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D Daneman

Publications and source records attributed to D Daneman.

At least 73 records · Page 4Linked to original sources
PubMed1990

Distinct antibody specificities to a 64-kD islet cell antigen in type 1 diabetes as revealed by trypsin treatment.

Type 1 diabetes is associated with antibodies that immunoprecipitate a 64-kD islet cell membrane protein from detergent extracts of pancreatic islets. In this study we have determined whether mild trypsin treatment of islet membranes can release fragments of the antigen that bind antibodies in the serum of Type 1 diabetic patients. Partial tryptic proteolysis of [35S]methionine-labeled 64-kD antigen immunoprecipitated from detergent extracts of rat islets resulted in the formation of 50-, 40-, and 37-kD fragments. Similar sized fragments were recovered when sera from diabetic patients were employed to immunoprecipitate polypeptides solubilized by mild trypsin treatment of a particulate fraction of radiolabeled rat islets. Of 27 diabetic patients, 22 possessed antibodies to the 50-kD polypeptide and 21 to the 40- and 37-kD polypeptides. A positive association was found between 64k antibodies and antibodies to the 50-kD fragment but not between 64k antibodies and antibodies to the 40- or 37-kD fragments. Some 64k antibody negative patients possessed antibodies that efficiently immunoprecipitated the latter fragments. Serum from 25 of 27 (93%) diabetic patients immunoprecipitated at least one of the three tryptic polypeptides. One of 20 nondiabetic controls immunoprecipitated a 50-kD polypeptide and all controls were negative for antibodies to 40- and 37-kD fragments. Thus, Type 1 diabetes is associated with the presence of at least two antibody reactivities to distinct determinants of the 64-kD antigen, and some patients may possess antibodies to a cryptic epitope on the detergent-solubilized molecule. These data suggest that the detection of antibodies (present in 93% of patients) to epitopes on tryptic polypeptides of the 64-kD antigen may be of even greater diagnostic value for the onset of Type 1 diabetes than analyses of antibodies reactive with the intact 64-kD antigen.

Adolescent↗
PubMed1990

Microalbuminuria in adolescents with insulin-dependent diabetes mellitus.

Two hundred ten adolescents aged 12 to 18 years with insulin-dependent diabetes mellitus were screened for microalbuminuria (albumin excretion rate of 15 to 300 micrograms/min). Sixteen (7.6%) showed persistent microalbuminuria (mean albumin excretion rate of 70.9 +/- 56.2 micrograms/min). There were no significant differences between those with and without microalbuminuria with respect to age, sex, disease duration, and blood pressure over the previous 9 months and hemoglobin A1c level measured over the preceding 3 years. Within the group with microalbuminuria, there was no correlation between albumin excretion rate and blood pressure. However, there was a significant positive correlation between log albumin excretion rate and mean hemoglobin A1c values measured over the preceding 3 years. Our findings suggest that when microalbuminuria has developed, poorer metabolic control is associated with a higher albumin excretion rate. An actual rise in systemic blood pressure may not always precede the development of microalbuminuria.

Adolescent↗
PubMed1990

Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus.

It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.

Adolescent↗
PubMed1990

Persistence of serum antibodies to 64,000-Mr islet cell protein after onset of type I diabetes.

Antibodies to an islet protein of 64,000 Mr (64K antibodies) were measured in 15 diabetic children who were followed prospectively for up to 3 yr after onset of type I (insulin-dependent) diabetes. Of the 15 children, 12 were positive for 64K antibodies at diagnosis. Those patients who were negative for these antibodies at onset remained negative throughout the study. Modest increases in 64K antibodies were observed in 7 patients within 1 mo of diabetes onset, concomitant with an increase in C-peptide concentrations. All antibody-positive patients were still positive at the end of the study, with no significant decrease in antibody levels relative to those at diagnosis, whereas C-peptide concentrations decreased between 3 and 24 mo after onset. Islet cell antibodies, measured by immunochemical staining on sections of rat pancreas, were detected in 9 of 15 patients at onset, whereas only 3 of 11 patients were still positive after 3 yr. In an additional group of 11 patients with diabetes for 6-7 yr, when basal and stimulated C-peptide concentrations were undetectable, 4 patients were still positive for 64K antibodies. These results demonstrate that levels of 64K antibodies persist during the first 3 yr of diabetes, despite declining beta-cell function and decreased immune responses to other islet antigens, but decrease during the next 3-4 yr as the remaining functional beta-cells disappear.

