Hyperinsulinemic Hypoglycemia Research Articles

Association of Fetal Catecholamines With Neonatal Hypoglycemia

Perinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided. To determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia. In a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings. Risk factor for neonatal hypoglycemia. Comparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes. In this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P < .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P < .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P < .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = -0.212, P = .005; rs = -0.182, P = .016; and rs = -0.183, P = .016, respectively [P < .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = -0.149, P = .01; and rs = -0.153, P = .008, respectively). Neonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal β-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.

Diagnosis of artificial hypoglycemia due to oral hypoglycemic drugs by high-performance liquid chromatography with tandem mass spectrometric detection

BACKGROUND: Artificial hypoglycemia (ArH) is a decrease of blood glucose levels less than 3 mmol/l due to the deliberate use of hypoglycemic drugs by a patient outside of medical appointments. Timely diagnosis of this kind of hypoglycemia avoids unnecessary numerous examinations and hospitalizations. However, the detection of ArH still remains an extremely difficult task for both the healthcare facility and the attending physician. The foreign literature describes cases of successful detection of deliberate intake of oral hypoglycemic drugs (OHD) using high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS). Thus, it is relevant to develop and validate a method for determining OHD using HPLC-MS/MS.AIM: To optimize the diagnosis of ArH due to the use of OHD.MATERIALS AND METHODS: A total of 92 patients were examined. The development of the HPLC-MS/MS method for the detection of the studied OHD (sOHD; n=1-glibenclamide, n=1-gliquidone, n=1-gliclazide, n=1-glimepiride, n=1-glipizide, n=1-nateglinide and n=1-repaglinide) in the blood was carried out in a group of patients with diabetes mellitus type 2 (n=7) who received sOHD, and a group of conditionally healthy people who did not receive any medications (n= 7). To validate the method, the determination of sOHD substances was carried out on groups of patients with hyperinsulinemic nondiabetic hypoglycemia (NDH) of unknown origin (n=11) and with insulinoma (n=67).RESULTS: In the study of blood samples by HPLC-MS/MS in the group of patients with diabetes mellitus type 2, was confirmed in 100% of the cases the use of the drug that the patient received, in the group of conditionally healthy — sOHD were not detected. A false positive result was not obtained in any conditionally healthy and in any patient with insulinoma. ArH was diagnosed in 5 out of 11 patients in the group with hyperinsulinemic NDH of unknown origin, the method identified sOHD glibenclamide and gliclazide in the patients’ blood samples. In the remaining 6 patients of this group, examinations were continued and other causes of NDH were diagnosed. The sensitivity of the method was 100% [74%; 100%], specificity — 100% [95%; 100%].CONCLUSION: The HPLC-MS/MS method has high diagnostic accuracy in the detection and identification of sOHD (glibenclamide, gliquidone, gliclazide, glimepiride, glipizide, nateglinide and repaglinide) in blood samples of patients receiving these drugs. Currently, due to the low availability of the method, this study is advisable to use in patients with hyperinsulinemic hypoglycemia with negative results of first-line insulinoma imaging methods (computed tomography with contrast enhancement, ultrasound and magnetic resonance imaging of the abdominal cavity).

Case report: Glycaemic management and pregnancy outcomes in a woman with an insulin receptor mutation, p.Met1180Lys

BackgroundHeterozygous insulin receptor mutations (INSR) are associated with insulin resistance, hyperglycaemia and hyperinsulinaemic hypoglycaemia in addition to hyperandrogenism and oligomenorrhoea in women. Numerous autosomal dominant heterozygous mutations involving the INSR β-subunit tyrosine kinase domain resulting in type A insulin resistance have been previously described. We describe the phenotype, obstetric management and neonatal outcomes in a woman with type A insulin resistance caused by a mutation in the β-subunit of the INSR.Case presentationWe describe a woman with a p.Met1180Lys mutation who presents with hirsutism, oligomenorrhoea and diabetes at age 20. She has autoimmune thyroid disease, Coeliac disease and positive GAD antibodies. She is overweight with no features of acanthosis nigricans and is treated with metformin. She had 11 pregnancies treated with insulin monotherapy (n = 2) or combined metformin and insulin therapy (n = 9). The maximum insulin dose requirement was 134 units/day or 1.68 units/kg/day late in the second pregnancy. Mean birthweight was on the 37th centile in INSR positive offspring (n = 3) and the 94th centile in INSR negative offspring (n = 1).ConclusionThe p.Met1180Lys mutation results in a phenotype of diabetes, hirsutism and oligomenorrhoea. This woman had co-existent autoimmune disease. Her insulin dose requirements during pregnancy were similar to doses observed in women with type 2 diabetes. Metformin may be used to improve insulin sensitivity in women with this mutation. Offspring inheriting the mutation tended to be smaller for gestational age.

Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects.

Hepatocyte nuclear factor-4 alpha (HNF-4A) regulates genes with roles in glucose metabolism and β-cell development. Although pathogenic HNF4A variants are commonly associated with maturity-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hypoglycemia, renal Fanconi syndrome and liver disease. While the association of rare functionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to robust functional assays, the impact of HNF4A variants on HNF-4A transactivation in tissues including the liver and kidney is less known, due to lack of similar assays. Our aim was to investigate the functional effects of seven HNF4A variants, located in the HNF-4A DNA binding domain and associated with different clinical phenotypes, by various functional assays and cell lines (transactivation, DNA binding, protein expression, nuclear localization) and in silico protein structure analyses. Variants R85W, S87N and R89W demonstrated reduced DNA binding to the consensus HNF-4A binding elements in the HNF1A promoter (35, 13 and 9%, respectively) and the G6PC promoter (R85W ~10%). While reduced transactivation on the G6PC promoter in HepG2 cells was shown for S87N (33%), R89W (65%) and R136W (35%), increased transactivation by R85W and R85Q was confirmed using several combinations of target promoters and cell lines. R89W showed reduced nuclear levels. In silico analyses supported variant induced structural impact. Our study indicates that cell line specific functional investigations are important to better understand HNF4A-MODY genotype-phenotype correlations, as our data supports ACMG/AMP interpretations of loss-of-function variants and propose assay-specific HNF4A control variants for future functional investigations.

Hyperinsulinemia in Sotos Syndrome with a de novo NSD1 Deletion.

Sotos syndrome belongs to the group of diseases characterised by features such as facial dysmorphism, intellectual disability, hypotonia and overgrowth. Usually, Sotos syndrome is caused by heterozygous mutations in the NSD1 gene at chromosome 5q35 or by large genomic deletions of the same region. Genotype-phenotype correlations have mainly been reported as an association of significant or major abnormalities and presence of 5q35 deletions rather than intragenic deletions or point mutations in NSD1. The congenital hyperinsulinaemic hypoglycaemia (CHI) has been described as an uncommon feature in the presentation of Sotos syndrome. Most of the patients with Sotos syndrome and transient CHI were carriers of 5q35 deletions while persistent CHI has been recently reported in individuals with point mutations or small NSD1 deletions. We report the clinical features and medical treatment in a new-born child with Sotos syndrome and CHI that was present for almost two years. Genetic cause of Sotos syndrome in this case was a novel, large genomic deletion encompassing 24 OMIM genes including the entire NSD1 gene and 6 other Morbid genes. Our report shows challenges in diagnostics and management of this rare genetic condition. We propose, that in neonatal diagnostics, the phenotypic spectrum of Sotos syndrome should include CHI as a characteristic feature and molecular genetic testing should be done by whole genome analysis.

Abstract TMP117: Exposure to Single or Recurrent Hypoglycemia Increases Stroke Risk in Insulin-Treated Female Diabetic Rats

