Transient Neonatal Diabetes Mellitus in a Pair of Twins

ABSTRACT. The occurrence of transient neonatal diabetes mellitus in male twins with almost identical courses of illness is reported. A trial with chlorpropamide treatment of twin A had no obvious influence on the insulin consumption or on duration of treatment. Very low values of plasma C-peptide and serum proinsulin with no detectable insulin antibodies supports the theory of delayed maturation of the beta-cell.     

Transient neonatal diabetes mellitus in a pair of twins

The occurrence of transient neonatal diabetes mellitus in male twins with almost identical courses of illness is reported. A trial with chlorpropamide treatment of twin A had no obvious influence on the insulin consumption or on duration of treatment. Very low values of plasma C-peptide and serum proinsulin with no detectable insulin antibodies supports the theory of delayed maturation of the beta-cell.     

Impaired beta-cell and alpha-cell function in African-American children with type 2 diabetes mellitus--"Flatbush diabetes"

The incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has substantially increased over the past decade. This is attributed to obesity, insulin resistance and deficient beta-cell function. In children a pubertal increase in insulin resistance and an inability to mount an adequate beta-cell insulin response results in hyperglycemia. Adults with T2DM have a diminished first phase response to intravenous glucose and a delayed early insulin response to oral glucose. Long-term studies show progressive loss of beta-cell function in T2DM in adults; however, such long-term studies are not available in children. To characterize beta- and alpha-cell function in African-American adolescents with established T2DM, we used mixed meal, intravenous glucagon and oral glucose tolerance testing and compared them to obese non-diabetic controls. T2DM was defined as fasting C-peptide >0.232 nmol/l and absent autoimmune markers. BETA-CELL FUNCTION: Meal testing in 24 children and adolescents with T2DM, mean age 14 years, BMI 30 kg/m2, Tanner stage II-V, HbA1c 8.9%, were compared with BMI- and age-matched controls. Forty percent presented with DKA. Half were treated with insulin and half with diet/oral anti-diabetic agents. Although absolute C-peptide response in both groups was similar, the incremental rise in C-peptide relative to plasma glucose in the patients with T2DM compared to controls was 40% and 35% lower 30 and 60 min after the meal, p <0.007 and p <0.026. Glucagon testing in 20 pediatric patients with T2DM compared with 15 matched controls showed significantly lower 6 min stimulated C-peptide relative to the ambient plasma glucose in patients with T2DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p <0.05). The clinical utility is that 78% of patients with a 6 min C-peptide <1.4 nmol required insulin, while 81% of those >1.4 nmol required oral anti-diabetic agents, p <0.0001. Furthermore, the duration of T2DM up to 5 years after diagnosis was associated with lower fasting and glucagon-stimulated C-peptide levels, implying worsening beta-cell function over time, even in children and adolescents. ALPHA-CELL FUNCTION: During meal testing, children and adolescents with T2DM had less suppression of plasma glucagon than non-diabetic controls; this was more severe with longer duration of T2DM and poorer glycemic control. BETA-CELL RECOVERY: In African-American and Hispanic adults, intensive treatment of blood glucose may achieve beta-cell recovery with 35-40% of newly diagnosed patients going into remission after 6 months treatment. They remain off anti-diabetic pharmacological agents in remission for a median of over 3 years with normal HbA1c levels. We hypothesize this to be due to removal of a critical component of glucose or lipotoxicity at the level of the beta-cell and/or peripheral tissue. Four of 20 African-American children presenting with mean glucose 650 mg/dl maintained normal HbA1c levels on small doses of metformin after initial treatment with multiple insulin injections with or without metformin. This suggests a marked recovery of beta-cell function, similar to that in adults. SUMMARY: T2DM in children, as in adults, is characterized by insulin deficiency relative to insulin resistance. Plasma C-peptide levels may be clinically useful in guiding therapeutic choices, since patients with lower levels required insulin treatment; beta-cell function is also diminished with longer duration of T2DM. The possibility exists that in children, as in adults, intensive glycemic regulation may allow for beta-cell recovery and preservation. Thus, optimum beta- and alpha-cell function are central to the prevention of DM and maintenance of good glycemic control in African-American and Hispanic children and adolescents with T2DM.     