Adolescent↗
PubMed1990

Comparison of children with type 1 (insulin-dependent) diabetes in northern Finland and southern Ontario: differences at disease onset.

This study was undertaken to evaluate whether differences in Type 1 diabetes incidence in two separate geographical locations are associated with any differences in biochemical and immunological features at the onset of the disease. We studied all children under 16 years of age who presented at the time of diagnosis with Type 1 diabetes to the children's hospitals in Oulu (n = 43) and Toronto (n = 87) during 1984-1985. At onset children from Northern Finland had lower blood glucose and HbAlc levels, and higher C-peptide concentrations than those from Southern Ontario (p's less than 0.01). The group from Northern Finland also had a higher incidence of multiplex families (18.6 vs 4.6%, p less than 0.01). Amongst the Finnish group, those from multiplex families had a higher C-peptide concentration and lower frequency of ketoacidosis than those from simplex families (p's less than 0.05). Thus differences do exist at the onset of diabetes in these groups from geographical locations with greatly different incidences of Type 1 diabetes.

Adolescent↗
PubMed1989

Severe hypoglycemia in children with insulin-dependent diabetes mellitus: frequency and predisposing factors.

We surveyed 311 children with insulin-dependent diabetes mellitus to evaluate the frequency and characteristics of those children experiencing severe hypoglycemia (defined by an episode of coma, convulsion, or both). The children and their parents completed a questionnaire, and we reviewed the hospital records to confirm reported episodes. Ninety-seven (31%) reported severe hypoglycemia, and a further 50 (16%) reported moderate hypoglycemia requiring the assistance of another person but not resulting in coma or convulsion. In 164 children (53%) there was no history of either moderate or severe hypoglycemia. Sixty-nine (22%) reported the occurrence of more than one severe hypoglycemic episode (range 2 to 20); 52 (16%) reported such an event in a single year. A total of 285 episodes were reported, 39% during sleep and 61% while awake. Children reporting such events tended to have diabetes of longer duration and be younger at the time of the first episode. Hemoglobin A1c concentration at the time closest to the severe episode was significantly lower than in children reporting no hypoglycemia. All families had been taught to use glucagon to reverse severe hypoglycemia at home, but it was available in only 80 of the 97 homes and used in only 30. These data suggest that severe hypoglycemia is common in children with insulin-dependent diabetes mellitus who are treated conventionally. Greater vigilance and education are required both to prevent and to treat severe hypoglycemia in children with insulin-dependent diabetes mellitus.

Adolescent↗
PubMed1989

Relationship of insulin autoantibodies to presentation and early course of IDDM in children.

Insulin antibodies have been documented before (insulin autoantibodies [IAAs]) and after (insulin antibodies) insulin administration in children with new-onset insulin-dependent diabetes mellitus (IDDM). Whereas the relationship of IAA to various factors at presentation has been studied in some detail, little is known about their relationship to events during the 1st yr after diagnosis. Furthermore, the course and factors affecting insulin-antibody response to human insulin administration in children with newly diagnosed IDDM remain poorly defined. To study these questions, we measured serum glucose, pH, bicarbonate, C-peptide, and IAA at diagnosis in 84 children between 0.5 and 18 yr of age. Basal and peak C-peptide responses to Sustacal ingestion, glycosylated hemoglobin (HbA1c), and IAA were then measured in 33 of these patients at 10 days and 1, 3, 6, and 12 mo after diagnosis. At presentation, IAAs were absent (binding below the mean + 3SD of the binding of control serums) in 51 patients (61%) and present (binding above the mean + 3SD) in 33 patients (39%). Multiple regression analysis showed a significant nonlinear relationship between IAAs and both age (P less than .005) and blood glucose (P less than .05) at onset. There was a stepwise increase in median insulin-antibody binding throughout the 1st yr. This increase was most marked during the 1st mo of insulin therapy and showed a statistically significant difference between successive measurements only during this period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Relationship of islet cell and islet cell surface antibodies to the presentation and early course of IDDM in childhood.

