Chronic non-insulin deficient hyperglycemia in children

Two per cent of "diabetic" children actually exhibit a specific condition which is not a disease in the conventional acceptance of the term. Characteristics of this biologic anomaly, whose pathophysiology is as yet incompletely understood, include the absence of clinical manifestations, with the diagnosis being established upon routine tests (e.g., as part of a school health check-up or during screening tests in family members of diabetics); blood glucose levels or glucose tolerance test results consistently above the 97th percentile of reference values, with some degree of variation over time; normal serum insulin levels; glycosylated hemoglobin levels usually near the upper limit of normal; dominant autosomal inheritance; lack of association with either HLA markers or insulin-dependent diabetes mellitus; lack of microvascular degenerative disease, at least in this study group, even after more than 30 years follow-up; lack of progression towards insulin-dependent diabetes mellitus.     

High IgE levels in diabetic children without atopy or insulin allergy

The combined occurrence of atopy and diabetes of type I in childhood is extremely rare; this is explained in the literature by the different genetic backgrounds. In the present work, a study was made whether juvenile diabetes can be accompanied by symptom-free atopy. In 67 insulin-dependent diabetic children, the total and the specific IgE, and the IgG, IgA and IgM levels were determined, and cutaneous prick test was performed. In 23 of the examined children, the total IgE level proved to be higher than the age-related normal mean + 2 SD; the prick test revealed various degrees of positivity in 30% of these same children, with a complete lack of atopic symptoms. The total IgE levels were found to be elevated not only in the first year of the disease, but also in the following 5-10 years. The results indicate the existence of symptom-free atopy in insulin-dependent diabetes; additionally, the possibility of a genetically determined disturbance of IgE synthesis is suggested. Data are provided on the autoimmune pathogenesis of insulin-dependent diabetes.     

Age, sex, and season of onset of juvenile diabetes in different geographic areas.

Age, sex, and estimated time of onset of insulin-dependent diabetes were determined for children in Pittsburgh (N = 673), Gainesville (N = 976), Galveston (n = 741), and Melbourne (N = 851). The US cities had a decrease in new cases during the summer and peak incidence in January through April. In Melbourne, monthly trends were reversed: there were more cases during May through August. In US cities, but not in Melbourne, children less than 6 years old showed a greater variation by season than children 6 years old and older. Observations of the same fall and winter onset (in different calendar months) of insulin-dependent diabetes in Australia and the United States, and exaggeration of seasonal differences in young US children, suggest that onset of insulin-dependent diabetes is associated with seasonally varying viral diseases. Mumps and rubella infections do not seem to be responsible for much of the seasonal variation. Seasonal peaks of mumps and rubella are later than those observed for insulin-dependent diabetes, and immunization with live mumps and rubella viruses has not been associated with changes in incidence of insulin-dependent diabetes. An increase in disease incidence in boys over girls below age 6 years and in girls over boys at ages 6 through 11 years was consistently observed but not explained.     

Slowly progressing form of type 1 diabetes mellitus in children: genetic analysis compared with other forms of diabetes mellitus in Japanese children

