Juvenile-onset Insulin-dependent Diabetes Research Articles

The effect of glucagon infusion on kidney function in short-term insulin-dependent juvenile diabetics.

Kidney function was studied in nine, metabolically well controlled, short-term insulin-dependent male diabetics before and during glucagon infusion of 4 to 5 and 8 to 10 ng/kg/min. Glomerular filtration rate, effective renal plasma flow (steady-state infusion technique, with urinary collections, using 125I-iothalamate and 131I-iodohippurate), and urinary albumin and beta 2-microglobulin excretion rates were measured. The mean plasma glucagon concentration increased during infusion from 254 +/- 19 pg/ml to 440 +/- 31 pg/ml (low dose) and 730 +/- 52 pg/ml (high dose). Glomerular filtration rate increased in all subjects from 133 +/- 5 before the glucagon infusion to 141 +/- 4 with the low dose, and 148 +/- 7 ml/min/1.73 m2 with the high dose (p < 0.01). The increase in glomerular filtration rate correlated with the rise in plasma glucagon concentration (r = 0.67; p < 0.01). Renal plasma flow increased from 530 +/- 21 before the glucagon infusion to 555 +/- 20 with the low dose and 572 +/- 29 ml/min/1.73 m2 with the high dose (p < 0.01). Urinary beta 2-microglobulin excretion rate rose from 5.8 +/- 1.0 before infusion to 8.7 +/- 1.7 with the low dose, and 17.9 +/- 5.7 micrograms X 10(-2)/min with the high dose (p < 0.01). Urinary albumin excretion remained unchanged during the glucagon infusion. These results suggest that glucagon may contribute to the reversible elevation of glomerular filtration rate typically found in poorly regulated insulin-dependent diabetics, but not to the moderate elevation found in well controlled diabetics.

Statistical Assessment of Hyperpepsinogenemia Data

Letters and Corrections1 August 1980Statistical Assessment of Hyperpepsinogenemia DataANTONY R. UNWIN, M.D.ANTONY R. UNWIN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-93-2-377_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: I was asked as a statistician to look at the paper by Rotter and colleagues (1) in your September 1979 issue. The medical side of the article was interesting, but I have had some doubts about the handling of data and presentation of results. In Table 1 (p. 374) the definite hyperpepsinogenemic group includes 93 affected patients (that is, those with a duodenal ulcer or an elevated pepsinogen level, or both). In Table 2 (p. 375) subset 2 "is equivalent to the entire definite hyperpepsinogenemic group" but only includes 83 affected patients. What is the reason for...Reference1. ROTTERPETERSENSAMLOFF JGI. Genetic heterogeneity of hyperpepsinogenemic I and normopepsinogenemic I duodenal ulcer disease. Ann Intern Med. 1979;91:372-7. LinkGoogle Scholar1. ROTTERPETERSENSAMLOFF JGI. Genetic herogeneity of hyperpepsinogenemic I and normopepsinogenemic I duodenal ulcer disease. Ann Intern Med. 1979;91:372-7. LinkGoogle Scholar2. HODGEROTTERLANGE SJK. A three-allele model for heterogeneity of juvenile onset insulin-dependent diabetes. Ann Hum Genet. 1980;43:399-412. CrossrefMedlineGoogle Scholar3. ROTTERRIMOINSAMLOFF JDI. Genetic heterogeneity in peptic ulcer. Lancet. 1979;1:1088-9. CrossrefMedlineGoogle Scholar4. FEINSTEIN A. Clinical Biostatistics. St. Louis: C. V. Mosby; 1977. CrossrefGoogle Scholar5. ROTTERSONESSAMLOFF JJI. Duodenal-ulcer disease associated with elevated serum pepsinogen I: an inherited autosomal dominant disorder. N Engl J Med. 1979;300:63-6. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: University of Dublin Dublin Ireland PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 August 1980Volume 93, Issue 2Page: 377-378KeywordsDuodenal ulcersStatistical data Issue Published: 1 August 1980 PDF DownloadLoading ...

