Plasma proinsulin and C-peptide concentrations in children with hyperinsulinaemic hypoglycaemia

Plasma concentrations of proinsulin and C-peptide were measured in five children presenting with severe hypoglycaemia associated with elevated plasma levels of immunoreactive insulin (IRI) in order to determine whether the profile of circulating B-cell products related to the underlying pathophysiology of the pancreas. Results were compared with data from 13 normal infants. Four children, three neonates and a nine year old girl, were subjected to partial or total pancreatectomy. The neonates had nesidioblastosis, nesidioblastosis with a microadenoma, and a functional abnormality without histological derangement respectively; the older child had a localised adenoma. The remaining child, a neonate, had transient hypoglycaemia and elevated IRI levels associated with hyperlactataemia and hyperalaninaemia. All the children had markedly elevated plasma proinsulin concentrations; the highest levels were seen in the child with an isolated adenoma and in the neonate with nesidioblastosis and a microadenoma. Both of these children also had substantially elevated plasma C-peptide concentrations. The remaining three neonates had plasma C-peptide levels, which although in the normal range for normoglycaemia were inappropriately elevated during hypoglycaemia. It is concluded that elevated proinsulin and C-peptide concentrations are seen in children with hypoglycaemia associated with increased plasma IRI levels and that the profile of the concentrations does not provide a reliable marker for the nature of the underlying pancreatic abnormality.     

The hyperinsulinaemic hypoglycaemias in infancy: a study of six cases

The aim of the present study was to evaluate various functional tests for the differentiation of hyperinsulinaemic hypoglycaemia. The pathophysiological and histological findings in six infants, aged 2–7 months, with persistent hyperinsulinaemic hypoglycaemia are described. Islet cell adenoma was found in four infants and pancreatic nesidioblastosis in two others. Circulating levels of blood glucose (BG), immunoreactive insulin and C-peptide immunoreactivity were measured under basal conditions and during both stimulation and suppression. The diagnosis of hyperinsulinaemia was made by estimation of the BG/serum insulin ratio, which was the most important diagnostic criterion of hyperinsulinism. Control subjects of comparable age showed a ratio of 8.3±4.4 (range 4.1–13.3), whereas the six patients had values between 0.3 and 5.1. At least four determinations with ratios lower than 2.6 were necessary for confirming the diagnosis. Preoperatively we performed oral glucose tolerance, diazoxide infusion, somatostatin infusion and C-peptide suppression tests. It is suggested that the various function tests, especially the suppression tests, do not differentiate hyperinsulinism caused by an adenoma from that caused by diffuse pancreatic nesidioblastosis.Abbreviations IRI Immunoreactive insulin - BG blood glucose - CPR C-peptide immunoreactivity - HCP human C-peptide - BW body weight     

Preoperative management of newborn infants with hyperinsulinemic hypoglycemia (2)

Four infants (three boys and one girl, ages 12-89 days) with persistent hyperinsulinism secondary to nesidioblastosis (two) or microadenoma of the pancreas (two) were treated with cyclic somatostatin (S) as part of the preoperative management until subtotal pancreatectomy was performed within 12 to 35 days. The individual dose dependent response of glucoregulatory hormones to exogenous was evaluated by means of the "somatostatin sensitivity test" (SST). Thereby S was infused in stepwise increasing doses, as dictated by the prevailing blood glucose levels, until normoglycemia was achieved concomitantly with a dextrose infusion at rates of 5 mg/kg/min. This procedure resulted only in a partial suppression of insulin, C-peptide, glucagon, HGH and cortisol, without recurrence of hypoglycemia. Compared to baseline levels, plasma concentrations of insulin decreased by 61%, of C-peptide by 64% and a rise of glucagon by 23% was observed. The SST which can be performed under routine clinical conditions, is a useful procedure for evaluating the individual S-dose necessary to achieve normoglycemia. The risk of total S-induced suppression of hormones, such as IRI, IRCP, HGH, glucagon and cortisol can be omitted.     