Beta-cell function assessed by plasma C-peptide evaluation in diabetic thalassaemic patients

In order to investigate the pancreatic function in patients with thalassaemia major, plasma glucose and immunoreactive C-peptide levels were determined in 9 diabetic thalassaemic patients and in 7 controls after arginine infusion. Mean basal and peak values and C-peptide areas in thalassaemic patients did not differ significantly from those of the controls. However, in the thalassaemic group there was a greater variation in values, since pancreatic beta-cell function was found either normal, reduced or increased. These findings could suggest that different factors may lead to diabetes which complicates thalassaemia, i.e. insulin-resistance, probably due to liver damage subsequent to iron deposition and infectious hepatitis, and insulinopenia, probably due to beta-cell lesion following iron storage in the pancreas.     

beta-Cell residual function in juvenile diabetes mellitus (author's transl)

Estimation of C-peptide (IRCP) can be used to measure the residual beta-cell function in insulin treated diabetics. IRCP was estimated in 46 juvenile diabetics. A significant correlation between basal IRCP-levels and duration of diabetes as well as daily insulin requirement could be shown. There was no linear correlation between glucosuria and IRCP. However, patients with IRCP > 1,0 ng/ml had significantly lower glucosuria ( p < 0,005). Endogenous residual function of the beta-cells seems to be of importance for metabolic control in diabetic children.     

Basal insulin secretion and erythrocyte insulin binding in preterm and term newborn infants

To study the ontogeny of the insulin secretion and the erythrocyte insulin receptor we measured plasma immunoreactive insulin and C-peptide concentrations and the binding of [125I]-insulin to the erythrocytes in cord blood from 16 preterm and 16 term infants. 20 normal-weight adults were also studied. The C-peptide concentrations and the molar ratio of C-peptide to insulin were lower in the newborn infants than in the adults. The immunoreactive insulin correlated positively with birth weight in the term infants. The insulin binding to erythrocytes from the newborn infants was increased when compared to the adults. Erythrocytes from the preterm infants bound more insulin than the cells from the term infants. There was a strong negative correlation between insulin binding and gestational age. In the term infants, plasma C-peptide correlated negatively with the insulin binding. The increased binding to erythrocytes from the term infants was due to an increase in the receptor concentration. The high insulin binding in the preterm infants was a result of both an increased receptor concentration and affinity. These data suggest that the basal insulin secretion is similar in preterm and term infants and that the clearance of insulin is decreased in newborn infants. The increased insulin binding in newborn infants may be a mechanism by which the growth stimulatory effect of insulin in fetal life is mediated.     

Prenatal diagnosis of familial neonatal hyperinsulinemia

A kindred with familial neonatal hyperinsulinemia is described. Infant A was macrosomatic and stillborn. Infant B was macrosomatic at birth following a pregnancy uncomplicated by maternal diabetes. Following diagnosis of hyperinsulinemic hypoglycemia, this patient was treated with oral diazoxide. Therapy continued until hyperinsulinemia resolved by two years of age. Based on this history, the pregnancy with infant C was intensively monitored using ultrasonography and amniocentesis. Insulin and C-peptide concentrations in amniotic fluid were markedly increased compared to control pregnancies. Based on these results, infant C was delivered immediately upon obtaining evidence of lung maturation. Neonatal hyperinsulinemia was confirmed by a markedly increased cord plasma insulin concentration. Based on our experience, we recommend that insulin concentrations in amniotic fluid be used as an indicator of fetal hyperinsulinemia in kindreds with prior newborn hyperinsulincmic hypoglycemia. This information may be used to direct timing of delivery and therapy in the immediate postnatal period.     

Prenatal diagnosis of familial neonatal hyperinsulinemia

A kindred with familial neonatal hyperinsulinemia is described. Infant A was macrosomatic and stillborn. Infant B was macrosomatic at birth following a pregnancy uncomplicated by maternal diabetes. Following diagnosis of hyperinsulinemic hypoglycemia, this patient was treated with oral diazoxide. Therapy continued until hyperinsulinemia resolved by two years of age. Based on this history, the pregnancy with infant C was intensively monitored using ultrasonography and amniocentesis. Insulin and C-peptide concentrations in amniotic fluid were markedly increased compared to control pregnancies. Based on these results, infant C was delivered immediately upon obtaining evidence of lung maturation. Neonatal hyperinsulinemia was confirmed by a markedly increased cord plasma insulin concentration. Based on our experience, we recommend that insulin concentrations in amniotic fluid be used as an indicator of fetal hyperinsulinemia in kindreds with prior newborn hyperinsulincmic hypoglycemia. This information may be used to direct timing of delivery and therapy in the immediate postnatal period.     