ALBUMINURIA IN DIABETIC CHILDREN

Sligth albuminuria has been induced by exercise in young adults with juvenile-onset insulin-dependent diabetes mellitus of short duration. We studied the influence of exercise on albuminuria in 46 diabetic and 38 healthy children using radioimmunoassay. The age of the children ranged from 9 to 18 years. The children worked on a bicycle ergometer for 16 minutes with increasing work load. In both groups, the pulse rate at the end of the exercise was 185±6/min.At rest the geometric mean of the albumin excretion rate of healthy children was 4.7 μg/min/m2, that of diabetics with a duration less than 5 years 6.0 μg/min/m2 and with a duration more than 5 years 9.1 μg/min/m2. During exercise the albumin excretion was 8.5, 10.0 and 19.5 μg/min/m2, respectively. During rest and exercise the albumin excretion was significantly increased in children with diabetes for more than 5 years.At rest the extent of albuminuria correlated with blood HbA1 concentration.During exercise there was a correlation between albuminuria and blood pressure rise in diabetic but not in healthy children. It is concluded that early signs of diabetic nephropathy can be detected with special techniques as soon as in childhood and the appearance of albuminuria is dependent on the metabolic balance of diabetes.

Application of the lod score method to detection of linkage between HLA and juvenile insulin-dependent diabetes.

The lod score method has been applied to 28 informative families with at least one child suffering from juvenile insulin-dependent diabetes (JIDD), assuming autosomal recessive inheritance, for detection of linkage between HLA and a susceptibility locus for this disease. These 28 families were pooled with 21 other families from the literature. The maximum lod scores were obtained for recombination fractions from 4 to 16%, according to the level of penetrance (10 to 90%). These high estimates of the recombination fraction are not in agreement with the hypothesis that the association between JIDD and specific HLA haplotypes is due to a simple linkage disequilibrium between the HLA region and a susceptibility locus for JIDD.

Fetal activity in pregnancies complicated by maternal diabetes mellitus.

SummaryThe incidence of fetal breathing movements (FBM), fetal trunk movements (FTM), and total fetal activity (TFA) was assessed in 25 pregnancies complicated by maternal diabetes mellitus; 20 mothers had been juvenile insulin dependent diabetics, 4 were diagnosed during pregnancy (one of whom required insulin) and there was one other who was changed from chlorpropamide to insulin during the first trimester of pregnancy. Thirty‐minute records were made postprandial between 32 and 38 weeks making a total of 161 recordings. There were 15 well‐controlled insulin‐dependent diabetic women with uncomplicated pregnancies; and in this group the mean percentage incidence of FBM was 60±25 (SD) per cent, FTM 16±10 (SD) per cent and TFA 73±22 (SD) per cent. The mean breathing rate per minute was 53±12 and the mean number of movements per 30‐minute period 29±18. The incidences of FBM and TFA were significantly higher than those found in postprandial recordings in normal pregnancies. There was only one recording out of 115 where the incidence of TFA fell below 10 per cent. The mean percentage incidences of FBM, FTM and TFA were similar in the four uncomplicated pregnancies in which diabetes was diagnosed during pregnancy. The mean percentage incidence of TFA was significantly lower in the six pregnancies with obstetric complications, and levels of TFA below 10 per cent correlated well with abnormal cardiotocograph traces or fetal distress in labour.

A three-allele model for heterogeneity of juvenile onset insulin-dependent diabetes.

A three-allele model is presented for the inheritance of 'juvenile' insulin-dependent diabetes mellitus (IDDM). The model postulates a susceptibility locus S tightly linked to the HLA complex. The model incorporates relative-risk and HLA-association data from the literature which suggest genetic heterogeneity within IDDM, together with population prevalence, twin and sib concordance rates, and distortions in HLA-haplotype concordance values for affected sib pairs. The model appears to provide a reasonable fit to existing data. It predicts low penetrances for some, but not all, genotypes and a strong association between HLA B8 and one of the S alleles. The model makes additional specific predictions about how different forms of IDDM are distributed in sporadic and familial cases. These predictions can be tested in future genetic-epidemiologic studies.