AIMS: Slowly progressing insulin-dependent diabetes mellitus (SPIDDM, hereafter referred to as IDDMS in this article) is a unique subtype of type 1 diabetes in Japanese children. To clarify the genetic background of IDDMS, we analyzed HLA-DRB1, -DQB1 and -DQA1 alleles, phenotypes, and genotypes and compared them with acute-onset type 1 diabetes, non-insulin-dependent diabetes mellitus (NIDDM), and control subjects. METHODS: HLA-DRB1, -DQA1, and -DQB1 types were defined by DNA analysis using polymerase chain reaction (PCR), and typing for human leukocyte antigen (HLA) was performed by the sequencing-based typing (SBT) method using Match Maker and MT Navigator in combination. HLA-A24 was determined by the PCR-sequence-specific oligo-nucleotide probe (PCR-SSOP) method. The 234 patients with type 1 diabetes were divided into three groups: 32 cases of IDDMS, 137 cases of acute-onset form aged more than 5 yr (IDDMA), and 65 cases of acute-onset form less than 5 yr of age at onset (IDDME). In addition, we studied 55 children with type 2 diabetes (NIDDM) and 97 normal controls. RESULTS: The patients with IDDMS were older at diagnosis and had a greater body mass index (BMI) than those with IDDM (A + E). The prevalence of islet autoantbodies was not significantly different from IDDMA. The allele frequencies of DRB1*0405, DQA1*0302, and DQB1*0401 were significantly increased; however, DRB1*0901, DQA1*03, DQB1*0303, and HLA-A24 were low and not significantly different from control subjects. CONCLUSIONS: HLA phenotypes and genotypes in patients with IDDMS were different from those in NIDDM and control subjects and were closer to those of IDDMA. Together with a low prevalence of HLA-A24, the genetic features are similar to those of SPIDDM and latent autoimmune diabetes in adults (LADA) in adults. In our series, the clinical features such as lack of obesity and lack of responsiveness to oral hypoglycemic agents were most different from those of adults' onset.     

Diabetes mellitus in cystic fibrosis: genetic and immunological markers

Family history, as well as genetic and immunological markers of diabetes mellitus, were studied in cystic fibrosis (CF) patients with and without diabetes mellitus. Positive family history of diabetes mellitus in first-degree relatives was found in only 6 of 210 (3%) CF patients, with no difference between non-diabetic and diabetic patients. The frequency distributions of the HLA types DR3, DR4 and DR3/4, which normally confer susceptibility to insulin-dependent diabetes mellitus and of HLA-DR2, which normally confers resistance to insulin-dependent diabetcs mellitus, were not different in non-diabetic CF patients, diabetic CF patients and normal subjects. The genotypic frequencies of tumor necrosis factor-β and of heat shock protein 70, located within the HLA region on chromosome 6, in CF patients with diabetes were not different from those in patients with insulin-dependent diabetes mellitus, while non-diabetic CF patients and normal subjects shared other patterns. The frequencies of the interleukin-1β alleles, located on chromosome 2, were not different in non-diabetic and diabetic CF patients, insulin-dependent diabetic patients and normal subjects. Islet cell cytoplasmic antibodies. measured before, at and after the diagnosis of diabetes in 33 diabetic CF patients and in 32 matched non-diabetic CF patients, were detected in only 2 of 236 (0.8%) serum samples; m a pre-diabetic patient and in a non-diabetic control patient. Birth weights were not different in diabetic and non-diabetic CF patients, arguing against the importance of the intrauterine environment as a determinant in the transmission of diabetes mellitus in CF patients. We conclude that diabetes mellitus in CF is without family history of diabetes mellitus, HLA-DR association, and serological evidence for autoimmune destruction of the β-cells. The significance of similar frequcncies of tumor necrosis factor-β and heal shock protein 70 alleles in insulin-dependent diabetic patients and diabetic CF patients remains to bc determined.     

von Willebrand factor and its propeptide in children with diabetes. Relation between endothelial dysfunction and microalbuminuria

It has been shown that patients with insulin-dependent diabetes mellitus have elevated von Willebrand factor (vWF) plasma concentrations. Plasma fibrinogen, vWF, and its propeptide concentrations have been evaluated in 102 children with insulin-dependent diabetes mellitus to determine whether an increase of vWF and its propeptide levels precedes and may predict the development of persistent microalbuminuria. The patients have been divided into two groups according to the presence or absence of microalbuminuria at the end of follow-up. They have been followed up for at least 8 y. Control group consisted of 80 age- and sex-matched healthy volunteers. At the beginning of the study there was no significant difference in fibrinogen, vWF, and its propeptide levels between patients and control subjects. During the follow-up, a significant increase of plasma vWF and its propeptide has been observed in the group of patients who later developed microalbuminuria but not in those who remained normoalbuminuric. This increase started 3 y and become statistically significant (p < 0.01) 2 y before the onset of microalbuminuria, persisting until the end of the study. During the entire follow-up plasma values of fibrinogen persisted in the normal range. In conclusion, an increase in plasma concentration of vWF and its propeptide precedes microalbuminuria and, therefore, can be useful to identify children with insulin-dependent diabetes mellitus at risk to develop incipient nephropathy later in life.     