A two year observational study of nicotinamide and intensive insulin therapy in patients with recent onset type 1 diabetes mellitus

BACKGROUND AND AIMS: A number of trials have evaluated residual beta-cell function in patients with recent onset type 1 diabetes mellitus (DM1) treated with nicotinamide in addition to intensive insulin therapy (IIT). In most studies, only a slight decline of C-peptide secretion was observed 12 months after diagnosis; however, no data is available on C-peptide secretion and metabolic control in patients continuing nicotinamide and IIT for up to 2 years after diagnosis. PATIENTS AND METHODS: We retrospectively analysed data from 25 patients (mean age 14.7 years +/- 5 SD) with DM1 in whom nicotinamide at a dose of 25 mg/kg b. wt. was added from diagnosis (< 4 weeks) to IIT (three injections of regular insulin at meals + one NPH at bed time) and continued for up to 2 years after diagnosis. Data were also analysed from patients (n = 27) in whom IIT was introduced at diagnosis and who were similarly followed for 2 years. Baseline C-peptide as well as insulin dose and HbA1c levels were evaluated at 12 and 24 months after diagnosis. RESULTS: In the course of the follow-up, patients on nicotinamide + IIT or IIT alone did not significantly differ in terms of C-peptide secretion (values at 24 months in the two groups were 0.19 +/- 0.24 nM vs 0.19 +/- 0.13 nM, respectively). Insulin requirement (0.6 +/- 0.3 U/kg/day vs 0.7 +/- 0.2 U/kg/day at 24 months, respectively) did not differ between the two groups. However, HbA1c was significantly lower 2 years after diagnosis in patients treated with nicotinamide + IIT (6.09 +/- 0.9% vs 6.98 +/- 0.9%, respectively, p < 0.01). No adverse effects were observed in patients receiving nicotinamide for 2 years. CONCLUSION: Implementation of IIT with the addition of nicotinamide at diagnosis continued for 2 years improves metabolic control as assessed by HbA1c. In both nicotinamide and control patients, no decline in C-peptide was detected 2 years after diagnosis, indicating that IIT preserves C-peptide secretion. We conclude that nicotinamide + IIT at diagnosis of DM1 prolonged for up to 2 years can be recommended, but longer follow-up is required to determine whether nicotinamide should be continued beyond this period.     

No evidence for a major beta-cell dysfunction in young adults born with intra-uterine growth retardation

The association between low birth weight and the later development of type 2 diabetes is well established. It has been hypothesized that in utero undernutrition may affect pancreatic beta-cell development, leading to an impaired beta-cell function in adulthood. We have previously demonstrated that intrauterine growth retardation (IUGR) is associated with insulin-resistance early in adulthood. The aim of this study was to test whether IUGR would affect beta-cell function in young adults. Twelve 25-yr-old insulin-resistant subjects with IUGR were matched for age gender and body mass index (BMI) to 13 controls. All of them had normal glucose tolerance. Mean fasting plasma glucose did not significantly differ between the group with IUGR and the control group (97 +/- 7 vs. 98 +/- 4 mg/dL; p = 0.83). Blood glucose was maintained at 124.8 +/- 6.5 vs. 126.2 +/- 7.5 mg/dL above the basal glycemia in the IUGR and control groups (p = 0.64) throughout the hyperglycemic clamp. Serum insulin concentrations did not significantly differ between the group with IUGR and the control group either during the first (0-10 min) phase (311 +/- 252 vs. 248 +/- 184 pmol/L, p = 0.85) or during the second (80-100 min) phase (575 +/- 284 vs. 559 +/- 413 pmol/L, p = 0.72). C-peptide concentrations were similar in both groups during the two phases (2.35 +/- 1.44 vs. 2.59 +/- 1.10 nmol/L, p = 0.39 and 4.86 +/- 1.36 vs. 4.96 +/- 1.41 nmol/L, p = 0.91). In conclusion, our data do not argue in favor of an impairment of beta-cell function at 25 yr of age as a consequence of in utero undernutrition, but rather suggest that insulin resistance might be the primary defect responsible for the development of metabolic disorders associated with IUGR in adulthood.     

