 cells use both CD11/CD18‐dependent and ‐independent mechanisms to adhere to EC. In the absence of stimulating agents, only a small proportion of the U937 cells (2–20%) adhered to fibronectin (FN), and almost none bound to either laminin (LN) or gelatin (denatured type I collagen). In the presence of phorbol esters, a much larger proportion of the U937 cells adhered to FN, with only slight increases in the proportion of cells which bound to LN or gelatin. Additional adhesion assays performed in the presence of a pentapeptide containing the amino acid sequence arg‐gly‐asp (RGD), which is part of one of the cell‐binding domains of FN, demonstrated that the RGD‐containing peptide almost totally blocked the phorbol ester‐induced adhesion of U937 cells to FN. In contrast, the peptide had no inhibitory effect on the phorbol ester‐induced binding of U937 cells to EC.

Familial and sporadic insulin-dependent diabetes: evidence for heterogeneous etiologies?☆☆☆

Heterogeneity within insulin-dependent diabetes mellitus (IDDM) has been hypothesized, but few studies have focused on differences which may exist between familial and sporadic IDDM cases. Presenting characteristics for 330 white, newly diagnosed IDDM cases were evaluated. Familial cases were older (10.2 +/- 5.1 years vs 7.9 +/- 4.2 years, P = 0.010) and had, on average, less severe metabolic disturbances at presentation, as demonstrated by lower mean hemoglobin A1 (12.6 +/- 2.4% vs 14.4 +/- 2.6%, P = 0.001) and mean insulin dose at discharge (0.62 +/- 0.35 U/kg/day vs 0.85 +/- 0.29 U/kg/day, P less than 0.001), and higher mean plasma bicarbonate concentrations (19.3 +/- 3.9 mmol/l vs 15.8 +/- 5.9 mmol/l, P = 0.023) and mean plasma C-peptide levels (0.35 +/- 0.36 pmol/ml vs 0.14 +/- 0.15 pmol/ml, P less than 0.001). Further analyses on a subset of IDDM cases (n = 100) indicated that initial differences in metabolic indices observed at diagnosis were no longer apparent at one-year post-diagnosis. These results suggest that the etiology of familial and sporadic IDDM is similar and that the less severe presentation observed at diagnosis in the familial cases may be due to earlier identification of the disease, reflecting increased parental knowledge of diabetic symptoms and/or frequent testing for diabetes.

Interactions between Endothelial Cells and the Cells of the Immune System

Publisher Summary This chapter reviews the interactions between endothelial cells and the cells of the immune system. Lymphocytes are motile cells, migrating from blood into lymphoid organs or sites of inflammation and then back to blood via the lymphatics. This process, known as lymphocyte recirculation, is of critical importance in the functioning of the immune system as it facilitates interactions between antigen-specific clones of lymphocytes and antigen-presenting cells (APCs) in secondary lymphoid organs or sites o f inflammation. Thus, for the immune system to function properly, lymphocytes should adhere to, and then migrate through, the endothelial cells (ECs) of the vasculature. Based on in vitro studies, it has been suggested that vascular ECs can be capable of acting as APCs during the adhesion event. In addition to this direct interaction, it is also clear that the cells of the immune system, both lymphocytes and monocytes/macrophages, interact with ECs in an indirect way, by means of soluble factors known as cytokines.

The pittsburgh diabetes mellitus study

SummaryA series of patients having onset of Type I (insulin-dependent) diabetes mellitus before age 17 years was identified from consecutive admissions to the Childrens Hospital of Pittsburgh. Family history data were obtained yielding 1006 families (1085 cases) with complete information. The prevalence of diabetes among the children differed by birth order, with a greater number than expected among first born. There was also an increased prevalence among children born to mothers older than 35 years, as well as an increased prevalence among children of very young mothers. The increased prevalence of diabetes among offspring of older mothers was apparent even after life table age corrections were made. However, both the increased prevalence among first born children and the increased prevalence among children of very young mothers could be attributed to an older attained age of these children in this particular population. This indicated that the maternal age effect was present but a birth order effect was absent when age was taken into account.

Glucose tolerance in siblings of Type 1 diabetic patients relationship to HLA status

SummaryIn this report, we present an analysis of glucose and insulin responses during oral glucose tolerance tests in 369 siblings of Type 1 diabetic patients. All have been HLA typed at the A, B and C loci. Though most had normal glucose tolerance by National Diabetes Data Group criteria (92% of the males and 95% of the females), siblings who shared both HLA haplotypes with the diabetic patient in the family had higher mean 3-hour glucose areas than those who shared one or neither HLA haplotype (p < 0.01). This difference was more marked in males and older siblings. Insulin concentrations did not differ significantly between the two groups except that, for those aged <16 years, the group sharing both haplotypes had lower fasting insulin concentrations (p = 0.05); for 16–29 year olds, the corresponding group had marginally higher 3-hour insulin areas than the remainder of siblings (p = 0.17). Little association with specific haplotypes (A1B8 or A2B15) was seen. Multivariate analyses, adjusting for age and obesity, eliminated the 3-h glucose difference in females by HLA sharing status (p = 0.37) although in males it remained significant (p < 0.001). Failure to account for age, sex and obesity may explain some of the conflicts in the reported literature. The glucose tolerance differences seen by HLA haplotype sharing status did not correlate with the presence of anti-islet cell antibodies. These results are consistent with the hypothesis that the HLA identical siblings, particularly males, have different (i. e. worse) glucose tolerance than their haplo-identical and non-HLA identical siblings.