The interaction of 2 diseases: diabetes mellitus and cystic fibrosis.

We have reviewed the hospital records of 24 patients with cystic fibrosis-associated diabetes, and 2 groups of CF patients (1 with normal and the other with abnormal oral glucose tolerance tests) who did not develop symptomatic fasting hyperglycemia, to define the clinical characteristics of the diabetes and to study its effects on the progression of the pulmonary disease, changes in sputum organisms, and mortality. Although maximum blood glucoses ranged from 322 to 1160 mg/dl with a median of 579 mg/dl, only 1 of 24 diabetic patients developed ketoacidosis. This patient developed diabetes 12 years prior to the diagnosis of CF and may have had type 1 diabetes. In contrast, hypoglycemia was frequent and 4 patients were hospitalized with serious neurologic manifestations. Two patients were found to have diabetic retinopathy, 1 with macular edema required laser photocoagulation to improve vision, and the other had multiple microaneurysms. CF-associated diabetes did not influence the deterioration of clinical scores, chest x-ray scores, pulmonary function tests, the number of hospital admissions, the type of organisms found in the sputum, or mortality rates. The development of diabetes in our CF patients was not related to the severity of pulmonary dysfunction, clinical, or chest x-ray scores. Thus, although the development of diabetes is an additional encumbrance upon the already therapeutically burdened existence of a CF patient, it does not appear to affect the course of the disease. Despite the demonstration of diabetic retinopathy in this study, most patients with CF-associated diabetes still do not live long enough to develop microvascular complications from the diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Islets of Langerhans in adolescents and adults with cystic fibrosis. A quantitative study.

The incidence of fasting hyperglycemia and diabetes mellitus (DM) in older patients with cystic fibrosis (CF) is reported to be 8%, but few quantitative studies of the islets of Langerhans in this disease have been done. Three groups of patients were studied in this morphometric autopsy analysis: patients with CF and insulin-dependent DM (n = 7), normoglycemic patients with CF (n = 4), and age-matched adolescents and young-adult controls (n = 11). The islets of Langerhans were stained with immunoperoxidase for insulin, glucagon, and somatostatin. The percentage of the total islet surface area occupied by each immunoperoxidase positive cell type was determined by a point-counting method. The mean percent surface area occupied by insulin-producing cells (28.3%) in diabetics with CF was significantly less than normoglycemics with CF (46.7%) and controls (53.4%). The mean percent surface area occupied by glucagon-producing cells was similar in all three groups: 21.9% in CF diabetics, 25.4% in normoglycemics with CF, and 22.4% in controls. The mean percent surface area occupied by somatostatin was increased in both CF groups compared with controls: diabetics with CF, 29.3%; normoglycemics with CF, 26.2%; and controls, 15.5%. These findings correlate with published clinical endocrine studies of hyperglycemia in CF. Endocrine cell quantitation in diabetics with CF differs from that in both juvenile (type 1) and adult-onset (type 2) DM.

A morphologic and fluorophotometric analysis of the corneal endothelium in type I diabetes mellitus and cystic fibrosis.

Seven patients with type I diabetes mellitus (Group 1), seven with normoglycemic cystic fibrosis (Group 2), seven with hyperglycemic cystic fibrosis (Group 3), and ten age-matched control subjects underwent corneal fluorophotometry and quantitative specular microscopy. Group 1 had background microangiopathic retinopathy but no evidence of proliferative disease by fluorescein angiography. Significant increases in mean corneal endothelial permeability and mean pump rate occurred in Group 1, indicating a defect in the endothelial barrier function early in type I diabetes mellitus. Similar significant increases in mean corneal endothelial permeability and mean pump rate occurred in both cystic fibrosis groups. The greatest increase was found in Group 3, suggesting a primary defect in the endothelial barrier function in cystic fibrosis, aggravated by the hyperglycemic state. No morphologic abnormalities were noted in Group 1, but both cystic fibrosis groups had smaller mean cell areas than did the control group. There were significant differences in the morphologic and functional correlations between Groups 1 and 3, suggesting different mechanisms for the increased endothelial permeability in these two disorders.

Quantitative vitreous fluorophotometry in insulin-treated cystic fibrosis patients.