Everything the pediatrician ever wanted to know about HLA but was afraid to ask.

Following a description of the genetic aspects of the human histocompatibility antigens system HLA and its principle typing methods, this paper reviews the relationship between HLA antigens, transplantation immunology and certain diseases. In particular, the role of the lymphocyte-defined antigens of the HLA-D system is emphasized on the basis of a special typing method, the PLT test, used in our laboratory. Aside from its necessity in bone marrow and kidney transplantation, HLA typing can be used as an additional diagnostic or prognostic tool for certain diseases. Among the pediatric age group, this includes rheumatic fever and other rheumatic diseases, insulin-dependent juvenile diabetes mellitus, some forms of Addison's disease, thyrotoxicosis, myasthenia gravis, celiac disease, and some complement deficiency disorders. Close linkage of the HLA system with steroid 21-hydroxylase deficiency has made it possible to diagnose this form of congenital adrenal hyperplasia in utero. This approach is illustrated in a large family at risk for this disorder.

Inhibition of allogeneic lymphocyte E-rosettes induced by sera from newly diagnosed type I diabetics.

Sera from 64 juvenile onset insulin-dependent diabetics (Type I diabetics) and 30 normal subjects were tested for their ability to inhibit sheep red blood cell rosette formation (E-rosette) by normal allogeneic lymphocytes. Inhibition of E-rosette formation by greater than 20% was found with 16 (66%) sera from newly diagnosed patients, 3 (16%) sera from patients with duration of disease between 2 and 12 months and with 4 (18%) sera from diabetics with duration of disease between 1 and 7 years. On the other hand, only 2 (6%) control sera showed inhibitory effect. No relationship between E-rosette inhibition and islet-cell antibodies presence, anti-lymphocyte antibodies occurrence, anti-HLA activity, blood glucose levels, respectively, was found. Investigation of the properties of this inhibitory factor suggests that it is different from other substances that reportedly inhibit E-rosette formation.

Increased plasma corticosteroid-binding globulin in insulin-dependent pubertal diabetics: relationships with other glycoproteins, growth hormone and prolactin.

A selected group of 13 juvenile-onset insulin-dependent diabetics in mid-late puberty (stages 3-4) and under comparable conditions of metabolic control was studied in order to evaluate the plasma levels of corticosteroid-binding globulin (CBG, transcortin: expressed as the binding capacity for cortisol) in relation to the levels of other glycoproteins and to growth hormone (GH) and prolactin (PRL) responsiveness to provocative tests (arginine infusion and TRH injection, respectively). Further evidence was provided that juvenile-onset diabetics show most frequently enhanced plasma CBG binding capacity; statistical significance with p-values less than 0.01 was attained in comparison to 25 age-matched controls. Among other variables examined, only hemoglobin A1c amd alpha 2-macroglobulin were significantly raised in the diabetic group (p less than 0.01 and less than 0.02, respectively). In our patients growth hormone response to arginine infusion was in the normal range, whereas PRL response to TRH was slightly but significantly supranormal in terms of maximum value and maximum increment above baseline value. No correlation was found between CBG binding capacity and other variables examined. We conclude that raised levels of CBG may occur as an additional alteration of the plasma glycoprotein pattern in juvenile-onset insulin-dependent diabetics. Specific regulatory factors conceivably subserve plasma concentrations of different glycoproteins.

Hemoglobin HbA1c: a predictor for the duration of the remission phase in juvenile insulin-dependent diabetic patients

Augmented HbA1c-concentrations in diabetics indicate retrospectively a poor metabolic control during the preceding 2-3 months. In the present study attempts have been made to use the HbA1c- concentration at the time of diagnosis as an indicator for the duration of the remission phase in 22 juvenile diabetic children. The regression analysis revealed a significant correlation between the initial HbA1c-concentrations and the duration of the remission phase defined as no glucose excretion and an insulin requirement of less than 0.5 U/kg/day (r=0.85 p:<0.001). The results suggest that the determination of the initial HbA1c-concentration may serve as a useful indicator to predict the duration of the remission phase in juvenile insulin-dependent diabetes mellitus.

