Experience of severe hypoglycaemia may influence both patient's and physician's subsequent treatment policy of insulin-dependent diabetes mellitus

Daily insulin doses and HbA1_c were studied 0–3 months before and 2–6, 7–11, and 12–16 months after 48 consecutive episodes of severe hypoglycaemia (coma and/or convulsion) in children and adolescents with insulin-dependent diabetes mellitus. After 69% of the attacks, either physicians or patients or both decreased daily insulin doses (for the whole group, mean ± SD: 0–3 months before the episode 0.93 ± 0.20 U/kg vs 2–6 months after 0.84 ± 0.20 U/kg, P < 0.001), which may have worsened the subsequent glycaemic control as evidenced by a significant increase in HbA1_c (8.3 ± 1.5% vs 9.1 ± 1.8%, P<0.001, respectively). Physicians decreased the insulin dose even in 14 of the 33 patients with a preventable cause for their hypoglycaemia other than erroneous excess of insulin. Conclusion Experience of severe hypoglycaemia may worsen the subsequent glycaemic control. This might in part be due to an excessive lowering of daily insulin doses by both physicians as well as patients and their families. Hypoglycaemia management must include intensive education about prevention without compromising diabetes control. Received: 30 September 1997 / Accepted in revised form: 13 February 1998     

Association between diabetes,severe hypoglycaemia,and electroencephalographic abnormalities.

Serial electroencephalographic recordings were made in 70 diabetic children and findings were related to age at electroencephalography and at diagnosis, duration of diabetes, daily insulin dose, long term metabolic control assessed by glycated haemoglobin A1 (HbA1) concentrations, and severe hypoglycaemic episodes. Abnormalities were found in 18 (26%) of diabetic children, and in only five (7%) of control subjects. There were no associations between electroencephalographic abnormalities and duration of diabetes, daily insulin dose, or HbA1 concentration. Diabetic children with electroencephalographic abnormalities were younger, had an earlier onset of diabetes and 21/34 (62%) of them had previously severe attacks of hypoglycaemia, whereas abnormalities were found in only 13/43 (30%) of diabetic children who had not had severe hypoglycaemia. All diabetic children with hypoglycaemic convulsions had permanent electroencephalographic abnormalities. The degree of metabolic control had no effect on the electroencephalographic findings during the early years of diabetes, but previous severe hypoglycaemia, young age, and early onset seem to be important risk factors for electroencephalographic abnormalities.     

Changes in attention with hypo- and hyperglycaemia in children with insulin dependent diabetes mellitus

We compared the results of a computerized attention test (TOVA) in 38 children with insulin dependent diabetes mellitus in relation to various spontaneously occurring blood glucose levels. Testing was performed at the following blood glucose levels: <3.3 mmol/l (hypoglycaemia), 3.3–8.3 mmol/l (normoglycaemia) and >8.3 mmol/l (hyperglycaemia) . The attention (sum of errors and response time) varied significantly with the blood glucose level (P=0.002). The highest number of errors of omission and the longest response time was observed during the test run with hypoglycaemia. Age, sex, age at manifestation of the disease, metabolic control and the results of the intelligence test had no significant influence on these results. We found that attention in children with diabetes was significantly reduced compared to TOVA norms especially during mild hypoglycaemia (P<0.001). Irrespective of the blood glucose levels, reaction time and the variability of the reaction time differed significantly between TOVA norms and diabetic children (P<0.01). Conclusion In children with diabetes mellitus a significant reduction in attention was found at mild hypoglycaemia but as well at low normal blood glucose levels. Attention deficits due to transient lowering of blood glucose may therefore occur in diabetic children even before they are aware of hypoglycaemic symptoms. Received: 24 November 1997 / Accepted: 2 March 1998     

Echocardiographic load-independent indices of contractility in children and adolescents with type I diabetes: Effect of metabolic control and insulin on left ventricular performance