Factors predicting cerebral edema in young children with diabetic ketoacidosis and new onset type I diabetes

We have attempted to identify any characteristics which could be used to predict the development of cerebral edema in four children under 5 years of age with new onset insulin-dependent diabetes mellitus and diabetic ketoacidosis. We retrospectively analysed and compared the concentration of serum sodium (corrected for serum glucose value) and effective serum osmolality of these 4 children with values of 10 age-matched controls with new onset insulin-dependent diabetes mellitus who did not develop cerebral edema during treatment of diabetic ketoacidosis. The initial serum sodium values of the two groups were not statistically different. Patients who developed cerebral edema had lower initial serum glucose values and effective serum osmolality. During treatment, patients who developed cerebral edema had consistently lower mean serum sodium and osmolality than controls at each 4-h interval after the first 4 h of therapy. Serum sodium and osmolality declined progressively after the initiation of therapy in cerebral edema patients, while remaining stable in controls. These data suggest that children who develop cerebral edema during treatment for diabetic ketoacidosis initially may have a relatively normal serum osmolality and subsequently develop progressive hyponatremia and/or a trend of declining serum sodium before developing cerebral edema.     

THE INCIDENCE OF DIABETES MELLITUS IN SWEDISH CHILDREN 0–14 YEARS OF AGE

ABSTRACT. This is a prospective study of the incidence of insulin-dependent diabetes mellitus (IDDM) in children 0–14 years of age, including all newly diagnosed cases in the whole of Sweden from July 1, 1977 until June 90, 1980. All 45 Swedish departments of paediatrics participated. During the three-year-period studied, 1108 Swedish children, 0–14 years of age had their onset of diabetes. That means around 369 new diabetics yearly in the age groups studied. The mean yearly incidences in the years 1977–80 were 22.6, 22.8 and 22.6 per 100000 children, respectively. Mean prevalence on June 30, 1980 was 1.48 per 1000 children 0–14 years with a wide range of 0.71-2.65. The age distribution at onset showed a gradual increase and peak incidences at 11 years of age for the girls and 4 and 13 years of age for the boys. There was a consistently higher incidence for boys in the younger age groups during the three-year-period studied. Peak incidences of new cases were reached in January, March and July through October for the age groups 5–9 and 10–14 years of age. No such seasonal variation was seen for children 0–4 years of age. The cumulative incidence of IDDM at 14 years of age was 3.2 per 1000 for the boys and 2.9 per 1000 for the girls. The degree of ascertainment in this study was 93.4 %.     

HLA-DR antigens in insulin-dependent diabetes.

HLA-A, B, C, and DR-typing was performed in 51 children with insulin-dependent diabetes. A close association between childhood diabetes and HLA-DR3 and DR4 was established. DR3 was found in 55% and DR4 in 75% of the diabetic children, compared with 20% and 26% respectively in healthy controls. The combination of DR3 and DR4 was present in 37% of the diabetic children compared with only 4% of the controls. This investigation provides strong evidence that the susceptibility genes for insulin-dependent diabetes are in close linkage disequilibrium with the HLA-DR locus. In diabetic children DR4 seems to be a more important susceptibility factor than in patients with manifestation of insulin-dependent diabetes after 15 years.     