B-CELL RESPONSE TO EXERCISE IN DIABETIC AND NON-DIABETIC CHILDREN

Abstract. Heding, L. G. and Ludvigsson, J. (Novo Research Institute, DK-2880 Bagsvaerd, Denmark and the Department of Pediatrics, Linköping University, S-581 85 Linköping, Sweden). B-cell response to exercise in diabetic and non-diabetic children. Acta Pediatr Scand, Suppl. 283: 57, 1980.—20 non-diabetic and 11 insulin dependent diabetic (IDD) children underwent short time (20 min) bicycle ergometer exercise followed by a 10 min rest period. Glucose, IRI, C-peptide and proinsulin were determined prior to and at the end of the exercise, and again after 10 min rest. While no significant change in mean glucose was observed during exercise in the non-diabetics, significant decreases were observed in IRI, C-peptide and proinsulin. After 10 min rest glucose as well as the three B-cell secretory products increased significantly. The change in glucose was Significantly ( p <0.001) correlated to the change in IRI. In the resting period IRI rose more than C-peptide in some subjects. IRI even rose without simultaneous rise in C-peptide indicating a release of tissue bound IRI. The group of IDD children did not show any significant changes in glucose and total IRI, while the endogenous insulin, as measured by C-peptide, did show a fall during exercise. The same was found for proinsulin. The lack of increased endogenous secretion during the rest period was most likely due to suppression of B-cell due to hyperinsulinism and lack of increased glucose concentrations during the rest period.     

A case of familial nesidioblastosis: prenatal diagnosis of foetal hyperinsulinism

Persistent neonatal hyperinsulinaemic hypoglycaemia due to nesidioblastosis is a rare condition probably transmitted by an autosomal recessive inheritance. Recurrent hypoglycaemic episodes become evident after birth and cause severe neurological damage without intensive treatment. The intrauterine detection of hypoglycaemia and hyperinsulinism in newborns subsequently diagnosed as affected by nesidioblastosis has not yet been reported. We describe a case of familial nesidioblastosis in which an intrauterine diagnosis could be suggested by high levels of insulin and C-peptide and low values of glucose in the amniotic fluid.     

Neonatal and infant beta cell hormone concentrations in relation to type 1 diabetes risk

Type 1 diabetes is preceded by the appearance of islet autoantibodies. Seroconversion to islet autoantibodies is greatest around 1 yr of age and is more frequent in children born to fathers with type 1 diabetes as compared to children born to mothers with type 1 diabetes. Here we asked whether changes in beta‐cell function in the neonate and infant reflect variations in the incidence of islet autoantibody seroconversion. Insulin, proinsulin, and c‐peptide concentrations were measured in sequential samples taken from birth to age 2 yr in 103 children who had a first degree relative with type 1 diabetes and who had been followed for islet autoantibody seroconversion. Serum insulin and proinsulin concentrations were highest at birth declining by age 3 months and stable thereafter until age 2 yr. C‐peptide concentrations, proinsulin/insulin, and proinsulin/c‐peptide ratios were stable from age 3 months. No differences were observed between children who developed islet autoantibodies and children who remained islet autoantibody negative. Children born to a mother with type 1 diabetes had higher birth concentrations of insulin (p = 0.005) and proinsulin (p = 0.014) as compared with children of non‐diabetic mothers. Increased insulin concentrations in children of type 1 diabetes mothers persisted until age 6 months. In conclusion, we could not relate excursions in beta‐cell hormones to autoantibody development, but suggest that the higher exposure to insulin and proinsulin in neonates born to mothers with type 1 diabetes may be linked to the relative protection against islet autoantibody seroconversion observed in these children.     

Reduced insulin removal and erythrocyte insulin binding in obese children

To study the relationship between childhood obesity, weight loss, hyperinsulinaemia and the erythrocyte insulin receptor, we measured the plasma concentrations of immunoreactive insulin (IRI) and C-peptide and the binding of ¹²⁵I-insulin to erythrocytes in 12 obese children with a mean age ±SD of 11.4±2.5 years and a mean relative weight score ±SD of 4.8±1.4 and 12 age-matched normal-weight children. Eight obese children were re-evaluated after 1 year's participation in a weight reduction programme. The obese children had higher fasting plasma concentrations of IRI (P<0.01) and C-peptide (P<0.05) and a lower C-peptide to IRI molar ratio (P<0.01) than the normal-weight children. The obese children had in addition a reduced erythrocyte insulin binding (P<0.05 or less) over the physiological range of circulating insulin concentration. There was a negative correlation (r=–0.60; P<0.01) between the insulin tracer binding and the relative weight. The weight reduction programme resulted in a decrease of 1.0SD (P<0.05) in the mean relative weight score. At the end of the therapy the obese children had lower fasting blood glucose levels (P<0.05) and lower plasma IRI concentrations at 90 min (P<0.05) after an oral glucose load than at the onset of therapy. There were no significant differences between the insulin binding characteristics at the commencement and at the end of the treatment. The low C-peptide to IRI molar ratio in obese children provides evidence of a decreased insulin clearance likely to contribute to their hyperinsulinaemia. The inverse relationship between insulin tracer binding and relative weight suggests a mechanism by which weight changes may be directly reflected in the peripheral insulin sensitivity. A moderate weight loss reduces hyperinsulinaemia in childhood obesity but does not normalize the impaired binding of insulin to its receptor.Abbreviations IRI immunoreactive insulin - ID₅₀ concentration of insulin required to reduce the tracer binding of ¹²⁵I-insulin by 50% - OGTT oral glucose tolerance test     

Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological 'nesidioblastosis' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child's tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.     