A series of 22 patients with cystic fibrosis (CF) of similar clinical severity (9 with normal carbohydrate tolerance and 13 with insulin-treated fasting hyperglycemia) was examined with quantitative vitreous fluorophotometry. All of the CF patients studied had normal fundi on ophthalmoscopy, fundus photographs, and fluorescein angiography. Mean vitreous fluorescein concentration in the CF patients whose hyperglycemia was treated with insulin (11.79 ng/ml) was significantly higher than in CF patients with normal carbohydrate tolerance (6.98 ng/ml, P less than 0.005). Thus, CF patients with fasting hyperglycemia demonstrate a breakdown of the blood-retinal barrier. When CF patients with fasting hyperglycemia were compared with age- and sex-matched type I diabetics, there was no significant difference in mean vitreous fluorescein accumulation. Thus, breakdown of the blood-retinal barrier, one of the earliest detectable functional abnormalities that may be associated with the microangiopathy of diabetes mellitus, also occurs with equal frequency and severity in the diabetes secondary to pancreatic fibrosis associated with CF.

Measurement of glycosylated hemoglobins in black diabetic patients: a note of caution.

Inspection of chromatography columns used for measurement of glycosylated hemoglobins revealed that blood samples from certain black diabetic patients produced two residual hemoglobin bands after chromatography rather than one. The levels of glycosylated hemoglobin were significantly lower in these subjects than in other diabetics. Further investigation revealed that each of these subjects had the hemoglobin AS or AC phenotype. The presence of hemoglobin S or C appears to cause spuriously low levels of glycosylated hemoglobin as determined by ion exchange chromatography. Other means to assess diabetic control should be used for patients with these abnormal hemoglobins.

Impairment of T-cell regulation of the humoral immune response to type III pneumococcal polysaccharide in diabetic mice.

The peak plaque-forming-cell (PFC) and serum antibody responses of diabetic mice to type III pneumococcal capsular polysaccharide (S3) were delayed compared with normals. Proliferation of PFC precursors was not inhibited in an insulin-deficient environment. The delay in the PFC response to S3 did not occur in diabetic nude mice but was demonstrable in their thymus-bearing heterozygote littermates. Therefore, T-cells appear to mediate the delay in the response of diabetic mice to S3 probably by delaying their differentiation into PFC. Diabetic mice responded normally to the induction of low-dose tolerance to S3, indicating the presence of active suppressor T-cells (Ts) in these mice. However, inactivation of Ts by anti-lymphocyte serum (ALS) required a higher dose in the diabetic mice. Furthermore, inactivation of Ts by ALS totally abolished the delay in peak PFC response. These findings suggest that the delayed PFC response to S3 in diabetic mice was the result of excessive splenic Ts activity. In peripheral blood, diabetic mice appeared to have more amplifier T-cell activity or less suppressor T-cell activity than normals. This response was normalized by insulin treatment. DIABETES 32:156-164, February 1983.

Antibody response to pneumococcal polysaccharides in insulin-dependent diabetes mellitus.

Twenty-one insulin-dependent diabetics and 11 healthy control children were immunized with polyvalent pneumococcal polysaccharide vaccine. Serum antibody to pneumococcal polysaccharides was measured by radioimmunoassay before and after immunization. Although there were some differences in type-specific antibody concentrations between diabetic and control subjects, the overall antibody concentrations preimmunization, 3-4 wk postimmunization, and 6-7 wk postimmunization were similar in both populations. In both groups antibody response to immunization correlated strongly with preimmunization antibody concentration. Among the diabetic subjects there was no correlation between antibody responses and duration of disease, insulin dose, or concentration of glycosylated hemoglobin. Insulin-dependent diabetic subjects have a serum antibody response to pneumococcal polysaccharides equivalent to that of controls, and in both populations the magnitude of the antibody response correlates with preimmunization antibody levels.

Defective suppressor cell generation in juvenile onset diabetes.

Lymphocytes of juvenile onset, insulin-dependent diabetics failed to generate suppressor cell activity after preincubation with concanavalin A (Con A). The mean suppression of the autologous proliferative response to phytohemagglutinin (PHA) was 6.1 +/- 7.8% (mean +/- SEM) in the diabetics and 34.0 +/- 4.9% in 9 age-matched healthy controls (p less than 0.01). Cell mixing experiments identified the defect to be in the generation of suppressor cells rather than in the responses to their action. Plasma of insulin-dependent diabetics had no effect on the generation of suppressor activity. In contrast to our findings in insulin-dependent diabetics, Con A preincubation of lymphocytes from 4 maturity onset diabetics induced normal suppression of PHA responses. Defective immunoregulation is present in insulin-dependent diabetes and may underlie autoimmunity.

Generation of a soluble immune response suppressor factor (IRSF) by unstimulated leukocytes of healthy subjects.