Normal stimulated growth hormone secretion but low peripheral levels of insulin-like growth factor I in prepubertal children with insulin-dependent diabetes mellitus

The hypothalamo-pituitary-insulin-like growth factor I (IGF-I) axis was studied in 24 prepubertal children with insulin-dependent diabetes mellitus (IDDM) and 12 non-diabetic children. There were no significant differences between the diabetic and control subjects in basal concentrations of immunoreactive growth hormone releasing hormone (ir-GHRH), growth hormone (GH) or stimulated GH levels, but after exercise ir-GHRH concentrations were higher in the diabetic children. Peripheral IGF-I levels were significantly lower in the diabetic children, and even lower in those with poor metabolic control. A positive correlation was found between IGF-I levels and circulating free insulin concentrations in the diabetic subjects (r = 0.49, p < 0.05). These observations suggest that the GH response to physiological stimulation is normal in prepubertal diabetic children. Exercise-induced GH response may not be mediated by GHRH. IGF-I levels were reduced in prepubertal children with IDDM and even more so in subjects with poor metabolic control. This may be a consequence of transitory hypoinsulineamia, emphasizing the importance of adequate insulinization to facilitate optimal growth in children and adolescents with IDDM.     

Hypercalciuria, hyperphosphaturia, and growth retardation in children with diabetes mellitus

The role of hypercalciuria and hyperphosphaturia in the growth retardation of children with diabetes mellitus was investigated in 157 children with diabetes whose mean height was less than that of 37 nondiabetic siblings of similar age (P less than .025). Hyperglycemia, hypercalciuria, and hyperphosphaturia were assessed coincident with the height measurement of each child in a cross-sectional survey. The distribution of height percentiles of the children with diabetes was skewed to the left with 61% at or below the 50th percentile. Eleven percent of the insulin-dependent children with diabetes mellitus were shorter than would be anticipated by a normal distribution of the 157 children. The duration of diabetes (hyperglycemia) had the greatest influence upon the children's height. Children with diabetes were shorter than the nondiabetic subjects by the fourth year of hyperglycemia, and this difference in height became statistically significant after 7 years or more of diabetes. The degree of hypercalciuria and hyperphosphaturia was more closely associated with reduced height in children with diabetes than was the degree of hyperglycemia, although the renal wastage of calcium and phosphorus seemed to be the result of glucosuria. Because hypercalciuria and hyperphosphaturia impair growth in nondiabetic children, they may also play an important role in the poor growth of children with diabetes mellitus.     

Transient incidental glucosuria in children

A consecutive series of 78 children with transient asymptomatic glucosuria was studied and followed up for up to 7.3 years. The age at presentation was 0.9–17.6 (median 4.6) years. One third of the patients had random blood glucose levels of >10.0 mmol/l (180 mg/dl). Five patients (6.4%) developed insulin-dependent diabetes mellitus within 2.1 years after the first incident of glucosuria. These patients presented with higher levels of glycaemia than others, and three out of five were positive for islet cell antibodies with a first-phase insulin response <46 mU/l in all four studied. Of the remaining 73 children, 3 were positive for islet cell antibodies and 12/55 had a first-phase insulin response under 46 mU/l. The insulin response deteriorated in 3 but reverted to normal in 7 patients.Conclusion For a child with transient glucosuria and with presence of islet cell antibodies and a subnormal first-phase insulin response, therapeutic attempts to prevent overt insulin-dependent diabetes mellitus should be considered.     

Transient focal neurologic deficits associated with hypoglycaemia in children with insulin-dependent diabetes mellitus

We describe 54 transient focal neurologic deficits (TFND) episodes in 44 children under 18 y observed retrospectively during a 5-y period (1991–96). Mean age and duration of insulin-dependent diabetes mellitus (IDDM) were 8.4 and 3.4 y, respectively. None of the children had a history of seizure disorder and only one had a personal history of migraine. Twenty-nine episodes were characterized by right- and 25 by left-sided hemiparesis. Three of six patients who presented more than one event had alternate episodes of right- and left-sided hemiparesis. On 8 occasions the episode was preceded by a brief convulsion, in 39 it was not witnessed, and in 7 it was certainly absent. Hypoglycaemia (<2.77 mmol/l) was documented on 26 occasions. On 18 of these 26 occasions, the episodes did not resolve promptly after sugar administration. The clinical course was benign, all patients remained neurologically normal and none developed migraine at follow up. Episodes of TFND were associated with hypoglycaemia in the majority of our cases and we do not consider invasive investigations to be mandatory, since the long-term prognosis was invariably good.     