Is Juvenile Diabetes Determined by a Single Gene Closely Linked to HLA?

The transmission behavior of insulin-dependent juvenile diabetes mellitus (JDM) has been studied with respect to its frequency in the relatives of JDM probands and its possible linkage to the HLA complex. Mathematical analysis shows that under a single locus hypothesis a very restricted range of incidence rates is possible in the full siblings of probands once the concordance rate in monozygotic (MZ) twins is specified. Specifically, for a given population prevalence of the disease, high concordance rates in MZ twins require high incidence rates in siblings, and low rates require low incidence rates, if a single locus model is th be valid. Moreover, if these rates do conform to a single locus model, then they give additional information about possible linkage between the purported JDM susceptibility gene and the HLA complex. By using observations on the identity by descent scores at the HLA locus of sibling pairs, both of whom are affected with JDM, it is shown that tight linkage of a disease susceptibility locus is possible only when the MZ twin and sibling incidence rates are low, whereas high rates support loose linkage. If the single locus model is rejected, then an alternative hypothesis, involving epistasis between a JDM susceptibility locus and genes in (or close to) the HLA complex can be suggested as a mechanism whereby JDM would appear to be linked to HLA within families while maintaining an association with HLA at the population level.

ENCEPHALOMYOCARDITIS VIRUS-INDUCED DIABETES MELLITUS TREATED BY ISLET TRANSPLANTATION

There is considerable evidence that at least some cases of juvenile onset diabetes mellitus in humans are a result of viral infection. Viral-induced diabetes in mice may provide an experimental counterpart more similar to the clinical situation than chemical-induced diabetes. Our experiments in such mice indicate that islet transplantation is effective in ameliorating viral-induced diabetes and is encouraging for ultimate clinical application of islet transplantation to juvenile onset insulin-dependent diabetics. In addition, our results show that islets in ectopic sites outside of the pancreas are resistant to damage induced by primary viral infection. The mechanism of this resistance is obscure and will be the subject of future investigations.

Circulating lymphocyte subpopulations in juvenile insulin-dependent diabetes. Correction of abnormalities by adequate blood glucose control.

Circulating lymphocytes from 39 juvenile insulin dependent diabetics of recent onset were studied by six membrane marker techniques and mitogen stimulation. Well controlled (n = 14) were grouped separately from poorly controlled (n = 25) patients. The total lymphocyte counts were not different from 50 control subjects. The percentage of T-cells detected by erythrocyte rosettes and B-cells detected by erythrocytes--antibody--complement rosettes was significantly decreased only in poorly-controlled diabetics (64.1 +/- 1.3 and 9.7 +/- 1.8, vs 71.0 +/- 1.0 and 15.3 +/- 0.6 in controls). Cells bearing receptors for the Fc fragment of IgG immunoglobulins were decreased in both groups. Mitogen stimulation was not different from controls but was significantly lower in poorly controlled than in well controlled diabetics. Optimal blood glucose control for 5 +/- 2 days using an external artificial pancreas led to a rapid normalisation of membrane marker values and mitogen responsiveness of lymphocytes from previously poorly controlled diabetics. Separate in vitro experiments showed that glucose had an inhibitory effect on mitogen stimulation at concentrations greater than or equal to 8.3 mmol/l and on T- and B-lymphocyte numbers at concentrations greater than or equal to 55.6 mmol/l. DL 3-hydroxybutyrate tested at 17.1 and 34.2 mmol/l only depressed mitogen responsiveness. Such results suggest a rapidly reversible T-cell defect closely linked to the existing metabolic disturbances.