Supernatants derived from unstimulated cultures of mononuclear leucocytes obtained from healthy subjects contained a factor(s) which consistently suppressed lymphocyte proliferative responses to antigens and mitogens. This factor(s) is produced by a non-adherent cell and was generated in vitro after 4 hr of culture. Cells from almost all healthy subjects produced this substance(s). Cell number and viability were not affected by it. Kinetic studies suggested that interference with antigen presentation was not the mechanism of its action. The release of this immune response suppressor factor(s) (IRSF) was not blocked by indomethacin and its biological activity was unrelated to levels of prostaglandin E2. Experiments with low-specific-activity thymidine showed that suppression was not due to release of unlabelled nucleotide. Preliminary characterization of IRSF revealed that it is heat-stable and partially dialysable through membranes with an exclusion size of 12,000 daltons. IRSF differs from previously reported soluble suppressor substances and may play a role in immunoregulation in health.

Pneumococcal immunization in adult diabetics.

The antibody responses of 102 adult insulin-treated diabetics who received 14-valent pneumococcal polysaccharide vaccine were measured. Grand mean preimmunization antibody levels were similar for diabetics, 255 ng protein N/ml, and controls, 234 ng protein N/ml. Postimmunization, the values in the diabetics, 1009 ng protein N/ml, and 834 ng protein N/ml in 48 healthy controls, were not significantly different. The height of antibody response in the diabetic group did not correlate with age, sex, duration of diabetes, insulin dose, concentration of glycosylated hemoglobin, fasting or 2-h postprandial glucose concentrations, or the presence of retinopathy. Side effects were minimal and occurred in 26%. Antibody response to pneumococcal polysaccharide vaccine is not impaired in adult diabetics. Pneumococcal immunization is safe and may reduce the frequency of pneumonia and its complications in the diabetic population.

A modern approach to management of pregnant diabetics: a two-year analysis of perinatal outcomes.

Increased understanding of maternal-fetal carbohydrate homeostasis together with modern perinatal technology now provides a more rational basis for obstetric management of the pregnant diabetic patient. These concepts were applied at MacDonald House in the care of 96 diabetic pregnant women over a two-year period. Pregnancy outcomes were compared with prior experiences with the same group of women. The perinatal mortality rate was reduced from 13.5 to 4.2%, and the rate of macrosomia (infants large for gestational age) was reduced from 30.9 to 17.7%. Patients with gestational diabetes, with a prior loss rate of 8.3%, suffered no losses in the current series. Maternal age was not found to correlate with an untoward outcome in this subgroup.

Stereospecificity of the hydrogen transfer catalyzed by human placental aldose reductase.

Placental aldose reductase (EC 1.1.1.21) was incubated with glucose in the presence of [4A-2H] NADPH prepared in the oxidation of [2-2H] isocitrate by isocitrate dehydrogenase (EC 1.1.1.42) or [4B-2H] NADPH prepared in the oxidation of [1-2H] glucose-6-phosphate dehydrogenase (EC 1.1.1.49). The sorbitol formed from [4A-2H] NADPH contained deuterium and from [4B-2H] NADPH it did not. Therefore, aldose reductase in an A-type enzyme.

Induced and spontaneous diabetes mellitus and suppression of cell-mediated immunologic responses. Granuloma formation, delayed dermal reactivity and allograft rejection.

These investigations delineate the recently described suppression of a form of cellular hypersensitivity in mice with streptozotocin-induced diabetes mellitus using a variety of cell-mediated immunologic responses in animals with several different forms of diabetes. Streptozotocin- and alloxan-induced diabetic mice and db/db genetically determined diabetic mice showed reductions in the areas of inflammation around Schistosoma mansoni eggs injected into the pulmonary vasculature of 68, 70, 77%, respectively. In contrast, streptozotocin-induced diabetes had no effect on the nonimmunologic foreign body granuloma around divinyl benzene copolymer beads injected into the pulmonary arterioles. Animals protected from diabetes by treatment with nicotinamide before streptozotocin administration did not develop hyperglycemia and had normal areas of immunologic granuloma formation around schistosome eggs. Treatment with insulin reversed the suppression of schistosome egg granuloma formation in both streptozotocin- and alloxan-diabetic animals. Two additional in vivo parameters of cellular immunologic reactivity were examined in streptozotocin-induced diabetes: delayed footpad swelling was essentially eliminated; skin graft survival across the H-2 area was significantly prolonged from 10.2 days in the controls to 14.4 days in moderately diabetic A/J mice. These observations suggest that diabetes mellitus is associated with suppression of cell-mediated reactions in vivo and that the defect is reversible with insulin treatment.