Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism

doi:10.1016/S0022-3476(97)70153-7

The Journal of Pediatrics

Volume 131, Issue 2, August 1997, Pages 193-199

Presented in part at the 1995 Annual Meeting of the Society for Pediatric Research, San Diego, Calif.

https://doi.org/10.1016/S0022-3476(97)70153-7 Get rights and content

Abstract

The diagnosis of hypoglycemia caused by hyperinsulinism may be difficult because insulin levels are not uniformly elevated at the time of hypoglycemia. Insulin-like growth factor binding protein-1 (IGFBP-1) is a 28 kd protein whose secretion is acutely inhibited by insulin. We hypothesized that serum levels of IGFBP-1 would be a useful marker of hyperinsulinism. We measured IGFBP-1 levels during the course of standardized fasting studies in hospitalized children; 36 patients became hypoglycemic during the fasting studies, and samples obtained at the point of hypoglycemia were analyzed. On the basis of the currently used diagnostic criteria, 13 children had hyperinsulinism, 16 had ketotic hypoglycemia or no disorder, 3 had hypopituitarism or isolated growth hormone deficiency, 2 had glycogen storage disease type I, and 2 had fatty acid oxidation disorders. In control subjects (children with ketotic hypoglycemia or no disorder), IGFBP-1 levels rose during fasting to a mean of 343.8 ± 71.3 ng/ml in the sample drawn at the time of hypoglycemia. Mean IGFBP-1 levels at hypoglycemia for the entire group with hyperinsulinism were 52.4 ± 11.5 ng/ml, significantly different from levels seen in control subjects (p < 0.0001). In children with moderately controlled hyperinsulinism (fasting tolerance >4 hours), mean IGFBP-1 levels at the time of hypoglycemia were 71.5 ± 16.9 ng/ml. IGFBP-1 levels in the children with poorly controlled hyperinsulinism (fasting tolerance <4 hours) failed to rise during fasting, with a mean of 30.1 ± 10.4 ng/ml in the final sample. IGFBP-1 levels were inversely correlated with serum insulin and C-peptide levels (r = –0.71 and –0.72, respectively; p < 0.0001). Patients with other endocrinologic or metabolic diseases that result in fasting hypoglycemia demonstrated a rise in IGFBP-1 levels similar to that seen in ketotic hypoglycemia. Low serum levels of IGFBP-1 at the time of hypoglycemia provide an additional marker of insulin action that might help to differentiate hyperinsulinism from other hypoglycemic disorders. (J Pediatr 1997;131:193-9)

Section snippets

Study Design

The patient population consisted of children aged 1 week to 17 years with known or suspected hypoglycemic disorders. Additionally, three patients who were undergoing fasts for a ketogenic diet protocol were studied. After the families gave informed consent, standardized fasting studies were conducted in the Children’s Hospital of Philadelphia Clinical Research Center under an institutional review board–approved protocol. Children were fed their standard diet in the days preceding the fasting

Results

In control patients and those with hypoglycemic disorders not caused by hyperinsulinism, IGFBP-1 levels rose during fasting from mean baseline levels of 27 ± 4 ng/ml. In general, IGFBP-1 levels in patients with hyperinsulinism displayed only a minimal rise with time above mean baseline levels of 42 ± 14 ng/ml and were suppressed at the time of hypoglycemia. Fig. 1 displays the IGFBP-1 levels in patients with and without hyperinsulinism in the “critical blood sample” drawn at the time of

Discussion

It was previously demonstrated that IGFBP-1 levels rise during fasting, 8, 9, 18 but most of the studies performed were not carried out to the point of hypoglycemia. Furthermore, there are few data correlating IGFBP-1 levels with fasting parameters other than insulin and glucose. We have confirmed that IGFBP-1 levels rise with fasting and are elevated in the “critical blood sample” of patients with ketotic hypoglycemia. IGFBP-1 levels are elevated in the “critical blood sample” in hypoglycemia

References (21)