Stroke is a serious complication of diabetes. Intensive treatment of diabetes increases the risk of recurrent hypoglycemia (RH). Hypoglycemia exposure causes prothrombotic effects. Earlier, we demonstrated that exposure to single hypoglycemia (SH), 5-day RH (once every day), and twice-a-week RH for 6 weeks increases stroke risk in male insulin-treated diabetic (ITD) rats. In the present study, we determined the effect of SH and RH on stroke risk/thrombosis in female rats. Streptozotocin diabetic female rats were treated for hyperglycemia using insulin pellets (Figure A). Rats were randomly assigned to either hyperinsulinemic euglycemia (ITD+RH+Glucose, control) or hyperinsulinemic hypoglycemia (ITD+RH) groups (3 h duration) (Figure B). Separate groups tested the effect of SH, RH for 5 days, or RH for 6 weeks. Based on the results of the male studies, stroke risk after SH, 5-day RH, and 6-week RH were assessed on days 1, 7, and 3 post-last hypoglycemia, respectively. Groups were balanced (confirmed by Chi square test) in terms of the proportion of animals at different stages of the estrous cycle. To assess the risk of stroke, the carotid artery and jugular vein were linked with a shunt containing a suture, and the weight of the clot accumulated on the suture following 15 min of blood flow was quantified as a measure of stroke risk/thrombosis. The clot weight in the SH-exposed ITD group was significantly higher by 47% (22±3 mg, n=9, p&lt;0.05) when compared to its respective control (15±1 mg, n=8). The clot weight determined 7 days after the 5-day ITD+RH group (18±1 mg, n=7) was significantly (p&lt;0.05) higher than its control group (15±1 mg, n=9). The clot weight in the 6-week ITD+RH group was significantly higher by 47% (20±2 mg, n=9, p&lt;0.01) when compared to its control (14±1 mg, n=7) (Figure C). Our results show that similar to male rats, SH and RH increase stroke risk in female ITD rats. We are currently evaluating the underlying mechanisms. Acknowledgment: NIH (NS122808).

Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants.

The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.

Factors associated with neonatal hyperinsulinemic hypoglycemia, a case-control study.

We aimed to identify perinatal risk factors associated with hyperinsulinemic hypoglycemia in neonates. Secondary objectives included an examination of clinical and biochemical characteristics at the time of diagnosis and an exploration of the duration of diazoxide therapy. A case-control study was conducted, involving individual chart reviews of inborn infants diagnosed with hyperinsulinemic hypoglycemia (the HH group) between 2014 and 2021. These cases were paired with controls (the non-HH group) belonging to the same gestational age (GA) strata who did not exhibit HH or only had transient postnatal hypoglycemia. A total of 52 infants with HH were matched with corresponding controls. The mean GA in the HH group was 34.4±3.1weeks. Notably, the HH group exhibited lower mean minimum plasma glucose (PG) levels and required higher glucose infusion rates in comparison to the non-HH group (26.5±15.6 vs. 49.1±37.7 mg/dL and 12.9±3.8 vs. 5.7±2.1 mg/kg/min, respectively; p<0.001 for both). After adjusting for potential confounding factors, only two variables, fetal growth restriction (FGR) and neonatal sepsis, demonstrated significant associations with HH (adjusted odds ratio [95 % confidence interval]: 8.1 [2.1-31.0], p=0.002 and 6.3 [1.9-21.4], p=0.003, respectively). The median duration of diazoxide therapy for the HH group was 4months. FGR and neonatal sepsis emerged as notable risk factors for HH. These infants exhibited lower PG levels and necessitated higher glucose infusion rates compared to their non-HH counterparts. Importantly, a substantial proportion of the HH group received diazoxide therapy, with a median treatment duration of 4months.

Genetic variants of ABCC8 and clinical manifestations in eight Chinese children with hyperinsulinemic hypoglycemia

BackgroundABCC8 variants can cause hyperinsulinemia by activating or deactivating gene expression. This study used targeted exon sequencing to investigate genetic variants of ABCC8 and the associated phenotypic features in Chinese patients with hyperinsulinemic hypoglycemia (HH).MethodsWe enrolled eight Chinese children with HH and analyzed their clinical characteristics, laboratory results, and genetic variations.ResultsThe age at presentation among the patients ranged from neonates to 0.6 years old, and the age at diagnosis ranged from 1 month to 5 years, with an average of 1.3 ± 0.7 years. Among these patients, three presented with seizures, and five with hypoglycemia. One patient (Patient 7) also had microcephaly. All eight patients exhibited ABCC8 abnormalities, including six missense mutations (c. 2521 C > G, c. 3784G > A, c. 4478G > A, c. 4532T > C, c. 2669T > C, and c. 331G > A), two deletion-insertion mutations (c. 3126_3129delinsTC and c. 3124_3126delins13), and one splicing mutation (c. 1332 + 2T > C). Two of these mutations (c. 3126_3129delinsTC and c. 4532T > C) are novel. Six variations were paternal, two were maternal, and one was de novo. Three patients responded to diazoxide and one patient responded to octreotide treatment. All there patients had diazoxide withdrawal with age. Two patients (patients 3 and 7) were unresponsive to both diazoxide and octreotide and had mental retardation.ConclusionsGene analysis can aid in the classification, treatment, and prognosis of children with HH. In this study, the identification of seven known and two novel variants in the ABCC8 gene further enriched the variation spectrum of the gene.

Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.

O-08 Mutation in insulin receptor gene with hypoglycemia symptoms

Abstract Introduction Monoallelic/heterozygous mutations in the insulin receptor INSR gene are typically associated with type A insulin resistance syndrome, but less is known about INSR-related hyperinsulinemic hypoglycaemia (HH) characterized by fasting hyperinsulinemia and postprandial hypoglycemia. Clinical Case A 38-year-old woman with a history of migraines not needing preventive medication was admitted to an endocrinology outpatient clinic because of general malaise, weakness, and reduced exercise tolerance. For several years, she has had to eat small snacks during the workday to avoid sudden hypoglycemic symptoms. As a result, she gained nearly 30 kilograms in a few years. The symptoms started after she lost 23 kg and weighed 55 kg after following a ketogenic diet in 2016. The symptoms worsened despite weight regain and dietary changes to attempt to avoid hypoglycemia. Diagnostic evaluation: Initial BMI was 31.5 kg/m2. Continuous glucose monitoring (CGM) showed low blood glucose levels during extended fasting, such as during the night or prolonged meal intervals during the workdays (Figure 1). Hypoglycemia also occurred during and after exercise. She underwent a 2-hour glucose tolerance test, a mixed-meal test and a 72-hour fasting test (Tables 1 and 2), abdominal CT, and endoscopic ultrasonography, none of which led to a specific diagnosis. The glucose profile of this patient had hypoglycemias &amp;lt;3.0 mmol/L only a few times, and normal findings on imaging suggest that insulinoma is unlikely. Blood samples were taken during a postprandial hypoglycemic episode at work, but the plasma glucose (3.2 mmol/L) did not meet the criteria for Whipple's triad (&amp;lt;2.7 mmol/L), despite pronounced symptoms that were relieved by consuming carbohydrates. Finally, gene panel for monogenic causes of hypoglycemia identified a likely pathogenic INSR mutation c.2106T&amp;gt;G, p. (Tyr702*), which turned out to have been found in a symptomatic third-degree relative several years ago. Isolated case reports have found a beneficial effect of metformin in decreasing hypoglycemic symptoms, although the exact mechanisms by which it may decrease symptoms are unclear. We conducted a treatment trial with increasing doses of metformin to manage the patient's symptoms and to decrease the insulin resistance that had developed as a result of the INSR mutation and pronounced weight gain. Before the treatment trial, BMI was 34.4 kg / m2. Patient responded positively to metformin and weight started to decrease. Her quality of health increased subjectively and hypoglycemic episodes decreased during work and exercise. Conclusion The differential diagnostics of hypoglycemia may be challenging. Monogenic causes for adulthood-onset hypoglycemia are very rare but should be considered in cases of prolonged hypoglycemia susceptibility impairing daily activities. Genetic testing is also warranted in cases of family history of hypoglycemia symptoms.Figure 1.Continuous glucose monitor (CGM)Patient had low blood glucose levels (2.9-3.6 mmol/L) during extended fasting, such as during the night or prolonged meal intervals during the workdays. Hypoglycemiasymptoms also occurred during and after exercise. Table 1.Laboratory Values Table 2.72-hour fasting test and 5-hour Mixed-Meal test

P-25 Unusual cause for spontaneous hypoglycemia: Hirata's Disease in Iraqi patient