A case-control study was carried out in a tertiary referral teaching hospital to evaluate left ventricular contractility in children and adolescents with type 1 diabetes and to study factors influencing left ventricular contractility. Thirty-four children and young adults with type 1 diabetes (age 10.8–21.8 years) were randomly selected from approximately 400 patients of the same age range in the outpatient department and compared with 16 nondiabetic controls (age 7.3–21.2 years). The relation of end-systolic wall stress to velocity of circumferential fiber shortening as a standard deviation score (SDS) from the normal range described by Colan et al. was used to assess left ventricular contractility. In the diabetic group the effect of age, duration of diabetes, metabolic control, insulin dose, and autonomic function on left ventricular contractility were studied. It was found that the end-systolic wall stress-velocity of circumferential fiber shortening relation was not different between diabetic subjects and controls [+0.52 (SEM 0.21) vs +0.90 (SEM 0.26) SDS,p=0.3]. In the diabetic subjects, the end-systolic wall stress-velocity of circumferential fiber shortening relation was positively correlated with glycated hemoglobin (r=0.37,p=0.03) and insulin dose per kilogram of body weight (r=0.36,p=0.04). Those two variables together explained 24% of the variability in the end-systolic wall stress-velocity of circumferential fiber shortening relation. Twenty-eight of the diabetic subjects were also assessed for cardiac autonomic function. Disturbances of cardiac autonomic function were not associated with increased contractility. It is concluded that left ventricular contractility assessed by load-independent echocardiographic indices was not different between children and adolescents with type 1 diabetes and controls. However, increased contractility was positively related to unfavorable metabolic control and higher insulin dose.     

Severe hypoglycaemia,metabolic control and diabetes management in children with type 1 diabetes in the decade after the Diabetes Control and Complications Trial – a large-scale multicentre study

Hypoglycaemia is frequently the limiting factor in achieving optimal glycaemic control. Therefore, insulin therapy, the incidence of hypoglycaemia, and glycaemic control were investigated in 6309 unselected children with type 1 diabetes in a large-scale multicentre study. Using standardised computer-based documentation, the incidence of severe hypoglycaemia, HbA1 _c levels, insulin regimen, diabetes duration, and the number of patients attending a treatment centre were investigated for the age groups 0-<5 years ( n =782), 5-<7 years ( n =1053), and 7-<9 years ( n =4474). The average HbA1 _c level was 7.6% (no significant difference between age groups). Young children had more severe hypoglycaemic events (31.2/100 patient years) as compared to older children (19.7; 21.7/100 patient years, P <0.05) independent of the treatment regimen. Our data suggest that diabetes centres treating less than 50 patients per year have a higher incidence of hypoglycaemia in 0-<5-year-old children (43.0/100 patient years) as compared to larger centres (24.1/100 patient years; P <0.0001). Significant predictors of hypoglycaemia were younger age ( P <0.0001), longer diabetes duration ( P <0.0001), higher insulin dose/kg per day ( P <0.0001), injection regimen ( P <0.0005), and centre experience ( P <0.05). Conclusion:Despite modern treatment, young children have an elevated risk for developing severe hypoglycaemia compared to older children, especially when treated at smaller diabetes centres. The therapeutic goal of carefully regulating metabolic control without developing hypoglycaemia has still not been achieved. Further advances in diabetic treatment may result from giving more attention to hypoglycaemia in young children.On behalf of the German Initiative on Quality Control in Paediatric Diabetology.     

Rapid appearance and onset of action of insulin aspart in paediatric subjects with type 1 diabetes

The pharmacokinetics of the novel, rapid-acting insulin aspart were compared with those of soluble human insulin following subcutaneous administration in nine children (aged 6–12 years) and nine adolescents (aged 13–17 years) with stable type 1 diabetes. The study had a randomised, double-blind, two-period crossover design. Each patient received a single subcutaneous dose of insulin aspart or human insulin (0.15 IU/kg body weight) 5 min before breakfast and the plasma insulin and glucose concentrations were measured at intervals during the following 5 h. The pharmacokinetic profile of insulin aspart differed significantly from that of human insulin with a higher mean maximum serum insulin (C_{max ins}), 881 ± 321 (SD) pmol/l versus 422 ± 193 pmol/l for human insulin (P < 0.001); and with a shorter median serum insulin t _{max ins}, 40.0 min (interquartile range: 40–50 min) versus 75.0 min (interquartile range: 60–120 min) for human insulin, (P < 0.001). An age-related effect on C_{max ins} and area under the curve (AUC_{0–5h ins}) was observed with higher values in adolescents than in children for both insulin aspart and human insulin. Postprandial glycaemic control was improved with insulin aspart; the baseline-adjusted ΔC_{max glu} being lower for insulin aspart compared with human insulin (increase of 7.6 ± 5.1 versus 9.4 ± 4.4 mmol/l respectively, P < 0.05). The incidence of adverse events was similar for the two insulin types. Conclusion The more rapid onset of action of insulin aspart versus human insulin, previously observed in adults, is confirmed in a paediatric population with type 1 diabetes. Received: 30 June 1999 and in revised form: 20 September 1999 and 23 November 1999 /Accepted: 9 December 1999     

Severe hypoglycaemia and cardiovascular autonomic dysfunction in type I diabetic children treated with intensified conventional insulin therapy.