Isolated glucocorticoid deficiency: metabolic and endocrine studies in a 5-year-old boy

A 5-year-old boy is described who presented with episodes of hypoglycaemia triggered by mild infections or fever. Subnormal glucocorticoid production was confirmed by demonstrating low urinary excretion of free cortisol, low plasma cortisol concentrations that did not rise after glucagon and ACTH stimulation, and by elevated plasma ACTH levels. The selective nature of the abnormality was confirmed by demonstrating normal plasma electrolyte concentrations and blood pressure on a salt-restricted diet. Plasma renin activity and plasma aldosterone levels were also normal and responded appropriately to salt restriction and to frusemide-induced diuresis. Starvation-induced hypoglycaemia was associated with raised levels of blood ketone bodies and low blood alanine concentrations. Catecholamine secretion during hypoglycaemia was reduced. Glucocorticoid replacement therapy was effective in restoring normal glucose homeostasis.Smith and Nephew Research Fellow     

Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade.

A preterm female infant presented with intractable hypoglycaemia within 10 minutes of delivery. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20-22 mg/kg/min. Persistent hyperinsulinaemic hypoglycaemia of infancy was diagnosed from an inappropriately raised plasma insulin concentration (33 mU/l) at the time of hypoglycaemia (blood glucose < 0.5 mmol/l). Medical treatment with glucagon, somatostatin, and diazoxide led to only a modest reduction in the intravenous glucose requirement; a 95% pancreatectomy was performed and histological ''nesidioblastosis'' confirmed. In vitro electrophysiological studies using patch clamp techniques on isolated pancreatic beta cells characterised the ionic basis for insulin secretion in nesidioblastosis. The beta cells were depolarised in low ambient glucose concentrations with persistently firing action potentials; these were blocked reversibly by the calcium channel blocking agent verapamil. Persistent postoperative hyperinsulinaemic hypoglycaemia was treated with oral nifedipine. This increased median blood glucose concentrations from 3.5 to 4.8 mmol/l and increased in duration the child''s tolerance to fasting from 3 to 10.5 hours. These data allude to an abnormality in the ionic control of insulin release in nesidioblastosis and offer a new logical approach to treatment which requires further evaluation.     

HUMAN PROINSULIN IN INSULIN-TREATED JUVENILE DIABETICS

Abstract. Human proinsulin was determined in a group of 73 diabetics, aged 5–20 years, with onset of diabetes at the age of 1–16 years and a duration of diabetes of 2–17 years. At the time of the investigation, the patients were receiving conventional 5 times crystallized insulin and all had detectable insulin binding IgC. Because of the binding of human proinsulin to insulin antibodies the serum was extracted with acid ethanol. Proinsulin was then determined in fasting serum after removal of human C-peptide which would have interfered with the proinsulin radioimmunoassay. The detection limit in normal serum not containing antibodies was 0.01 pmol/ml. The detection limit in sera that had to be extracted was approximately 0.05 pmol/ml. 31 of the patients (42 %) had detectable serum proinsulin, ranging from 0.055 to 2.00 pmol/ml. In the same group of patients, 19 (26%) had detectable C-peptide. There was a strong correlation between the concentration of human proinsulin and C-peptide ( P < 0.001). 38 normal fasting sera contained from 0 to 0.033 pmol/ml, mean ±S.D.: 0.009 ± 0.008 pmol/ml. The human proinsulin constituted from 0.1 to 92% of the total immunoreactive insulin (IRI) in the 31 patients with detectable proinsulin (mean: 8.5%). Thus it appears that proinsulin was secreted in 42% of 73 insulin treated juvenile diabetics who had had diabetes for 3–14 years, whereas C-peptide was found in 26% of the patients. The insulin antibodies bind a portion of the secreted proinsulin, prolonging its half-life and increasing its serum concentration. Hence, the levels of proinsulin in patients having insulin antibodies are not comparable to those in persons without antibodies.     

Hypoglycaemia in Childhood Diabetes I.

ABSTRACT. Hypoglycaemia (blood glucose 1.3–2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and Cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.     

Persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis): a report from Kuwait

We report nine Bedouin children from Kuwait with persistent hyperinsulinaemic hypoglycaemia (PHHI) seen over a 13-year period in two regional hospitals. The incidence of PHHI in this inbred community is high (1:20,000); five of them came from two families. All the children presented with seizures associated with severe and recurrent hypoglycaemia, eight presenting in the neonatal period and one at the age of 2 months. One child died soon after birth. All the others received diazoxide initially, which achieved remission in one while two siblings remain dependent on the drug. Long-acting somatostatin analogue (octreotide) was successfully used in one child. Four children underwent pancreatectomy, two showed diffuse and two had localized nesidioblastosis. Two children achieved normal neurodevelopmental milestones, four suffered mental retardation of varying degrees and three died. Early diagnosis and prompt treatment are essential to avoid the neurological damage associated with hypoglycaemia. In some cases, this condition is due to an autosomal recessive pattern of inheritance and it is therefore important to offer genetic counselling to families with one or more affected siblings.     

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     

Hypoglycaemia in childhood diabetes. I. Clinical signs and hormonal counterregulation

Hypoglycaemia (blood glucose 1.3-2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.     

Sympatho-adrenal response to hypoglycaemia in infants

The response of the sympathoadrenal system to hypoglycaemia of different etiology was studied in seven infants, aged 10–189 days. Five infants had hyperinsulinism secondary to nesidioblastosis or to a -cell adenoma of the pancreas, one infant had neonatal sepsis due to staphylococcal infection and one infant congenital growth hormone (HGH) and adrenocorticotropic hormone (ACTH) deficiency. In babies with hyperinsulinism, plasma noradrenaline increased from 0.29±0.03 to 0.61±0.09 ng/ml (P<0.01), whereas adrenaline increased only in three, but did not change in two babies. Increases in heart rate and blood pressure paralleled these changes. In hypoglycaemia due to congenital sepsis, noradrenaline increased from 0.39 to 1.64 ng/ml and adrenaline from 0.05 to 0.86 ng/ml. This was associated with marked haemodynamic changes. In congenital HGH and ACTH deficiency, the low basal plasma levels of noradrenaline (0.12 ng/ml) and adrenaline (0.01 ng/ml) remained unchanged in response to hypoglycaemia. Heart rate and blood pressure were unaffected. The sympathoadrenal system was activated by hypoglycaemia in all infants except in congenital HGH and ACTH deficiency. In contrast to adults, noradrenaline was the preferentially released catecholamine, suggesting an involvement of noradrenaline in glucose counter regulation in infancy.Abbreviations ACTH adrenocorticotropic hormone - HGH human growth hormone     

PANCREATIC ISLET CELL FUNCTION AND METABOLIC CONTROL IN AN INFANT WITH PERMANENT NEONATAL DIABETES

ABSTRACT. A girl with typical clinical manifestations of neonatal diabetes was observed for 16 months with consecutive evaluations of pancreatic beta and alpha-cell function and metabolic control. At the diagnosis both the plasma immunoreactive insulin (IRI) and C-peptide concentrations were inappropriate for the contemporaneous hyperglycemia. During the follow-up, the C-peptide fell twice below the detection limit but the beta-cell function recovered partially on both occasions. Based on 24-hour urinary C-peptide excretion, the endogenous insulin secretion was less than 10% of that in non-diabetic infants. When diagnosed the patient had plasma immunoreactive glucagon (IRG) and glucagon-like immunoreactivity (GLI) concentrations below the reference range for normal neonates. The IRG normalised within the first month, while the GLI increased to a level exceeding the reference range. Hemoglobin A₁ had already risen at the time of diagnosis and subsequently rose to a level indicating poor metabolic control. The findings indicate an immature function of both beta- and alpha-cells at the diagnosis with the alpha-cells maturing within the first month. The recovery of the beta-cell function, after two failures in this patient with permanent neonatal diabetes, suggests that the beta-cell damage was at least partially reversible.     

Nesidioblastosis in infants: report of two cases and review of the literature

In the last 2 years, two newborns were found to have persistent hypoglycaemia due to nesidioblastosis. Both required more than 15 mg/kg/min IV glucose and had inappropriately high plasma insulin levels. Near-total pancreatectomy (NTP) with splenic conservation was curative in both, with negligible morbidity and no mortality. Prompt diagnosis and stringent control of plasma glucose with hourly monitoring in an intensive care unit, use of a central venous line, and oral diazoxide prevented subsequent neurological handicaps. A high index of suspicion for this rare disorder should be kept in mind in a chubby infant who is jittery, apathetic, and has seizures with hypoglycaemia. Medical management is required to confirm the nonketotic, hyperinsulinaemic hypoglycaemia, whereas NTP provides a long-term cure. Offprint requests to: M. Roohatgi     

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.