Abstract Introduction Hirata's Disease, is a rare condition characterized by episodes of spontaneous hypoglycemia associated with hyperinsulinemia with positive insulin autoantibodies. Hypoglycemia is common in patients with diabetes mellitus especially those who are taking insulin therapy or insulin secretogogues oral medications but spontaneous hypoglycemia is rare and there is no clear figures about those patients in Iraq. We receive a lot of persons claim to have hypoglycemia but most of them fail to fulfill the Whipple triad. Although endogenous hyperinsulinemic hypoglycemia especially insulinoma is very rare condition, it is still concern for endocrinologist in patients presented with presumed hypoglycemia. Clinical Case A 43 year old female presented with frequent fainting attacks over several weeks. She has no past medical history a part of localized areas of vertigo for which she received no systematic treatment. Initial medical evaluation was unremarkable but with documented hypoglycemia below 40 mg/dl. She has normal heart, brain, kidney, liver, thyroid and adrenal function. She has multiple emergency admissions treatment with glucose infusion. She gains more weight as she eats more to avoid hypoglycemia. Her specific lab during the attack shows high serum insulin level (141.10 mIU/ml) with high C-peptide 18.55 ng/ml Work up for insulinoma shows normal MRI abdomen, normal endoscopic ultrasound and negative PET Gallium 68 scan. There are no previous reports of Insulin autoimmune syndrome in Iraq. The insulin autoantibodies in this patient were very high (more than 300.00 U/ml) which highly suggestive of this syndrome after excluding other factors that may cause elevation of these autoantibodies. Patient condition persist for about eight months and was advised for small multiple meals and diazoxide was not used much because it is not available in Iraq widely. Her condition resolved spontaneously after one year with dietary modifications. Conclusion Hirata syndrome is very rare but important cause of spontaneous hypoglycemia that should not be ignored. Up to our knowledge this is the first documented case in Iraq.

P-23 Insulin autoimmune syndrome possibly induced by Alpha-Lipoic acid

Abstract Introduction Insulin autoimmune syndrome (IAS) is a relative rare cause of hypoglycemia due to the presence of extremely high circulating insulin levels and elevated serum concentrations of autoantibodies to human insulin despite no prior exposure to exogenous insulin, insulin analogues or oral hypoglycemic agents. It is characterized by repeated fasting hypoglycemia or episodes of hypoglycemia late after meals in non-diabetic, non-acutely ill patients. Increasing the titer of insulin autoantibodies and immune reactive insulin occurs owing to both genetic influences and environmental triggers such as medication, genetic instability and other factors. It is associated with the use of drugs comprising sulfhydryl groups, such as methimazole, clopidogrel and alpha lipoic acid, mostly. Insulin autoantibodies appear a few weeks after the exposure of sulfhydryl radicals. Here, we summarize the case of IAS caused by drug administration. Clinical Case A 60-year-old female patient who has a history of migraine for 30 years was referred to our hospital for feeling of hunger, dizziness, sweating, tremor, and palpitations for 1 month. These symptoms had commenced episodically, soon after starting 600 mg/day of alpha lipoic acid. She was diagnosed with hypoglycemia based on a plasma glucose concentration of 31 mg/dL. There was no personal or family history of diabetes mellitus, or previous use of oral hypoglycemic drugs such as sulfonylureas or exogenous insulin. No abnormality was detected in the systemic examination. She had no smoking and alcohol abuse. Her regular medication was tricyclic antidepressant (amitriptyline). Laboratory results are presented in Table 1. On our evalution, the serum levels of insulin, C-peptide, and anti-insulin antibody titers were inappropriately elevated in the presence of hypoglycemia, confirming the diagnosis of hyperinsulinemic hypoglycemia. Thyroid function, human growth hormone, insulin growth factor-1 (IGF-1), and cortisol result were within normal limits. Screening for antinuclear factor, serum protein electrophoresis, serology for viral hepatitis, and other autoimmune diseases were negative. Insulinoma was excluded with computed tomography. In light of the above results, a diagnosis of IAS was made with possible alpha lipoic acid. Because, alpha lipoic acid was the only medication being taken associated with a sulfhydryl group. The patient was prescribed oral methylprednisolone (32 mg once daily), alpha lipoic acid was withdrawn. Hypoglycemia did not occur after methylprednisolone treatment of follow-up. Methylprednisolone treatment was tapered to 4 mg once daily within 2 months. The insulin, and anti-insulin antibody titers had decreased. Conclusion We report a rare case of IAS. Sulfhydryl group containing drugs such as alpha lipoic acid might induce or exacerbate hypoglycemia in patients with a history of IAS. For this reason, the use of alpha lipoic acid should be questioned in patients with IAS. Table 1. Laboratory test results

Nesidioblastosis and Subsequent Diabetes Mellitus in a Dog with Hyperinsulinemic Hypoglycemia Treated with Partial Pancreatectomy.

