E. Bognetti

Persistent Renal Hypertrophy and Faster Decline of Glomerular Filtration Rate Precede the Development of Microalbuminuria in Type 1 Diabetes

Soon after the onset of type 1 diabetes, renal hypertrophy and hyperfiltration become manifest, particularly among patients who will subsequently develop diabetic nephropathy. Whether these early renal dysfunctions are involved in the pathogenesis of diabetic nephropathy is currently unclear. We evaluated, during the same day, kidney volume and glomerular filtration rate (GFR) in 146 patients with type 1 diabetes and normal renal function. All the individuals were then monitored for a mean of 9.5 ± 4.4 years for the development of microalbuminuria. Kidney volume and GFR were reevaluated in a subset of 68 patients 4 years after baseline. During follow-up, microalbuminuria developed in 27 of 146 diabetic patients. At baseline, kidney volume (312.8 ± 52.6 vs. 281.4 ± 46.1 vs. 236.8 ± 41.6 ml/1.73 m2, P < 0.05) but not GFR was increased in patients predisposed to microalbuminuria. Risk of progression was higher in patients with increased kidney volume (P = 0.0058). Patients predisposed to microalbuminuria showed a stable increase in kidney volume (P = 0.003), along with a faster decline of GFR (P = 0.01). Persistent renal hypertrophy and faster decline of GFR precede the development of microalbuminuria in type 1 diabetes. These findings support the hypothesis that renal hypertrophy precedes hyperfiltration during the development of diabetic nephropathy.

Parameters associated with residual insulin secretion during the first year of disease in children and adolescents with Type 1 diabetes mellitus.

Factors associated with residual insulin secretion and spontaneous remission in Type 1 diabetic patients are important in the evaluation of treatment aimed at modifying the natural history of Type 1 DM. We investigated the effect of parameters at onset on residual beta cell function in 215 Type 1 DM children and adolescents. Blood gas analysis, HLA, GAD and IA‐2 antibodies before the start of insulin treatment were recorded for each patient. Residual C‐peptide secretion was assessed by the glucagon test, and parameters of metabolic control (HbA1c and insulin dose U kg−1 day−1) were examined at disease onset and after 3, 6, and 12 months. Residual C‐peptide secretion throughout the first year of disease was significantly reduced in patients with disease onset before age 5. Multiple regression analysis showed that low pH at onset showed a significant and independent association with reduced C‐peptide at 3 months (p = 0.02) and that the detection of GAD antibodies had a significant independent association with decreased C‐peptide secretion at 6 months of follow‐up (p = 0.02). Insulin requirement was higher in the youngest patients group and in patients with GAD antibodies. Spontaneous insulin remission (HbA1c <6 % and insulin <0.3 U kg−1 day−1) occurred in 22/192 (11 %) patients at 3 months of follow‐up, in 15/190 (8 %) patients at 6 months and in 8/169 (5 %) patient at 12 months. Remission was more prevalent in older patients (p = 0.01) and in patients without detectable GAD antibodies: (14/64 vs 8/128, p = 0.001). Sex, IA‐2 antibodies and HLA DR were not independently associated with C‐peptide secretion, insulin requirement or remission in the first year of Type 1 DM. This study confirms the association of young age, severe acidosis at disease onset, and GAD antibodies with decreased residual beta‐cell function and spontaneous remission during the first year of insulin treatment. These factors should be considered in trials evaluating therapies to retain beta‐cell function and induce remission at and after disease onset.