The leucocyte migration inhibition test and subpopulations of peripheral lymphocytes in insulin-dependent diabetics.

The leucocyte migration inhibition test (LMT) was performed by the agarose plate method with thyroid and pancreatic antigens in patients with insulin-dependent or independent diabetes mellitus. The mean migration indices with thyroglobulin, thyroid mitochondria and beef insulin were not significantly different in insulin-dependent diabetics from those in insulin-independent diabetics or normal controls. However, significant inhibition of leucocyte migration was observed in insulin-dependent diabetics when thyroid microsome or pancreatic extract was used as antigen. Although no significant difference was found in the percentages of T and B lymphocytes between insulin-dependent diabetics and insulin-independent diabetics or normal controls, the results of LMT strongly suggest the presence of cellular immunity against the thyroid and pancreas in insulin-dependent juvenile-onset diabetes.

Plasma lipid levels in insulin-dependent diabetes mellitus.

Because several recent reports have indicated a high incidence of hyperlipidemia in insulin-dependent juvenile diabetes, the plasma lipid levels were measured in a population of insulin-dependent diabetic patients to determine if hyperlipidemia is necessarily associated with diabetes. Only one patient had an elevated cholesterol concentration (greater than 220 mg. per deciliter) and two patients had an elevated triglyceride concentration (greater than 140 mg. per deciliter), giving an incidence of 6.4 per cent. A normal control group had an incidence of hyperlipidemia of 5.7 per cent. The mean cholesterol level (164 "/- 38 mg. per deciliter) of the diabetic population was significantly less than that of the normal control group (183 +/- 38 mg. per deciliter). The diabetic patients were divided into groups on the basis of 24-hour urinary glucose excretion and records of glycosuria. The serum triglyceride of the patients in group 4 (highest urinary glucose content and spills) was significantly elevated above three other groups with less glucosuria. Dietary history revealed that group 4 patients consumed a significantly higher percentage of fat. Cholesterol levels did not correlate with parameters of regulation of the diabetes.

A simple microchromatographic column for determination of hemoglobins A1a + b and A1c.

A simple microchromatographic homemade column was devised for the measurement of glycosylated minor hemoglobin fractions. The mean and one standard deviation of hemoglobins A1a + b, A1c and A1a + b + c determined by the homemade column in 150 nondiabetic controls and 56 juvenile onset insulin-dependent diabetics were 2.6 +/- 0.5%, 6.0 +/- 1.0%, 8.6 +/- 1.1%, 3.3 +/- 0.9%, 13.7 +/- 2.2% and 16.9 +/- 2.8% respectively. A twofold increase in hemoglobins A1c and A1a + b + c levels was observed in the diabetics as compared to the non-diabetic controls suggesting that the homemade column is valid for the measurement of all three glycosylated hemoglobin fractions and assessment of blood glucose control in diabetic patients. The homemade column procedure yields accurate and reproducible results, is simple to perform, inexpensive, relatively rapid and may be used in the routine clinical laboratory. Hemoglobin A1a + b + c levels measured by a commercial column in 35 non-diabetic controls and in 56 diabetics showed good correlation (R = 0.91) with hemoglobin A1a + b + c levels determined by the homemade column. The commercial column is valid for the measurement of the combined glycosylated hemoglobin A1a + b + c fraction and may be used in the routine clinical laboratory to assess diabetic control.

Immunopathology of Juvenile-onset Diabetes Mellitus: I. IgA Deficiency and Juvenile Diabetes

There is an increased prevalence (P less than 0.001) of IgA deficiency in children with juvenile-onset insulin-dependent diabetes mellitus (9/366) but not in adults with insulin-dependent diabetes (0/421). The juvenile diabetics with IgA deficiency have other immune-associated diseases, such as thyroiditis and chronic active hepatitis, and have a history of infections. Four of the nine IgA-deficient diabetics we studied have autoantibodies to endocrine organs. Seven of eight have the HLA-B8, a proportion significantly (P less than 0.05) greater than control populations. Based on the clinical findings of IgA deficiency and multiple autoantibodies in patients with ataxia-telangiectasia and chronic mucocutaneous candidiasis, diseases associated with thymus deficiency, we suspect that thymus deficiency and autoimmunity may play a role in the pathogenesis of some types of juvenile-onset diabetes mellitus. In addition, an excess morbidity of the IgA-deficient juvenile diabetic population may explain the lack of IgA deficiency in older insulin-dependent diabetic individuals.