A 6.5 yr old castrated male mixed-breed dog was presented for clinical signs associated with hypoglycemia. Hyperinsulinemic hypoglycemia was diagnosed as the cause of the persistent hypoglycemia. No obvious pancreatic mass was seen on abdominal computed tomography and exploratory laparotomy. A partial pancreatectomy was performed with the suspicion of an insulinoma-causing hyperinsulinemic hypoglycemia. Nesidioblastosis was diagnosed based clinical, biochemical, and histopathologic findings. There was beta cell hyperplasia and no evidence of neoplasia. The dog was euglycemic postoperatively after a partial pancreatectomy. Long-term follow-up after 2 yr revealed that the dog was diagnosed with diabetes mellitus.

Successful treatment of dumping syndrome with diazoxide in an infant with hypoplastic left heart syndrome.

Dumping syndrome is a rare but potentially serious condition that causes inappropriate postprandial hyperinsulinemia leading to hypoglycemia in children following gastrointestinal surgeries. While dietary modifications are often the first line of treatment, severe cases may require pharmacological intervention to prevent severe hypoglycemia. We present a case of successful treatment of dumping syndrome with diazoxide. A 2-month-old infant with left hypoplastic heart syndrome who underwent single ventricle palliation pathway and developed feeding intolerance that required Nissen fundoplication. Postprandial hypoglycemia was detected following the procedure, with glucose level down to 12 mg/dL, and the diagnosis of dumping syndrome was established. The patient was successfully managed with diazoxide, which effectively resolved postprandial hypoglycemia without any major adverse events. The patient was eventfully weaned off the medication at the age of 5 months. This case highlights the potential role of diazoxide in the management of pediatric patients with postprandial hyperinsulinemic hypoglycemia secondary to dumping syndrome. Dumping syndrome is a possible complication of gastrointestinal surgeries and should be suspected in children with abnormal glucose levels. Postprandial hyperglycemia should be monitored closely for significant subsequent hypoglycemia. Diazoxide might be considered as part of the treatment plan for dumping syndrome.

Hypoglycemia in Children Referred to a Tertiary Care Pediatric Endocrine Clinic: Age-Dependent Etiological Variations

Introduction: Diagnosing hypoglycemia in infants and children presents significant challenges. Our objective was to elucidate the diagnoses and clinical features of children with hypoglycemia referred to a pediatric endocrine tertiary clinic. Methods: This was a retrospective study of 154 children (0–18 years old) presenting with hypoglycemia, during 1992–2018. Results: The cohort was divided by clinical diagnosis into six groups: ketotic hypoglycemia (n = 45, 29.2%), congenital hyperinsulinemic hypoglycemia (n = 35, 22.7%), transient hyperinsulinemic hypoglycemia (n = 28, 18.2%), metabolic disorder (n = 14, 9.1%), systemic disease/syndrome (n = 15, 9.7%), and hormone deficiencies (n = 8, 5.2%). Two patients had insulinoma, and in 7 (4.5%), no diagnosis was elucidated. At diagnosis, 58 (37.7%) were Conclusions: Hypoglycemia etiology in children is heterogeneous and varies by age. Any hypoglycemia measured in a child should be seriously evaluated as 7% are asymptomatic. Workup should be tailored based on age, and clinical, biochemical, and imaging findings. Despite extensive workup, in a significant number of patients the mechanism underlying pediatric hypoglycemia remains an enigma. This emphasizes the unmet needs and challenges in studying pediatric hypoglycemia.

Low-dose diazoxide therapy in hyperinsulinaemic hypoglycaemia.

Low-dose diazoxide therapy in hyperinsulinaemic hypoglycaemia.