CA Stanley et al.
Hyperinsulinism in infants and children: diagnosis and therapy
Adv Pediatr
(1976)
DR Powell et al.
Insulin inhibits transcription of the human gene for insulin-like growth factor binding protein-1
J Biol Chem
(1991)
F Pekonen et al.
Decreased 34K insulin-like growth factor binding protein in polycystic ovarian disease
Fertil Steril
(1989)
M. Novak
Colorimetric ultramicro method for determination of fatty acids
J Lipid Res
(1965)
AS Pagliara et al.
Hypoglycemia in infancy and childhood. Part II
J Pediatr
(1973)
CA Stanley et al.
Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia
Pediatrics
(1976)
LEL Katz et al.
Clinical significance of IGF binding proteins
The Endocrinologist
(1995)
P Cohen et al.
Clinical aspects of insulin-like growth factor binding proteins
Acta Endocrinol (Copenh)
(1991)
PDK Lee et al.
Regulation and function of insulin-like growth factor-binding protein-1 [Minireview]
Proc Soc Exp Biol Med
(1993)
GT Ooi et al.
Insulin rapidly decreases insulin-like growth factor binding protein-1 gene transcription in streptozotocin-diabetic rats
Mol Endocrinol
(1992)

There are more references available in the full text version of this article.

Cited by (56)

Hypoglycemia in the Toddler and Child
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and Print
Glucose is an obligate fuel for the brain. Profound and prolonged hypoglycemia causes permanent brain injury. At plasma glucose concentrations less than 54 mg/dL, the cerebral metabolic rate of glucose decreases; at even lower plasma glucose concentrations functional brain failure occurs. Systemic glucose balance is maintained by physiologic endocrine and metabolic processes that ensure normoglycemia and a continuous supply of glucose to the brain. Hypoglycemia is uncommon beyond the newborn period and early infancy, and is usually caused by disturbances in fasting adaptation: an acquired disorder of the endocrine system; prolonged fasting in susceptible individuals (e.g., an intercurrent gastrointestinal illness); congenital abnormalities, such as hyperinsulinism or inborn errors of metabolism; or accidental exposure to medication or toxins. During fasting, the brain initially uses glucose provided from a combination of glycogenolysis and gluconeogenesis in the liver. As liver glycogen stores diminish, adipose tissue lipolysis is activated to increase availability of free fatty acids as fuel for peripheral tissues, such as muscle and for ketogenesis in the liver, which makes ketones available as a brain fuel and partly replaces glucose utilization. Because of their larger ratio of brain relative to muscle mass, the time to reach the fasting hyperketonemia stage is markedly shorter in younger infants and children than in adults. This chapter describes an approach to diagnosis of fasting hypoglycemia, based on identifying the specific cause of failure to maintain normal glucose homeostasis. Key diagnostic information is often best derived from blood and urine specimens (referred to as critical samples) obtained at the time of hypoglycemia and immediately before reversing hypoglycemia.
Diagnosis and management of hyperinsulinaemic hypoglycaemia
2018, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
In addition, the inappropriately low or suppressed levels of serum ketone bodies (predominately 3-β-hydroxybutyrate) and fatty acids during the hypoglycaemic episode and the absence of ketonuria are highly suggestive of HH. Low insulin-like growth factor binding protein-1 (IGFBP-1) is a supplementary marker of excess insulin secretion, because the IGFBP-1 gene transcription is suppressed by insulin [116]. Increased serum ammonia concentrations in a patient suspicious for congenital HH may be associated with the presence of HI/HA syndrome [51], while increased plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate may indicate HADH deficiency [59,60].
Hyperinsulinaemic hypoglycaemia (HH) is a heterogeneous condition with dysregulated insulin secretion which persists in the presence of low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. Recent advances in genetics have linked congenital HH to mutations in 14 different genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, PPM2, CACNA1D, FOXA2). Histologically, congenital HH can be divided into 3 types: diffuse, focal and atypical. Due to the biochemical basis of this condition, it is essential to diagnose and treat HH promptly in order to avoid the irreversible hypoglycaemic brain damage. Recent advances in the field of HH include new rapid molecular genetic testing, novel imaging methods (18F-DOPA PET/CT), novel medical therapy (long-acting octreotide formulations, mTOR inhibitors, GLP-1 receptor antagonists) and surgical approach (laparoscopic surgery). The review article summarizes the current diagnostic methods and management strategies for HH in children.
Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children
2016, Journal of Pediatrics
Citation Excerpt :
The incomplete suppression of lipolysis may reflect hypoglycemia-mediated release of catecholamines, which can stimulate lipolysis even in the presence of excess insulin.40,41 IGFBP-1 is negatively regulated by insulin and has been shown to be elevated to a much greater extent in children with ketotic hypoglycemia, growth hormone deficiency, fatty acid oxidation disorders, and glycogen storage disease relative to children with congenital hyperinsulinism.21,42 In our study of untreated congenital hyperinsulinism vs ketotic hypoglycemia, an IGFBP-1 concentration ≤110 ng/mL provided the best sensitivity and specificity for this marker.
To evaluate thresholds of various biomarkers for defining excess insulin activity to recognize congenital hyperinsulinism.
This was a retrospective chart review of diagnostic fasting tests in children with ketotic hypoglycemia (n = 30) and genetically/pathology confirmed congenital hyperinsulinism (n = 28). Sensitivity and specificity for congenital hyperinsulinism were determined for plasma insulin, β-hydroxybutyrate, free fatty acids (FFA), C-peptide, insulin-like growth factor binding protein-1 (IGFBP-1), and the glycemic response to glucagon (through the glucagon stimulation test [GST]) at the time of hypoglycemia.
Only 23 of the 28 subjects with congenital hyperinsulinism had detectable insulin (median, 6.7 μIU/mL), and insulin was undetectable in all subjects with ketotic hypoglycemia. Compared with ketotic hypoglycemia, subjects with congenital hyperinsulinism had higher GST values (57 vs 13 mg/dL; ΔGST ≥30 mg/dL in 24 of 27 subjects with congenital hyperinsulinism vs 0 of 30 subjects with ketotic hypoglycemia) and C-peptide levels (1.55 vs 0.11 ng/mL), with lower levels of FFA (0.82 vs 2.51 mM) and IGFBP-1 (59.5 vs 634 ng/mL). At the time of hypoglycemia, the upper limits of β-hydroxybutyrate and FFA in subjects with congenital hyperinsulinism were higher than reported previously (β-hydroxybutyrate <1.8 mM and FFA <1.7 mM), providing the best sensitivity for congenital hyperinsulinism vs ketotic hypoglycemia. A C-peptide level ≥0.5 ng/mL was 89% sensitive and 100% specific, and an IGFBP-1 level ≤110 ng/mL was 85% sensitive and 96.6% specific.
Because low or undetectable insulin level during hypoglycemia does not exclude the diagnosis of hyperinsulinism, C-peptide and IGFBP-1 may inform the diagnosis of congenital hyperinsulinism. In this group of children with well-defined congenital hyperinsulinism, thresholds for “suppressed” β-hydroxybutyrate and FFA are higher than previously reported levels.
Hyperinsulinemic Hypoglycemia
2015, Pediatric Clinics of North America
Citation Excerpt :
Glucagon stimulates the release of stored hepatic glycogen and causes a rapid increase in the blood glucose level in HH. Other tests that provide evidence of HH are improvement of hypoglycemia after a subcutaneous dose of octreotide and the finding of decreased serum concentrations of insulin-like growth factor binding protein 1 (IGFBP-1) because insulin suppresses the transcription of the IGFBP-1 gene.84 An elevated serum ammonia concentration (between 2 and 5 times the upper limit of normal)85 in a patient with HH suggests HI/HA syndrome,40 although normal ammonia concentrations do not necessarily exclude it.
Hypoglycemia in the toddler and child
2014, Pediatric Endocrinology: Fourth Edition
Hypoglycemia in Neonates and Infants
2008, Pediatric Endocrinology