Islet cell (ICA) and islet cell surface (ICSA) antibodies were measured in 30 children (aged 6-17.7 years) with newly diagnosed insulin-dependent diabetes mellitus (IDDM) to determine the relationship of antibody positivity/negativity to a variety of factors both at presentation (e.g., age, severity of onset, residual insulin secretion, insulin autoantibodies) and during the first year thereafter (HbA1c, insulin antibody binding, residual insulin secretion). At diagnosis, 10 of 30 were ICA (+) and 13 ICSA (+): no differences were found between ICA (+) and (-) subjects at onset; however ICSA (+) children had a lower bicarbonate concentration than those (-) for ICSA (P less than 0.01). During the first year after diagnosis the only significant finding was that in ICA (+) patients insulin dose (units/kg) was lower at both 6 and 12 months (mean +/- SD 0.55 +/- 0.14 and 0.67 +/- 0.12 U/kg, respectively) than ICA (-)'s (0.70 +/- 0.22 and 0.96 +/- 0.38, respectively, both P less than 0.05). Those children positive for both ICA and ICSA did not differ in any way at onset or during the subsequent 12 months from those negative for both antibodies. These results suggest that, except for minor differences, the presentation and course during the first year after diagnosis of IDDM do not differ in those children positive or negative for either or both ICA and ICSA.

Adolescent↗
PubMed1988

Thyroid scanning, ultrasound, and serum thyroglobulin in determining the origin of congenital hypothyroidism.

Congenital hypothyroidism (CH) can be due to an absent gland (athyrosis), an ectopic gland (usually lingual), or an inborn metabolic error (goiter). In this study, radionuclide scanning was compared with ultrasound (US) and serum thyroglobulin (Tg) concentration as a method of determining the cause of CH in 50 newborns. Mean serum Tg values were significantly lower in athyrotic children (7.9 pmol/L) than in either those with goitrous (149.1 pmol/L) or ectopic (60.5 pmol/L) glands, but there was marked overlap among all three groups. With the interpreter "blinded" to the radionuclide diagnosis, a cervical gland could be delineated reliably on US. All 12 goiters and five of five normal glands were identified. In contrast, the correlation between US and radionuclide scanning was poor in patients in whom there was no cervical thyroid tissue. Ultrasound failed to identify 13 lingual glands and was reported as normal in four of 12 children with no radionuclide uptake in the neck and biochemical hypothyroidism. Two children with absent thyroid glands on scanning were biochemically euthyroid. The serum of two others who had normal results of radionuclide studies showed persistent hypothyroidism. Thyroid scanning remains the most accurate diagnostic modality to determine the cause of CH. Serum Tg and cervical US have not been established as reliable alternatives.

Choristoma↗
PubMed1988

Evidence for a critical role of diet in the development of insulin-dependent diabetes mellitus.

The role of diet in human insulin-dependent diabetes mellitus (IDDM) has not been properly examined, mainly due to a lack of reliable markers to identify prospective diabetics and the difficulties in obtaining accurate and representative dietary information. Nonetheless, there is some circumstantial evidence suggesting a role for diet in human IDDM. The validity of this relationship in humans must await a sufficiently large, well designed prospective study or the discovery of better markers for diabetes predisposition. The recent availability of the spontaneously diabetic BB rat has permitted prospective studies under controlled conditions which indicate diet, particularly dietary proteins, such as wheat gluten or cow's milk proteins may be prerequisites for maximum expression of the insulin-dependent syndrome in these animals. The early suckling and/or post-weaning period appears to be important and may be the crucial time when these proteins or portions of them pass the gastrointestinal barrier and initiate a process, possibly immunological, which results in destruction of the beta cells of the pancreas.

Animals↗
PubMed1987

Factors affecting and patterns of residual insulin secretion during the first year of type 1 (insulin-dependent) diabetes mellitus in children.

We measured serum C-peptide, glucose, pH, islet antibodies and insulin antibody binding at diagnosis in 84 children with Type 1 (insulin-dependent) diabetes. In a subgroup of 33 children, residual insulin secretion (basal and peak C-peptide response to Sustacal), insulin antibody binding and HbA1c were measured at 10 days, 1, 3, 6 and 12 months. At presentation C-peptide correlated positively with age at onset and negatively with the blood glucose concentration. Median C-peptide concentration at diagnosis was low, rose significantly (p less than 0.05) at 10 days, reached a maximum at 1-3 months and declined gradually to 1 year. C-peptide concentration both at diagnosis and at 10 days correlated with that at 3 and 6 months. Of the factors investigated, only age (p less than 0.005) and sex (higher in females, p less than 0.01) were found to have a significant influence on basal/peak C-peptide levels throughout the first year. In particular there was no relationship between C-peptide, HbA1c and insulin dose during this period. A peak C-peptide response at 3-6 months greater than/less than 0.32 nmol/l was used to divide the group into two: 16 had a peak response less than 0.32 nmol/l (low secretors) while in 17, the peak C-peptide was greater than 0.32 nmol/l (high secretors). While the low secretors had significantly (p less than 0.05) lower C-peptide levels during the first year, there were no differences between low and high secretors in HbA1c or insulin dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Factors affecting insulin antibody binding in children with insulin-dependent diabetes mellitus.