Evaluation of plasma cortisol during fasting test in patients with endogenous hyperinsulinemic hypoglycemia. Fifteen years experience

BackgroundEndogenous hyperinsulinemic hypoglycemia (EHH) is a rare clinical condition. The aim of this study was to evaluate baseline plasma cortisol concentration and its concentration during hypoglycemic crisis in fasting tests (FT) performed in our center. Secondarily, the aim was to establish the relationship between baseline cortisol and the time of evolution of EHH. Material and methodsA retrospective, observational, descriptive study was carried out which included patients with hypoglycemic disorder with positive FT. ResultsOf a total of 21 patients, 16 presented insulinoma, 1 nesidioblastosis, 2 malignant insulinoma and 2 EHH without pathological diagnosis. The time from the onset of symptoms to diagnosis was 2 years (Q1=1.5–Q2=5.5). The comparison between median baseline cortisol (BC)=11.8 mcg/dl (nmol/L 340.68) (Q1=9–Q3=14.1) and median cortisol during hypoglycemic episode (HC)=11.6 mcg/dl (nmol/L: 303.44) (Q1=7.8–Q3=16.1) showed no differences (Z=−0.08; P>.05). When correlating BC with HC, no significant relationship was observed (r=0.16; P>.05). When correlating the glycemic value in the crisis and the HC, a slight negative trend was found (r=−0.53; P=.01). In addition, we found that recurrent hypoglycemic disorder is associated with lower baseline cortisol values ​​the longer the time of its evolution. ConclusionWe confirmed that cortisol values ​​remain low during hypoglycemic episodes, reinforcing the hypothesis of lack of response of this counterregulatory hormone in cases of recurrent hypoglycemia.

Focal congenital hyperinsulinism

In congenital hyperinsulinemic hypoglycemia - the most common cause of persistent hypoglycemia in infancy - a focal lesion can be identified in 50% of the cases. With appropriate medical care based upon early diagnosis, these patients can be cured by the resection of the lesion rendering unnecessary long time medical care, and avoiding serious brain damage from recurrent hypoglycemic episodes. Genetic testing and 18F-fluoro-dihydroxyphenylalanine PET/CT imaging are essential for determining the best possible treatment. We report 2 cases of focal congenital hyperinsulinism - both male infants: 22 and 2 months of age - treated successfully with enucleation of the pancreas lesion (Semmelweis University, Budapest). Both patients had the pathognomonic mutation of the ABCC8 gene of the ATP-sensitive potassium channel. Radiologic imaging and histology confirmed the diagnosis, and after the operation, pharmacological treatment was terminated in both cases. During the follow-up period (5 and 1.5 years, respectively) they are euglycemic, with no morbidities attributed to the operation. We believe that these two operations for focal hyperinsulinism - diagnosed and localised by the above detailed genetic and specific radiological testing - were the first of their kind in Hungary. Based on the acquired experience, every necessary examination can be achieved in our country to improve patient care, reduce morbidity and medical costs. Orv Hetil. 2023; 164(47): 1877-1884.

Evaluación del cortisol plasmático durante el test de ayuno en pacientes con síndrome hipoglucémico por hiperinsulinismo endógeno. Experiencia de 15 años

BackgroundEndogenous hyperinsulinemic hypoglycemia (EHH) is a rare clinical condition. The aim of this study was to evaluate baseline plasma cortisol concentration and its concentration during hypoglycemic crisis in fasting tests (FT) performed in our center. Secondarily, the aim was to establish the relationship between baseline cortisol and the time of evolution of EHH. Material and MethodsA retrospective, observational, descriptive study was carried out which included patients with hypoglycemic disorder with positive FT. ResultsOf a total of 21 patients, 16 presented insulinoma, 1 nesidioblastosis, 2 malignant insulinoma and 2 EHH without pathological diagnosis. The time from the onset of symptoms to diagnosis was 2years (Q1=1.5-Q2=5.5). The comparison between median baseline cortisol (BC)=11.8μg/dl (nmol/l 340.68) (Q1=9-Q3=14.1) and median cortisol during hypoglycemic episode (HC)=11.6μg/dl (nmol/l: 303.44) (Q1=7.8-Q3=16.1) showed no differences (Z=−0.08; P>.05). When correlating BC with HC, no significant relationship was observed (r=0.16; P>.05). When correlating the glycemic value in the crisis and the HC, a slight negative trend was found (r=−0.53; P=.01.) In addition, we found that recurrent hypoglycemic disorder is associated with lower baseline cortisol values the longer the time of its evolution. ConclusionWe confirmed that cortisol values remain low during hypoglycemic episodes, reinforcing the hypothesis of lack of response of this counterregulatory hormone in cases of recurrent hypoglycemia.