To assess the relationship between severe hypoglycaemias and autonomic dysfunction, five cardiovascular tests (resting heart rate, hyperventilatory arrhythmia, standing/lying heart rate ratio, orthostatic decrease in blood pressure, and increase in blood pressure during sustained handgrip) were performed in a 1-yr prospective study of 34 insulin-dependent diabetic children treated with intensified conventional insulin therapy (ICIT). There were twelve severe episodes in 7 diabetic children, and the remaining 27 patients had no severe hypoglycaemia. The hypoglycaemic group had a longer duration of diabetes than the nonhypoglycaemic group (5.4 SD 2.5 years vs. 2.8 SD 2.2 years, p less than 0.02). The hyperventilatory arrhythmia in the hypoglycaemic group in comparison with the nonhypoglycaemic group was significantly decreased (before ICIT: 16.1 SD 3/min vs. 24.4 SD 5/min, p less than 0.01; 1 yr thereafter: 17.3 SD 3/min vs. 26.0 SD 5/min, p less than 0.01). The hypoglycaemic group showed a pronounced orthostatic decrease in blood pressure compared to the nonhypoglycaemic group (before ICIT: 13.2 SD 4 mmHg vs. 6.0 SD 4 mmHg, p less than 0.01; 1 yr thereafter: 12.3 SD 4 mmHg vs. 5.6 SD 4 mmHg, p less than 0.01). Three or more abnormal cardiovascular test results were found in patients of the hypoglycaemic group who showed abnormal hyperventilatory arrhythmia and abnormal orthostatic decrease in blood pressure simultaneously, whereas such a coexistence was not found in the nonhypoglycaemic group. These observations may support the view that diabetic children and adolescents with autonomic dysfunction are susceptible to severe hypoglycaemia during ICIT.     

Early atherosclerosis in childhood type 1 diabetes: role of raised systolic blood pressure in the absence of dyslipidaemia

The intentions of our investigation were (1) to search for atherogenic risk factors and signs of incipient atherosclerosis in children and adolescents with type 1 diabetes (T1DM) in comparison to well-matched control subjects, (2) to evaluate risk factor associations with carotid intima media thickness (cIMT) in diabetic patients and control subjects, and (3) to acquire a better knowledge of early atherogenesis in children and adolescents with and without T1DM. 94 diabetic children (age median 12.3 years, HbA_1c median 7.7%) and 40 non-diabetic controls (age median 12.3 years) were investigated. Mean cIMT was determined using high-resolution B-mode ultrasound with an automated contour identification procedure. Compared to controls, subjects with diabetes had significantly elevated cIMT (p = 0.041) and systolic BP (p = 0.007) but showed a less atherogenic lipid profile. Most markers of inflammation, endothelial function and fibrinolytic activity were higher in diabetic subjects than in controls. Multiple linear regression analysis revealed a significant relationship (r = 0.53, p = 0.036) between bilateral mean cIMT and diverse risk factors in patients with T1DM. Spearman rank correlation showed that diabetes duration (rho = 0.32, p = 0.029), systolic BP (rho = 0.32, p = 0.004), weight (rho = 0.257, p = 0.022), and height (rho = 0.265, p = 0.018) significantly correlated with bilateral mean cIMT in the 94 diabetic patients. In conclusion, in well-controlled type 1 diabetic children systolic BP may be of greater importance than dyslipidaemia in early atherogenesis. BMI, markers of sustained inflammation, endothelial dysfunction and fibrinolytic activity are increased in diabetic versus non-diabetic children but none of them correlates significantly with cIMT. Their prognostic value remains to be determined.     