We measured insulin antibody binding in 2 groups of patients: Study 1, 32 children with newly diagnosed IDDM before onset of insulin therapy, and, in 20 of these, 10 days, 1, 3, and 6 months after beginning therapy; and Study 2, 35 children with long-standing IDDM, 20 of whom had free insulin concentrations measured before, and for 2 hours following subcutaneous injection of 0.25 U/kg regular insulin. Almost 35% of new onset subjects had insulin antibody binding above control levels. In those studied prospectively, binding increased significantly with time. Pre-treatment binding did not correlate with later insulin antibody binding nor metabolic control. In Study 1 we have confirmed previous studies showing abnormally high insulin antibody binding in children with IDDM pre-treatment. We have been unable to demonstrate a relationship between this binding and that found 6 months after initiation of therapy. In Study 2, we have shown that insulin antibody binding is not related to either the level of metabolic control or the rate of rise of free insulin levels in children with IDDM.

Adolescent↗
PubMed1987

Residual beta-cell function in children with type 1 diabetes: measurement and impact on glycemic control.

We studied residual beta-cell function in 84 children with IDDM to assess (1) relationship between basal and stimulated C-peptide concentrations; (2) reproducibility of testing (Group 1, n = 20); (3) the effect of exogenous insulin on test interpretation (Group II, n = 20); and (4) impact on metabolic control. Sustacal (a mixed liquid meal) was utilized as the test stimulus. In C-peptide positive subjects (n = 44) there was a strong correlation between basal and peak C-peptide concentrations (r = 0.88, p less than 0.001). In Group 1 subjects, Sustacal proved to be a highly reproducible test stimulus producing identical results on two tests 7-14 days apart. The results of the tests were not affected by the administration of subcutaneous regular insulin prior to the second test in Group II. Peak C-peptide correlated inversely with HbA1, insulin dose, and disease duration (r = -0.29, -0.40, and -0.33 respectively, p less than 0.05) and positively with age (r = 0.34, p less than 0.05). We conclude that Sustacal is a highly reproducible stimulus to residual beta-cell function in IDDM and is not affected by exogenous insulin. This residual insulin secretion has a small but significant effect on glycemic control.

Adolescent↗
PubMed1987

Dietary triggers of insulin-dependent diabetes in the BB rat.

Environmental "triggers" (including viruses, toxins and dietary factors) have been implicated in the pathogenesis of insulin-dependent diabetes mellitus. Data have suggested a possible role for cow's milk protein (CMP) as a trigger of diabetes. To study this further, 86 BB rats were divided into 2 groups during the weaning period (days 13-25): Group A received rat chow without CMP; Group B, rat chow with 1% CMP added. Each group was subdivided afterwards into 2: Groups A1 and B1 received chow without CMP; Groups A2 and B2, chow with CMP. Animals weaned with chow containing CMP (B1 and B2) had a higher incidence of diabetes (66%) than those weaned without (A1 and A2; 29%, p less than 0.001). The incidence in both B1 and B2 was significantly greater than in either A1 or A2 (p less than 0.05). The highest incidence of diabetes occurred in male rats weaned on rat chow with CMP (90%), the incidence being significantly higher than female rats weaned with (43%) or without CMP (18%) and males weaned without CMP (39%). Thus, it appears that (a) the presence of cow's milk protein in the diet increases the incidence of diabetes in the BB rat; (b) the critical time for exposure to CMP appears to be the weaning period; and (c) male rats appear to be more susceptible to the development of diabetes than female rats, when exposed to this trigger. This supports the hypothesis that dietary triggers may play an important role in the expression of diabetes in the susceptible host and that its prevalent action occurs early in life.

Animals↗