Beta-cell response to intravenous glucagon in African-American and Hispanic children with type 2 diabetes mellitus

The incidence of type 2 diabetes mellitus (DM) in children and adolescents has substantially increased over the past decade. The present study was conducted to evaluate the beta-cell response to intravenous glucagon (a non-glucose secretagogue) in children with type 2 DM. Twenty pediatric patients with type 2 DM were compared to 15 control subjects matched for body mass index and sexual maturation. The patients' ages ranged between 10 and 19 years. The duration of DM ranged from 1 to 5 years. Nine patients were on insulin treatment and 11 were on diet alone (3 patients) or metformin (8 patients). The criteria for type 2 DM were absent islet cell (IA-2) and glutamic acid decarboxylase (GAD65) antibodies and a fasting serum C-peptide level of > or = 0.23 nmol/l. Plasma glucose and serum C-peptide levels were determined in the fasting state and six minutes after an intravenous injection of 1 mg of glucagon. The fasting and stimulated plasma glucose levels and the fasting serum C-peptide levels (1.02 +/- 0.43 vs 0.79 +/- 0.26 nmol/l, p < 0.05) were higher in the patients with DM compared to weight-matched control subjects. While the absolute C-peptide responses to glucagon were not different between the two groups, the stimulated C-peptide to glucose ratios were significantly lower in the patients with DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p < 0.05). Patients with DM treated with diet or oral therapy had significantly greater basal and stimulated C-peptide concentrations, incremental C-peptide, and C-peptide to glucose ratios than patients on insulin treatment. Both the fasting and the stimulated C-peptide levels were inversely correlated with the duration of DM (r = -0.53, p < 0.05). HbA1c at one year follow-up was inversely correlated with glucagon-stimulated C-peptide levels at the time of the study (r = -0.658, p < 0.01) and positively correlated with the duration of diabetes (r = 0.671, p = 0.002). The apparently normal serum C-peptide levels measured after glucagon challenge in these children with type 2 DM reflect their higher glucose levels. The lower stimulated C-peptide to glucose ratios in these children with type 2 DM compared to normal controls demonstrate their diminished beta-cell response to intravenous glucagon, a non-glucose secretagogue. Among the patients with DM, a higher glucagon-stimulated serum C-peptide response was associated with diet/metformin treatment, a shorter duration of DM and predicted improved glycemic control up to one year later. Thus, the fasting and glucagon-stimulated serum C-peptide levels provide an estimate of the potential insulin secretory capacity of the beta-cell and may predict glycemic control in pediatric type 2 DM.     

EIF2AK3基因相关Wolcott-Rallison综合征1例并文献复习

患儿，女，1个月29 d。因抽搐6 d、发现血糖增高5 d入院。血糖波动于正常或增高，糖化血红蛋白因过高无法检测，尿糖+~++++，空腹C肽0.19 ng/mL，胰岛素11.68 μIU/mL。遗传性内分泌疾病基因Panel（检测基因412个，包含已知糖尿病相关基因49个）高通量测序发现患儿EIF2AK3基因存在新发c.2731_2732delAG和c.2980G > A复合杂合突变，均位于基因的激酶结构域。该婴儿被确诊为Wolcott-Rallison综合征（WRS）。WRS是一种罕见的常染色体隐性遗传疾病，以新生儿糖尿病、多发性骨骺发育不良和肝脏疾病为特征，新生儿糖尿病是WRS诊断的必备条件，EIF2AK3基因是WRS的致病基因。     

Metabolic Control in Children and Adolescents with Insulin-Dependent Diabetes Mellitus