Nocturnal hypoglycaemia and sleep disturbances in young teenagers with insulin dependent diabetes mellitus

OBJECTIVE: To determine the effect of nocturnal hypoglycaemia on sleep architecture in adolescents with insulin dependent diabetes mellitus (IDDM). DESIGN: 20 adolescents with IDDM (mean age 12.8 years, mean glycated haemoglobin (HbA1c) 8.9%) were studied on one night. Plasma glucose was measured every 30 minutes and cortisol and growth hormone levels every 60 minutes. Sleep was recorded using standard polysomnographic montages, and sleep architecture was analysed for total sleep time, stages 1-4, rapid eye movement, fragmentation, and arousals. RESULTS: Six subjects (30%) became hypoglycaemic (five subjects < 2.5 mmol/l), with one being symptomatic. There were no differences in age, HbA1c, duration of diabetes, or insulin regimen between hypoglycaemic and non-hypoglycaemic subjects. Hypoglycaemia was not predicted by glucose measurements before bed. There was no detectable rise in plasma cortisol or growth hormone concentrations during hypoglycaemia. Sleep architecture was not disturbed by nocturnal hypoglycaemia with no differences found in sleep stages, fragmentation, or arousals. CONCLUSIONS: Nocturnal hypoglycaemia is a common and usually asymptomatic complication of treatment in adolescents with IDDM. Moderate hypoglycaemia has not been shown to affect sleep architecture adversely. These findings are consistent with, and may explain, the observation that severe hypoglycaemia, with consequent seizure activity, is more common at night than during the day. Counterregulatory hormone responses to nocturnal hypoglycaemia may be less marked than with similar degrees of diurnal hypoglycaemia.     

Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes

OBJECTIVES—To examine the frequency of nocturnal hypoglycaemia, and the effects on cognitive function and mood, in children with insulin dependent diabetes mellitus (IDDM).DESIGN—Two overnight glucose profiles, in the home environment, and assessments of cognitive function and mood the following day. Twenty nine prepubertal patients with IDDM (median age, 9.4 years; range, 5.3-12.9) and 15 healthy controls (single overnight profile), median age 9.5 (range, 5.6-12.1) years were studied.RESULTS—Asymptomatic hypoglycaemia (glucose < 3.5 mmol/l) was observed in 13 of 29 patients studied on night 1: four of these and seven others were hypoglycaemic on night 2. The median glucose nadir was 1.9 (range, 1.1-3.3) mmol/l and the median duration of hypoglycaemia was 270 (range, 30-630) minutes. Hypoglycaemia was related to insulin dose, but not glycosylated haemoglobin (HbA1c) values, and was partially predicted by a midnight glucose of < 7.2 mmol/l. Cognitive performance was not altered after hypoglycaemia but a lowering of mood was observed.CONCLUSIONS—Young children on conventional insulin regimens are at high risk for profound, asymptomatic nocturnal hypoglycaemia, which is difficult to predict. There was no short term effect on cognitive function but mood change was detected.     

Delayed menarche in young German women with type 1 diabetes mellitus: recent results from the DPV diabetes documentation and quality management system

Background  Findings have been inconsistent regarding the effect of T1DM (type 1 diabetes) on age at menarche. Objective  The purpose was to investigate in young German women with T1DM menarcheal age and factors potentially affecting menarche, including glycemic control, BMI (body mass index), relative T1DM duration (proportion of life with diabetes), insulin dose, and insulin therapy intensity. Initiated in 1990, the DPV program is an ongoing, prospective long-term longitudinal follow-up study to benchmark the quality of care provided to pediatric and, more recently, adult diabetes patients. Two hundered two German diabetes centers participated in nationwide data collection. Based on ethnicity and the availability of menarche and T1DM onset data as the main inclusion criteria, 643 young German women were selected from 11,629 female T1DM patients aged <20 years, recruited by referral, clinic or hospital ascertainment, or self report. Mean age at menarche (±SD) was 13.22 ± 1.31 years, representing a delay of 0.52 years (p < 0.001) relative to the general population. Significant delay (p < 0.05) was also found for relative T1DM duration, BMI SD score, insulin dose, and HbA1c level, with a 1% increase in HbA1c resulting in a delay in menarche by 0.07 years. Conclusions  Age at menarche is delayed in type 1 diabetes mellitus. The delay increases with relative T1DM duration and poor quality of glycemic control.     

Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus

Increased emphasis on strict glycaemic control of insulin dependent diabetes mellitus (IDDM) in young patients may be expected to cause increases in rates of significant hypoglycaemia. To evaluate whether this is the case for a large population based sample of IDDM children and adolescents rates of severe (coma, convulsion) and moderate (requiring assistance for treatment) hypoglycaemia were studied prospectively over a four year period.
A total of 709 patients were studied yielding 2027 patient years of data (mean (SD) age: 12.3 (4.4); range 0-18 years, duration IDDM: 4.9 (3.8) years). Details of hypoglycaemia were recorded at clinic visits every three months when glycated haemoglobin (HbA1_c) was also measured.
Overall the incidence of severe hypoglycaemia was 7.8 and moderate was 15.4 episodes/100 patient years. Over the four years mean (SD) clinic HbA1_c steadily fell from 10.2 (1.6)% in 1992to 8.8 (1.5)% in 1995. In parallel with this there was a dramatic increase in the rate of hypoglycaemia, especially in the fourth year of the study, when severe hypoglycaemia increased from 4.8to 15.6 episodes/100 patient years. This increase was particularly marked in younger children (<6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient years in 1995.
It is concluded that attempts to achieve improved metabolic control must be accompanied by efforts to minimise the effects of significant hypoglycaemia, particularly in the younger age group.

     

Autoimmune thyroid disease in Libyan children and young adults with type 1 diabetes mellitus

Diabetes mellitus is a common autoimmune endocrine disorder associated with organ-specific autoantibodies which are frequently detected at the time of diagnosis. Some of these antibodies are specific to the pancreas (GAD, IA2, ICA) while others are related to different autoimmune diseases. Aim of the study: To define the prevalence of thyroid autoimmune disease in Libyan patients with type 1 diabetes mellitus (T1DM) since no similar studies have been performed in Libya. Materials and methods: Blood samples were collected from 218 patients with T1DM who are followed by the Pediatric Department, Tripoli Medical Center, Libya. All sera were analyzed in Italy (Laboratory of Immunopathology and Allergy, Udine). The patients were composed of 123 females (56.4%) and 95 males (43.6%), mean age 12.2 ± 4.6 years (range 2.1–24.5 years), mean duration of diabetes 4.7 ± 4.0 years (range 0.1–17.5 years). Sera were tested for anti-thyroperoxidase (TPO) and anti-thyroglobulin antibodies (TG). TSH and FT4 concentrations were measured in all subjects. GAD, IA-2 was also measured. Results: Of the diabetic children, 23.4% were positive for anti-microsomal peroxidase antibodies (TPO-Ab) and 7.8% for antithyroglobulin antibodies (TG-Ab); whereas 6.9% of the patients were positive for both TPO-Ab and TG-Ab. Of the T1DM patients who were positive for TPO-Ab, 66.6% were females. The majority (57%) of the patients who were positive for TPO had diabetes for longer than 5 years. Five patients (2.3%) had evidence of subclinical hypothyroidism whereas two patients (0.9%) had overt hypothyroidism. Two patients had subclinical hyperthyroidism and two (0.9%) had overt hyperthyroidism. Interestingly, 16.2% of patients were positive for both thyroid and pancreatic antibodies. Conclusions: The prevalence of autoimmune thyroid disease in type 1 diabetic patients is higher than in the general population. A routine screening strategy should be implemented with the determination of anti-thyroid antibodies and TSH in type 1 diabetic patients, particularly in girls, and in patients with diabetes of more than 5 years duration. Patients who have positive TPO antibodies may need the assessment of thyroid function at shorter intervals.     

Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes.

OBJECTIVES: To examine the frequency of nocturnal hypoglycaemia, and the effects on cognitive function and mood, in children with insulin dependent diabetes mellitus (IDDM). DESIGN: Two overnight glucose profiles, in the home environment, and assessments of cognitive function and mood the following day. Twenty nine prepubertal patients with IDDM (median age, 9.4 years; range, 5.3-12.9) and 15 healthy controls (single overnight profile), median age 9.5 (range, 5.6-12.1) years were studied. RESULTS: Asymptomatic hypoglycaemia (glucose < 3.5 mmol/l) was observed in 13 of 29 patients studied on night 1: four of these and seven others were hypoglycaemic on night 2. The median glucose nadir was 1.9 (range, 1.1-3.3) mmol/l and the median duration of hypoglycaemia was 270 (range, 30-630) minutes. Hypoglycaemia was related to insulin dose, but not glycosylated haemoglobin (HbA1c) values, and was partially predicted by a midnight glucose of < 7.2 mmol/l. Cognitive performance was not altered after hypoglycaemia but a lowering of mood was observed. CONCLUSIONS: Young children on conventional insulin regimens are at high risk for profound, asymptomatic nocturnal hypoglycaemia, which is difficult to predict. There was no short term effect on cognitive function but mood change was detected.     