Two cases of insulin-dependent diabetes mellitus under insulin treatment with slow height velocity: Relationship of growth hormone-binding protein,metabolic control and growth

Inadequate blood sugar control in children with insulin-dependent diabetes mellitus (IDDM) sometimes results in low insulin-like growth factor-I (IGF-I) and sluggish height growth. High affinity growth hormone-binding protein (GHBP), which is identical to the extracellular domain of growth hormone (GH) receptor, is present in the human sera. We have determined GHBP activity in two cases of poorly controlled IDDM with low height velocity in relation to metabolic control in order to determine the mechanism of resistance to GH in this condition, as indicated by low levels of GH-dependent growth factor IGF-I in the face of high serum GH levels. GHBP activity was within the normal range in two cases of IDDM with slow height velocity, low IGF-I and high hemoglobin-A₁. In both cases, improved blood sugar control normalized IGF-I to result in accelerated height velocity without a major change in GHBP levels. These results may indicate either normal peripheral GH receptor or normal free portion of serum GH, and may suggest that the major defect in slow growth in poorly controlled diabetes is due to the post GH receptor.     

Proteinuria in children with insulin-dependent diabetes: relationship to duration of disease, metabolic control, and retinal changes

The relationship of early retinal changes and subclinical proteinuria to duration and metabolic regulation of insulin-dependent diabetes was studied in 67 children. Retinopathy was found in 25 patients and occurred almost exclusively (96%) in those with duration of disease longer than five years. Glomerular filtration rate was normal or increased in all patients. Urinary excretion of beta 2-microglobulin, albumin, transferrin, and IgG was significantly increased in patients, as compared with controls, whereas serum concentrations of these proteins were generally normal. The mechanisms responsible for the hyperexcretion of both large and small proteins are unclear but probably involve both glomerular and tubular dysfunction. Increased urinary protein excretion occurred independently of duration of disease. Retinopathy but not microproteinuria was more common in patients with glycosylated hemoglobin greater than 11% and in those with duration of disease longer than five years. Although a significant association was found between retinopathy and the hyperexcretion of one or more of the large molecular weight proteins, the weight of the evidence suggests that these two sequelae of diabetes differ in their pathogenesis. Long-term follow-up of these patients may provide insight as to their risk of developing more serious retinopathy or nephropathy, and whether good glycemic control may protect against these complications of insulin-dependent diabetes.     

The nutrition of young diabetic patients

Objectives of management of insulin-dependent diabetes mellitus in pediatric patients include elimination of symptoms, achievement of normal growth and maintenance of blood glucose levels close to normal values. Nutritional management can contribute to achievement of these goals. In non-overweight children with diabetes mellitus, energy intake should not be restricted and distribution of nutrients should be identical to that recommended in normal children. Except in specific circumstances, reduced intake of pure, sweet-tasting carbohydrates is desirable. The central point is appropriate distribution of the main meals and snacks throughout the day. Food intake should occur at the times of peak insulin activity to avoid both hypoglycemia and postprandial hyperglycemia. Nutritional recommendations for the child and family should be part of the general guidelines for healthy eating appropriate for all individuals. Nutrition education, as well as education on use of insulin, are components of a program aimed at providing the patient with knowledge and know-how. Correction of eating mistakes and optimal adjustment of insulin dosages are the two main aspects of daily therapy.     

Tubular dysfunction and microalbuminuria in insulin dependent diabetes.