ABSTRACT. The metabolic control, assessed from the mean daily glucosuria, mean daily glucosuria index based on home tests, and mean haemoglobin A₁ (HbA₁) concentrations during 1980, and the influence of various factors on the control were analysed in 177 diabetic children and adolescents. The mean daily glucosuria was 21 % of the carbohydrates in the subscribed diet, and the mean glucosuria index 55 %. The mean HbA] was 14.0 %. Boys had better metabolic control than girls. Good motivation towards treatment was associated with better metabolic control. There was a negative correlation between metabolic control and both the age of the child and the duration of diabetes. Prepubertal children were better controlled than those in puberty. Adherence to the dietary regimen was related to better control, as was the patient's endogenous insulin secretion, measured by serum C-peptide concentration. There was also an association between the season and the metabolic control, the control being better in the spring than during the other seasons. On the basis of these results male sex, a good motivation towards treatment, residual beta-cell function and adherence to the prescribed diet favor good metabolic control, while a long duration of the disease, the presence of puberty and relatively high age in childhood are factors impairing the metabolic control.     

The epidemiology of lost residual beta-cell function in short term diabetic children

Using the country-wide Swedish childhood diabetes register 526 children, who had had diabetes for 6-30 months were traced for measurements of 24-hour urinary C-peptide. Lost beta-cell function was defined as a 24-hour urinary C-peptide excretion per kg body weight less than 10% of the mean for healthy children (less than 0.025 nmol/kg). The estimated cumulative incidence of lost beta-cell function was 0.64 at 30 months. The incidence of lost beta-cell function did not differ by sex. Neither was there any significant variation in season at onset for cases with lost beta-cell function. A significant age dependency was shown for the cumulative incidence of lost beta-cell function with the highest incidence in the young age groups, i.e. a reversed age dependency compared to that of clinical onset. In contrast to the clinical onset of diabetes no significant geographical variation was found for lost beta-cell function when comparing standardized morbidity ratios. The urinary C-peptide excretion was significantly correlated to age at onset but not to degree or duration of ketonuria at onset. It is concluded that there are striking differences when comparing the epidemiology of lost beta-cell function to that of clinical onset in terms of age, sex, seasonal and geographical variations. The timing of clinical onset may thus partly be determined by factors different from those determining the rate of fall in beta-cell function.     

Inappropriately high plasma insulin levels in suspected perinatal asphyxia

The aim of this study was to determine differences in levels of the major hormones responsible for glucose homeostasis (insulin and glucagon) in babies with acute neonatal encephalopathy secondary to perinatal asphyxia and to correlate these with outcome. In a prospective observational study, plasma insulin, C-peptide, glucagon and serum glucose levels were determined using standard techniques at specified times in term babies with a diagnosis on admission of perinatal asphyxia or acute neonatal encephalopathy. The setting comprised two university-affiliated, regional, tertiary level neonatal intensive care units. Thirty-one babies with a diagnosis of perinatal asphyxia or acute neonatal encephalopathy were entered into the study over 15 months and neurodevelopmental outcomes at 18 months of age for 28 babies were available for analysis. Babies with a poor neurodevelopmental outcome had significantly higher insulin and C-peptide levels than those who had a good outcome. Glucose delivery, serum glucose and glucagon levels did not differ significantly between the babies with a poor outcome and those with a good outcome. In conclusion, babies with significant foetal or neonatal asphyxia frequently have inappropriately high plasma insulin levels. This, either alone or in combination with other hormonal disturbances, may lead to the hypoglycaemia often associated with severe asphyxia and may predict a poor outcome.     

肥胖伴黑色棘皮病儿童胰岛分泌功能的临床研究

目的　研究肥胖伴黑棘皮病儿童胰岛素分泌功能的改变 ,探讨其临床意义。方法　对35例肥胖伴黑色棘皮病患儿、38例单纯肥胖患儿及 39例正常儿童进行胰岛 β细胞功能指标的测定。结果　肥胖伴黑色棘皮病组空腹胰岛素、C肽、胰岛素原、真胰岛素、胰岛素原与胰岛素、C肽比值、胰岛素抵抗指数和胰岛 β细胞分泌指数 (中位数及范围 )分别为 18 5 (5 0～ 6 0 5 )pmol/L、3 9(1 3～14 0 ) μg/L、2 8 84 (9 9～ 6 4 2 )pmol/L、32 96 (6 2～ 6 6 0 )pmol/L、1 2 (0 4～ 8 9)、6 9(2 5～ 36 6 )、5 0(0 8～ 14 1)和 30 3 3(5 2 2～ 116 3 8) ,均显著高于单纯肥胖组和正常组 (P <0 0 0 1)。结论　肥胖伴黑色棘皮病已经存在严重的胰岛 β细胞分泌亢进和胰岛素抵抗 ,是儿童患 2型糖尿病的高危 信号     

Immune intervention at diagnosis – should we treat children to preserve beta-cell function?