Does the long-term clinical course of type I diabetes mellitus differ in patients with prepubertal and pubertal onset? Results of the Berlin Retinopathy Study

The objective of the present study was to investigate potential differences at presentation of type I diabetes and during its long-term clinical course in children and adolescents with prepubertal and pubertal manifestation. Clinical, immunological and biochemical characteristics at diabetes onset of 453 patients (320 prepubertal, 133 pubertal; median age at manifestation 7.1 years (0.7–13.9) and 13.1 years (9.2–17.6), respectively) were evaluated. Glycaemic control and exogenous insulin requirements were followed prospectively, with a median follow up of 9.4 years. At the onset of the disease no differences concerning the degree of metabolic decompensation, impairment of somatic health, and islet cell antibody status could be detected between the groups, except for a smaller body weight loss in pubertal patients (P=0.011). The duration of partial remission (insulin requirements <0.5 IU/kg body weight/day) was unrelated to age or pubertal status at onset. It was found to be longer in boys than in girls in the total cohort (median duration: 279 vs 215 days, P=0.0071). Despite an absence of differences during the early course of the disease, glycaemic control was better, and daily insulin doses were significantly lower in patients with pubertal onset, after 6 years of diabetes. Conclusion Adolescents with a pubertal onset of type I diabetes have a more benign long-term course of the disease demonstrating better glycaemic control and lower insulin requirements, although the presentation of the disease at onset and its course during the first 6 years are not different from those of children with a prepubertal manifestation of diabetes. Received: 7 October 1996/Accepted in revised form: 12 August 1997     

Serum IgG levels to bovine insulin in type I diabetes mellitus

Objectives: This study was undertaken to determine humoral immune response to bovine insulin in Iranian children with type 1 diabetes mellitus.Methods: Serum samples were taken from 93 children aged 4–17 years with type I diabetes mellitus from two centers in Iran (the Iranian Association of Diabetes in Tehran and Center for Diabetes Research in Hamedan), 17 apparently healthy siblings of the diabetic patients (related controls), 28 apparently healthy age- and sex-matched controls (unrelated controls), 14 patients aged 11–15 years with auto-immune thyroiditis, and 45 patients with type II diabetes (aged 44–68 years). Samples were then examined for specific IgG to bovine insulin by enzyme-linked immunosorbent assay (ELISA). A questionnaire on medical history, duration of exclusive and non-exclusive breast feeding and daily intake of dairy products was completed before bleeding.Results: Duration of exclusive and non-exclusive breast-feeding showed no significant difference between patients with type I diabetes, related and unrelated controls and thyroid patients. Diabetic children, however, had significantly higher serum levels of anti-bovine insulin IgG than did unrelated and related healthy controls and patients with type II diabetes (P < 0.01). There was no significant difference between healthy siblings of diabetic children and unrelated controls. In type I diabetic patients and their healthy siblings, serum levels of IgG to bovine insulin were inversely correlated with the duration of non-exclusive breast feeding (r_s= -0.37, P= 0.016 and r_s -0.53, P= 0.049, respectively). There was no con-elation between serum levels of IgG to bovine insulin with daily intake of dairy products. Bovine insulin cross-reacted with human insulin as judged by ELISA inhibition assay.Conclusion: The emergence of anti-insulin antibodies in Iranian patients with type I DM, which is associated with the duration of breast-feeding is less likely to be due to early exposure of infants with the proteins found in cow’s milk. One speculation could be that the production of antibodies to insulin in type I diabetes may just be a physiologic response (probably to increase the half-life of the circulating insulin). The importance of anti-insulin antibodies in type I diabetes mellitus needs further studies.     

Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria

Primary persistent hyperinsulinaemic hypoglycaemia of infancy is rare. Diazoxide treatment remains the mainstay of medical therapy in long-term management. We reviewed 77 cases of primary persistent hyperinsulinism in neonates and infants who were treated with diazoxide and studied criteria predictive of therapeutic efficacy. The only criterion identified was age at manifestation. All but 1 of the 31 neonatal cases were unresponsive to diazoxide. Responsiveness increased with age: 12 of 39 early-infantile cases, and all seven late-infantile cases were diazoxide-responsive. In responders, a diazoxide dose of 10–15 mg/kg per day was always effective, suggesting an “all or none” response. Diazoxide-resistant hyperinsulinism is characterized by its severity with higher plasma insulin levels. The analysis of 46 surgically treated patients showed that the efficacy of diazoxide is not related to the aetiology of the pancreatic lesions. In six cases, after many years of management, diazoxide treatment was stopped without recurrence of hypoglycaemia. Conclusion Diazoxide is an efficient treatment in the long-term management of most persistent hyperinsulinaemic hypoglycaemia of infancy revealed in infants and children but is usually ineffective in neonatal forms. Drug efficacy does not correlate with anatomical lesions. Medical treatment can sometimes be stopped after many years of management without recurrence of disease manifestations. Received: 29 April 1997 / Accepted: 9 February 1998     