Growth Changes in Children and Adolescents With Short-Term Diabetes

OBJECTIVE Height and weight changes during the first 3 years of diabetes were prospectively followed in 152 diabetic children and adolescents. RESEARCH DESIGN AND METHODS The study sample consisted of 152 Caucasian diabetic patients (84 boys; 68 girls) followed from diabetes onset in the Paediatric Diabetes Unit and 80 Caucasian normal subjects (49 boys; 31 girls) assessed in the Outpatient General Paediatric Clinic of the same hospital for routine examination and not affected by problems that might influence growth. Diabetic patients and control subjects were consecutively enrolled in the study between 1989 and 1992; diabetic patients with positive markers for celiac disease (positive antiendomysial antibodies) and thyroid disease (positive antimicrosomial antibodies) or any other chronic disease were not considered in the study. Mean age of diabetic patients (8.9 ± 4.1 years) and control subjects (8.5 ± 4.2 years) at recruitment in the study was similar. RESULTS At onset of diabetes, the mean height expressed as the height standard deviation score (HSDS) was significantly greater than the expected values (P < 0.0001) and was independent of sex and pubertal stage. During the first 3 years of diabetes, HSDS decreased significantly (F = 6.9; P < 0.001). Meanwhile, growth velocity as standard deviation score (SDS) decreased significantly between the 1st and 2nd year (−0.12 ± 2.1; −0.76 ± 2.6, respectively; P < 0.05), but it was similar between the 2nd and 3rd year of diabetes. Weight expressed as SDS increased significantly during the first 2 years of diabetes but not thereafter. Height changes during the study period were independent from pubertal stage and sex. Metabolic control and insulin requirement, in our series, were not clearly related to height and weight changes. CONCLUSIONS Diabetic patients at onset of diabetes are taller than age- and sex-matched nondiabetic subjects. During the first years of the disease, linear growth decreases independently of metabolic control and weight changes.

Residual beta-cell function and spontaneous clinical remission in type 1 diabetes mellitus: the role of puberty

Abstract To investigate the role of puberty on spontaneous clinical remission and on secretion of residual C-peptide during the first year of type 1 diabetes mellitus, we studied 77 pre-pubertal, 39 pubertal and 41 post-pubertal type 1 diabetic patients. Spontaneous partial clinical remission (HbA1c within the normal range and insulin dose less than 0.3 U ⋅ kg–1 body weight ⋅ day–1 lasting for at least 10 days) decreased with duration of diabetes: months 3 vs 6 vs 12, respectively 13 vs 7 vs 4% (P<0.025). Remission was higher in post-pubertal than pubertal and pre-pubertal patients: month 6 respectively 20 vs 5 vs 1% (P<0.001). Secretion of C-peptide was significantly lower in pre-pubertal than the other two groups of patients. Basal and stimulated C-peptide secretion were higher in patients in clinical remission than in those who were not: basal value 0.4 (0.26–0.53) vs 0.28 (0.14–0.4) nmol/l (P<0.05); stimulated value 0.63 (0.5–0.95) vs 0.56 (0.31–0.74) nmol/l (P<0.05). Spontaneous remission is less frequent in children and adolescent patients than in adult post-pubertal patients, but different mechanisms may be involved. Low residual insulin secretion seems implicated in children meanwhile low insulin sensitivity could be more important in pubertal patients.

Bone Modeling Indexes at Onset and During the First Year of Follow-Up in Insulin-Dependent Diabetic Children

Abstract. Osteopenia has been described as a complication of insulin-dependent diabetes mellitus (IDDM). We measured bone modeling indexes during the first year of IDDM. At each time point the values obtained from diabetic children have been compared with those of control subjects. We selected 27 prepubertal children with IDDM (6.35 ± 2.16 years). We also enrolled 30 healthy prepubertal children of comparable age (5.85 ± 3.05 years). Height, height standard deviation scores, glycated haemoglobin (HbA1C), basal c-peptide concentrations, insulin dose, serum concentrations of procollagen type I C-terminal propeptide (PICP), and collagen type I C-terminal telopeptide (ICTP) were measured at onset of IDDM and at 3, 6 and 12 months. ICTP was in the normal range at onset of IDDM and decreased during the follow-up to reach a significant difference compared to controls after 3, 6 and 12 months of insulin treatment (P < 0.04). PICP concentrations increased significantly at 3 months (P= 0.05) compared to onset. At 3 and 12 months PICP values were significantly higher than those of control children (P= 0.04). Correlations were found between PICP concentrations and HbA1C and c-peptide at onset of diabetes (r =−0.45 and r = 0.47, respectively). Bone formation at onset of IDDM is not impaired; the introduction of insulin therapy, together with the achievement of a good metabolic control, determines an increase of bone matrix formation coupled with a decrease of bone resorption, that determines a positive balance of bone modeling.