The nature of microproteinuria in the early years of insulin-dependent diabetes was investigated in a cross sectional study of 80 children with insulin-dependent diabetes and 40 normal children. Urinary excretion of three low molecular weight proteins: alpha-1-microglobulin, beta-2-microglobulin and kappa light chains was used as an index of proximal renal tubular function. The first urine samples of the morning were collected and excretion of proteins measured was expressed as ratio of protein to creatinine. There was a strong correlation between excretion of alpha-1-microglobulin and chi light chains and their excretion was significantly higher in diabetic children indicating decreased proximal tubular reabsorbtion. The excretion of beta-2-microglobulin was found to be an unsatisfactory index of proximal tubular function. Urinary albumin excretion was not significantly raised in diabetic children and did not correlate with urinary alpha-1-microglobulin or chi light chain excretion. Glycaemic control might influence proximal tubular function as both urinary glucose concentration and glycosylated haemoglobin showed correlations with urinary alpha-1-microglobulin excretion and with urinary chi light chain excretion.     

The incidence of diabetes mellitus in Swedish children 0-14 years of age. A prospective study 1977-1980

This is a prospective study of the incidence of insulin-dependent diabetes mellitus (IDDM) in children 0-14 years of age, including all newly diagnosed cases in the whole of Sweden from July 1, 1977 until June 30, 1980. All 45 Swedish departments of paediatrics participated. During the three-year-period studied, 1108 Swedish children, 0-14 years of age had their onset of diabetes. That means around 369 new diabetics yearly in the age groups studied. The mean yearly incidences in the years 1977-80 were 22.6, 22.8 and 22.6 per 100000 children, respectively. Mean prevalence on June 30, 1980 and 1.48 per 1000 children 0-14 years with a wide range of 0.71-2.65. The age distribution at onset showed a gradual increase and peak incidences at 11 years of age for the girls and 4 and 13 years of age for the boys. There was a consistently higher incidence for boys in the younger age groups during the three-year-period studied. Peak incidences of new cases were reached in January, March and July through October for the age groups 5-9 and 10-14 years of age. No such seasonal variation was seen for children 0-4 years of age. The cumulative incidence of IDDM at 14 years of age was 3.2 per 1000 for the boys and 2.9 per 1000 for the girls. The degree of ascertainment in this study was 93.4%.     

Epidemilogy of Insulin-Dependent Diabetes Mellitus in Korea

The prevalence of diabetes mellitus in the age group5–16 years, determined from 13,152 subjects residing in Kwangju, Chonnam Provice was 0.099 per cent or 98.9/100,000 in a study performed from December, 1976 to June 1977. On the other hand an epidemiologic study carried out on 254,835 subjects in the age groups14–15 and17–18 years from March 1981 to March 1982 in Seoul City revealed on overall prevalence of 7.85/100,000. In a retrospective study, 88.0/100,000 or out of a total of 10,228 pediatric inpatients were confirmed casesw of insulin-dependent diabetes mellitus, during 7 years and 2 months (from january 1974 to March 1981) at a general hospital located in Jeonju City. The wide range in the prevalence and incidence figures of diabetes mellitus in Korean children probably resulted from lack of uniformity in epidemiological methodology and the degree of ascertainment. The adge distribution at onset of diabetes mellitus showed a gradual incdrease and peak incidences at 3,8 and 12 years of age. The4 sex difference in incidence was not obvious, though girls slightly outnumbered boys. Seasonal variation at onset of diabetes mellitus showed the highest frequency of new cases in winter and spring months.     

Increased height in diabetes mellitus corresponds to the predicted and the adult height

This study was conducted to analyse the effect of childhood-onset diabetes mellitus on adult height. The height at time of diagnosis of 35 children with insulin-dependent diabetes mellitus (IDDM) was compared with growth reference data. Predictions of the adult height were made at the time of diagnosis using the target height and the Tanner-Whitehouse II method. The adult height was compared with both the predicted values and the height of healthy adults. The height at time of diagnosis of the prepubertal children was increased compared with growth reference data, in contrast to pubertal children who had normal heights. Only the prepubertal boys were taller at time of diagnosis. The adult height of the prepubertal patients was taller than growth reference data. The mean adult height in all patients did not differ significantly from the predicted heights. In conclusion, the increased height at the start of IDDM in prepubertal children persists until adulthood.