Cognitive function in Type 1 diabetic children with and without episodes of severe hypoglycaemia

We assessed the effect of diabetes and of episodes of severe hypoglycaemia on cognitive function in 28 diabetic children. Fifteen diabetic children (age 12.9 (SD 2.0) years) had experienced 1–4 episodes of severe hypoglycaemia. Five of these children diseased before the age of 5 years (SH-eod subgroup), and ten diseased after this age (SH-lod subgroup). Thirteen diabetic children (age 13.1 (SD 2.0) years) had not experienced episodes of severe hypoglycaemia (non-SH group). Each diabetic child was compared with a healthy control child of the same age and gender and with a similar social background. Neuropsychological assessment was blinded. The neuropsychological tests were grouped into one of seven cognitive domains. We found no effect on cognitive performance from diabetes per se or from severe hypoglycaemia in children with late-onset diabetes. However, early-onset diabetes was associated with low scores in two cognitive domains: psychomotor efficiency and attention. The SH-eod subgroup had lower scores than the SH-lod subgroup in psychomotor efficiency ( p < 0.05) and also had lower scores than the SH-lod subgroup and the non-SH group in measures of attention ( p < 0.05). Our results may indicate a slight cognitive dysfunction in children with early-onset diabetes who have experienced episodes of severe hypoglycaemia early in childhood.     

Risk factors for type I diabetes mellitus in children in Austria

The aim of this study was to investigate environmental risk factors in the development of type 1 diabetes mellitus in a population-based case-control study. Parents of all patients with manifestation of type 1 diabetes between 1989 and 1994 in Vienna were asked to complete a questionnaire (n = 114). Control children (n = 495), matched for age and sex, were randomly recruited from all schools in Vienna. Fathers of diabetic children were significantly older at the time their children were born than fathers of control children (P = 0.015). Children with diabetes were more likely to be second- or third-born children (P < 0.05) and fewer went to kindergarten than the control group children (P = 0.007). No significant difference in duration of gestation, percentage of delivery by caesarean section, birth weight or length was found. Neonatal jaundice was more often observed in the patient group (P = 0.038). Breast feeding was reported by 82.7% of mothers of diabetic children and by 81% of mothers of control children, and the duration of breast feeding was longer in patients than in controls (n.s.). Conclusion In our study, the development of type 1 diabetes mellitus was associated with higher paternal age and neonatal jaundice. No correlation could be found with dietary intake of cow's milk products in early infancy, vaccination and other environmental factors. Received: 5 May 1998 / Accepted in revised form: 27 August 1998     

Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus

Increased emphasis on strict glycaemic control of insulin dependent diabetes mellitus (IDDM) in young patients may be expected to cause increases in rates of significant hypoglycaemia. To evaluate whether this is the case for a large population based sample of IDDM children and adolescents rates of severe (coma, convulsion) and moderate (requiring assistance for treatment) hypoglycaemia were studied prospectively over a four year period. A total of 709 patients were studied yielding 2027 patient years of data (mean (SD) age: 12.3 (4.4); range 0-18 years, duration IDDM: 4.9 (3.8) years). Details of hypoglycaemia were recorded at clinic visits every three months when glycated haemoglobin (HbA1c) was also measured. Overall the incidence of severe hypoglycaemia was 7.8 and moderate was 15.4 episodes/100 patient years. Over the four years mean (SD) clinic HbA1c steadily fell from 10.2 (1.6)% in 1992 to 8.8 (1.5)% in 1995. In parallel with this there was a dramatic increase in the rate of hypoglycaemia, especially in the fourth year of the study, when severe hypoglycaemia increased from 4.8 to 15.6 episodes/100 patient years. This increase was particularly marked in younger children (< 6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient years in 1995. It is concluded that attempts to achieve improved metabolic control must be accompanied by efforts to minimise the effects of significant hypoglycaemia, particularly in the younger age group.