View all citing articles on Scopus

^☆: ^a Recipient of the Society for Pediatric Research Fellow’s Clinical Research Award for this presentation.

^☆☆: Supported in part by U.S. Food and Drug Association grant FD-R 001181-01 (Dr. Cohen), National Institutes of Health grant RR-00240 (Drs. Baker and Stanley), an American Diabetes Association Career Development Award (Dr. Cohen), and a Lawson Wilkins Pediatric Endocrine Society Serono Fellowship (Dr. Levitt Katz).

^★: Reprint requests: Lorraine E. L. Katz, MD, Assistant Professor of Pediatrics, Children’s Hospital of Philadelphia, Division of Endocrinology, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.

^★★: 0022-3476/97/$5.00 + 0 9/21/79490

View full text

Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism☆,☆☆,★,★★

Abstract

Section snippets

Study Design

Results

Discussion

Adv Pediatr

J Biol Chem

Fertil Steril

J Lipid Res

J Pediatr

Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia

Pediatrics

Clinical significance of IGF binding proteins

The Endocrinologist

Clinical aspects of insulin-like growth factor binding proteins

Acta Endocrinol (Copenh)

Regulation and function of insulin-like growth factor-binding protein-1 [Minireview]

Proc Soc Exp Biol Med

Insulin rapidly decreases insulin-like growth factor binding protein-1 gene transcription in streptozotocin-diabetic rats

Mol Endocrinol