Abstract:  Type 1 diabetes (T1D) is characterized by loss of beta-cell function. If beta-cell function can be preserved, it will lead to improved metabolic balance with improved quality of life and fewer acute and late complications, and if residual insulin secretion improves well enough, then that could lead to complete remission and even cure of the disease. Several efforts to save residual beta-cell function have been made for more than three decades without success. Proof of principle has been possible, and it seems clear that immune suppression or immune modulation, in fact, can stop the destructive process and thereby preserve beta-cell function. However, the effect seen in adult patients with T1D have been minimal or absent in diabetic children who seem to have another or at least more aggressive disease process. Furthermore, the immune interventions have had too serious and common adverse events in comparison to the scarce-positive effect. Recent more specific immune modulation with anti-CD3 monoclonal antibodies seems more encouraging with at least postponement of the C-peptide decline, but unfortunately still with common and quite threatening adverse effects. Even more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown good results with impressive preservation of residual insulin secretion in 10- to 18-year-old type 1 diabetic patients with recent onset. In patients with short diabetes duration at intervention the effect was remarkable. Furthermore, these effects were achieved with no adverse events. Future studies will show whether the good effect seen so far can be confirmed. If so there is hope that GAD vaccination will cause remission and even cure and prevention of T1D will then no longer be just a dream.     

Use of specific immunoradiometric assay to determine preterm neonatal insulin-glucose relations.

Highly specific immunoradiometric assays were used to measure plasma concentrations of insulin, proinsulin, and 32-33 split proinsulin in neonates (n = 16). Neonatal plasma insulin concentrations were high relative to blood glucose concentrations and compared with adult insulin-glucose relations. Concentrations of proinsulin and 32-33 split proinsulin together accounted for 34-70% of the total concentration of insulin and pro-peptides. This study confirms the need to use a specific assay and neonatal reference data in the diagnosis of neonatal hyperinsulinism, and shows that neonatal pancreatic beta cell function may differ from that of older subjects.     

Variation within the PPARG gene is associated with residual beta-cell function and glycemic control in children and adolescents during the first year of clinical type 1 diabetes

Context:  Conflicting evidence exists as to whether the Pro12Ala single nucleotide polymorphism of the type 2 diabetes susceptibility gene peroxisome proliferator-activated receptor gamma ( PPARG ) also confers risk for type 1 diabetes (T1D).
Objective:  The objective of this study was to investigate the PPARG gene in relation to residual beta-cell function and glycemic control in newly diagnosed T1D.
Design:  Prospective, non-interventional, 12-month follow-up study, conducted in 18 centers in 15 countries.
Patients:  Two hundred and fifty-seven children and adolescents (aged <16 yr) with newly diagnosed T1D.
Main outcome measures:  Beta-cell function was determined as 90-min meal-stimulated C-peptide (Boost test) 1, 6, and 12 months after diagnosis. Hemoglobin A1c (HbA1c) and daily insulin dose (IU/kg/d) were recorded at 1, 3, 6, 9, and 12 months after diagnosis. Haplotypes within PPARG were estimated by SNPH ap program. Statistical analyses were performed in a repeated measurements model.
Results:  Five haplotypes within PPARG were generated (h1, 68.4%; h2, 16.3%; h3, 8.3%; h4, 3.5%; and hx, 3.5%). Compared with the most frequent h1 haplotype, the haplotypes h3 and h4 of the PPARG associated with residual beta-cell function during the first year of clinical disease: h3 with a 27% lower C-peptide (p = 0.02) and h4 with a 39% lower C-peptide (p = 0.01). Haplotype h4 also associated with a 0.86% (absolute) higher HbA1c, after adjustment for the insulin dose (p = 0.02).
Conclusion:  Variation in the PPARG locus may influence disease progression during the first year after the presentation of T1D.