Prevalence of Thyroid Autoantibodies and Thyroid Autoimmune Disease in Diabetic Children and Adolescents

newly diagnosed IDDM (697 patients) in the group of population-based control children (n = 86) and control siblings (415 children). Still, when studying the significance of increased levels of cows milk, /3-LG, and BSA antibodies as an independent risk factor for IDDM, the increase of levels of IgA antibodies to cows milk remained a significant risk factor for IDDM even when dietary factors were included in the model of conditionalmatched logistic regression (4). In the earlier study on 116 Swedish IDDM patients, we found increased levels of IgA antibodies to /3-LG and cows milk to be significantly related to IDDM (3). In that study, the duration of breast-feeding was significantly inversely related to the level of IgG antibodies to /3-LG and IgA antibodies to cows milk (3). We feel that the findings of increased levels of antibodies to cows milk and its protein fractions are an important hint to the role of cows milk in the pathogenesis of IDDM. Clearly, more immunological studies on patients, focusing particularly on the T-cells and antigens in cows milk, are needed. However, the role of cows milk in the pathogenesis of IDDM remains speculative as long as no direct evidence, based on dietary intervention trials, is available.

Frequency and correlates of severe hypoglycaemia in children and adolescents with diabetes mellitus

AbstractFrequency and correlates of severe hypoglycaemia have been retrospectively analysed in a cohort of diabetic children and adolescents with median (range) age 14.5 (3.2–25.5) years followed from the onset of the disease by the same diabetic clinic. During the years 1992–1994, 53 of the 187 patients reported 74 hypoglycaemic episodes: the average frequency of hypoglycaemia during the 3 years surveyed was 14.9 episodes/100 patients per year. Frequency of hypoglycaemia decreased significantly with age (χ2 = 24.1; P < 0.0001) and was independent of duration of diabetes. Glycosylated haemoglobin and insulin dose were similar in patients with and without hypoglycaemia, matched for age and duration of diabetes. One out of two hypoglycaemic episodes occurred during sleep and no explanation was available for 50% of episodes. Conclusion In this study severe hypoglycaemia was more frequent in young children than in adolescents and was independent of metabolic control and insulin dose.

Disseminated intravascular coagulation and severe peripheral neuropathy complicating ketoacidosis in a newly diagnosed diabetic child

Disseminated intravascular coagulation is a very rare complication of diabetic ketoacidosis. Central nervous system plasy but not peripheral neuropathy has been reported in these patients. On the other hand, signs of peripheral neuropathy may also be present at the onset of diabetes, but they are usually reversible within a few days after correction of the metabolic derangement. We describe an unusual case of mononeuritis multiplex syndrome still present after 2 months of follow-up in a child with diabetic ketoacidosis complicated by disseminated intravascular coagulation at the onset of insulin-dependent diabetes. These neurological impairments may be consistent with functional neural lesions due to vasa nervorum thrombosis and prolonged ischaemia.

HLA antigens in Italian type 1 diabetic patients: role of DR3/DR4 antigens and breast feeding in the onset of the disease

HLA-A, B, C, DR and DQ typing was performed in 381 Italian insulin-dependent diabetic patients and in 905 normal Italian subjects. The diabetic patients had significantly higher frequencies of HLA-Cw7, B8, B18, DR3, DR4, DQw2 and DQw3 and significantly lower frequencies of HLA-B17, Bw51, DR2, DR7 and DRw11. The frequency of heterozygosity for HLA-DR3/DR4 was significantly higher in patients who developed the disease in the first 2 years of life and DR3+/DR4-, DQw2 and DQw3 alleles were higher in those aged less than 14 years at onset. The HLA-DR4 allele was associated with onset of diabetes in autumn and HLA-B18 with onset in Autumn-winter. Diabetic children who were breast fed had a later onset of insulin-dependent diabetes mellitus than those who were bottle fed but these differences were independent of HLA typing (11.18±0.72 years vs 9.23±0.42 years; mean±SEM). We conclude that: (1) in general, HLA distribution in Italian insulin-dependent diabetic patients reflects previous data reported in other European and North American populations; (2) HLA-DR3 and DR4 are strongly associated with insulin-dependent diabetes in Italy as well, and these alleles seem to predispose to an earlier onset of the disease; and (3) breast feeding may delay the onset of the disease.

An unusual case of recurrent hypoglycaemia: 10-year follow up of a child with insulin auto-immunity

We report the case of a child with hypoglycaemia due to insulin auto-immunity. Insulin autoimmunity is the third most frequent cause of hypoglycaemia in Japan where the first cases were described. The child has been followed for the past 10 years with recurrence of hypoglycaemic symptoms and high titres of insulin antibodies.