HLA--Bw54 (Bw22-J, J-1) antigen in juvenile onset diabetes mellitus in Japan.

HLA--B8 and/or Bw15, associated with juvenile onset insulin-dependent diabetes mellitus (JDM) in Caucasians, have a very low frequency in the Japanese population. Thus, we were interested in investigating the association between JDM and HLA antigen in a Japanese population. Eighty-nine patients with JDM and 128 unrelated random controls were HLA-typed by the microlymphocytotoxicity test. The data revealed a significant, positive association between this type of diabetes mellitus and HLA--Bw54 (Bw22-J, J-1) antigen (Japanese-specific split antigen of HLA--Bw22).

529 GENETICS AND NATURAL HISTORY OF MATURITY ONSET DIABETES OF THE YOUNG

Families with a 3 generation of a mild autosomal dominant form of diabetes mellitus (MODY) were HLA typed at the A and B loci. In family A, 6/6 affected members shared the same haplo type (A1,B8). In family B, 4/5 affected members had haplotype A29,B7. In family C, 1/2 affected members had haplotype A1,B8. With one exception, family members who lack these particular haplotypes do not develop MODY. This indicates a possible linkage between the genes in the HLA region and the gene(s) coding for susceptibility to MODY. Several affected members in family A have been followed with serial oral glucose tolerance tests (OGTT). Suring childhood, the fasting plasma glucose is high and the glucose peak during the OGTT is elevated and delayed. Simultaneous plasma insulin levels are quantitatively normal, but inappropriately low in relation to the elevated plasma glucose. During adolescence, deterioration in the OGTT often occurs; affected individuals fail to produce the physiologic increase in insulin output expected at this age. Treatment with tolbutamide displaces the OGTT curve downwards, but does not alter its shape. These individuals may at times be placed on insulin. Since the mode of inheritance and the prognosis appear to be entirely different from that of insulin dependent juvenile onset diabetes (JOD), it is important to distinguish children with MODY from those with classical JOD when planning studies of etiology or of assessments of therapy.

359 GENETIC AND EPIDEMIOLOGIC STUDIES IN FAMILIES WITH MULTIPLE DIABETIC OFFSPRING

Families with 2 or more insulin-dependent juvenile onset diabetics (JOD) were ascertained from an ongoing epidemiologic study. Patients and offspring in 15 families were HLA typed at the A and B loci. In 10/15 families, the diabetic offspring share 2 identical haplotypes. In about half of these families there is no previous history of diabetes and the possibility exists that the disease may be due to an autosomal recessive HLA-linked gene. In 4/15 families the diabetic offspring share only 1 HLA haplotype. This group includes a family in whom three members (a mother and two sons sharing haplotype A2B40) became diabetic within the same year, and another family in whom three siblings became diabetics by the age of 5 years. Diabetic siblings share no HLA haplotypes in only 1 family. This distribution differs from that predicted by the null hypothesis of random assortment of HLA-haplotypes. The data suggest genetic heterogeneity of JOD as well as a linkage between the HLA region and gene(s) predisposing to the development of some types of JOD. No A/B recombinants were found among the 31 diabetics and 12 unaffected siblings, nor among the 7 offspring tested at the D locus by mixed lymphocyte culture. Comparison of the familial diabetics with the total JOD patients ascertained since 1971 showed in both a higher incidence in the winter months and a clustering of cases at around age 11 years. However, in the families there is an increased number of children in whom the diagnosis was made before the age of 6 years.