Hypothalamic-pituitary-gonadal axis disturbance and its association with insulin resistance in kidney transplant recipients / Distúrbio do eixo hipotálamo-hipófise-gonadal e sua associação com resistência à insulina em receptores de transplante renal

Abstract Objective: To evaluate hypothalamic-pi- tuitary-gonadal (HPG) axis alterations at 1 and 12 months after kidney transplan- tation (KT) and their association with in- sulin resistance. Methods: A retrospective clinical study was conducted in a tertiary care center in kidney transplantation recipients (KTRs) aged 18- 50 years with primary kidney disease and stable renal graft function. LH, FSH, E2/T, and HOMA-IR were assessed at 1 and 12 months after KT. Results: Twenty-five KTRs were included; 53% were men, and the mean age was 30.6±7.7 years. BMI was 22.3 (20.4-24.6) kg/m2, and 36% had hypogonadism at 1 month vs 8% at 12 months (p=0.001). Re- mission of hypogonadism was observed in all men, while in women, hypogonadotropic hypogonadism persisted in two KTRs at 12 months. A positive correlation between go- nadotrophins and age at 1 and 12 months was evident. Fifty-six percent of patients had insulin resistance (IR) at 1 month and 36% at 12 months (p=0.256). HOMA-IR showed a negative correlation with E2 (r=- 0.60; p=0.050) and T (r=-0.709; p=0.049) at 1 month, with no correlation at 12 months. HOMA-IR at 12 months after KT correlated positively with BMI (r=0.52; p=0.011) and tacrolimus dose (r=0.53; p=0.016). Conclusion: Successful KT restores the HPG axis in the first year. Hypogonadism had a negative correlation with IR in the early pe- riod after KT, but it was not significant at 12 months.

Resumo Objetivo: Avaliar as alterações do eixo hipotálamo-hipófise-gonadal (HHG) em 1 e 12 meses após transplante renal (TR) e sua associação com a resistência à insulina. Métodos: Foi realizado um estudo clínico retrospectivo em um centro de cuidados terciários em receptores de transplante renal (RTR) com idade entre 18-50 anos com doença renal primária e função do enxerto renal estável. LH, FSH, E2/T e HOMA-IR foram avaliados em 1 e 12 meses após o TR. Resultados: foram incluídos 25 RTR; 53% eram homens e a média de idade foi de 30,6±7,7 anos. O IMC foi de 22,3 (20,4-24,6) kg/m2 e 36% apresentaram hipogonadismo em 1 mês vs 8% aos 12 meses (p=0,001). A remissão do hipogonadismo foi observada em todos os homens, enquanto nas mulheres, o hipogonadismo hipogonadotrófico persistiu em dois RTR aos 12 meses. Ficou evidente uma correlação positiva entre gonadotrofinas e idade em 1 e 12 meses. Cinquenta e seis por cento dos pacientes apresentaram resistência à insulina (RI) em 1 mês e 36% aos 12 meses (p=0,256). O HOMA-IR mostrou uma correlação negativa com E2 (r=-0,60; p=0,050) e T (r=-0,709; p=0,049) em 1 mês, sem correlação em 12 meses. O HOMA-IR aos 12 meses após TR correlacionou-se positivamente com o IMC (r=0,52; p=0,011) e a dose de tacrolimus (r=0,53; p=0,016). Conclusão: O TR bem-sucedido restaura o eixo HHG no primeiro ano. O hipogonadismo apresentou uma correlação negativa com a RI no período inicial após o TR, mas essa correlação não foi significativa aos 12 meses.

A family with hyperinsulinemia caused by a novel mutation of SLC16A1 gene / 中华内分泌代谢杂志

Objective:Congenital hyperinsulinemia is a heterogeneous disorder characterized by severe hypoglycemia due to dysregulated insulin secretion. Sixteen genes have been reported to be associated with congenital hyperinsulinemia. In this study, whole exome sequencing was performed on a patient with obesity, hyperinsulinemia, and postprandial hypoglycemia to further explore its genetic etiology.Methods:The clinical data and peripheral blood of a patient with hyperinsulinemia and his family members were collected. Genomic DNA was extracted from the peripheral blood. Sanger sequencing and pedigree verification were performed on the pathogenic variants filtered by whole-exome sequencing. The function of the mutation sites was analyzed by bioinformatics software.Results:The proband presented with obesity, hyperinsulinemia, and postprandial hypoglycemia, but without exercise-induced hypoglycemia. A heterozygous SCL16A1 gene c. 1259A>G(p.K420R) mutation was identified in the proband. Co-segregated analysis showed that the c. 1259A>G mutation was also found in his father and brother, who had obesity and hyperinsulinemia, which was consistent with autosomal dominant inheritance. The mutation c. 1259A>G was predicted to be pathogenic by the MutationTaster, FATHMM-MKL, PolyPhen2, and CADD programs, and has not been reported in HGDM database yet, which was considered to be a novel mutation.Conclusion:This study reported a patient with hyperinsulinemia caused by a new mutation of SCL16A1 gene, which expanded our understanding of the pathogenic mutation spectrum of hyperinsulinemia.

Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS)/Nesidioblastosis as the underlying cause of recurrent hypoglycemia in a diabetic adult

ABSTRACT Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), without previous bariatric surgery, is a rare form of hypoglycemia in adult patients and is associated with nesidioblastosis. Adult-onset nesidioblastosis in diabetic patients is rare and histologically identical to "non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS)". Nesidioblastosis is rare in adults and clinically and biochemically mimics Insulinoma. In the literature, there have only been four cases of adult nesidioblastosis that followed diabetes mellitus. We report a case of nesidioblastosis in a 36-year-old diabetic female presenting with dizziness, sweating, and palpitations for three years. Selective non-invasive techniques failed to detect a tumor. Based on the pursuit of an insulinoma, a distal pancreatectomy specimen was received at our laboratory, and a diagnosis of nesidioblastosis was made. She is currently on follow-up with a favorable outcome. The definitive diagnosis of nesidioblastosis is made on a histological basis. The preferred form of treatment is pancreatic surgical resection. Nesidioblastosis should be taken into consideration in cases where diabetes transforms into hyperinsulinemic hypoglycemia.

Prevención de hipoglicemia neonatal en recién nacidos con factores de riesgo mediante la administración bucal de una dosis de gel de dextrosa al 40%: ensayo clínico aleatorizado / Prevention of neonatal hypoglycemia in newborns with risk factors by buccal administration of a dose of 40% dextrose gel: randomized clinical trial / Prevenção da hipoglicemia neonatal em recém-nascidos com fatores de risco através da ingestão bucal de gel de dextrose no 40%: ensaio clínico randomizado

Introducción: la hipoglicemia neonatal es un trastorno metabólico frecuente en neonatos, con mayor incidencia en aquellos con factores de riesgo como ser hijos de madre diabética, pequeño para la edad gestacional y pretérmino tardíos. Material y métodos: se realizó un ensayo analítico aleatorizado, controlado por placebo para evaluar la eficacia de la administración de gel de dextrosa al 40% para la prevención de hipoglicemia neonatal en esta población. Se reclutaron un total de 120 pacientes. Resultados: se encontró una menor incidencia de hipoglicemia neonatal al compararla con la incidencia reportada en la literatura internacional. No se encontraron diferencias estadísticamente significativas en cuanto al número de ingresos a áreas de internación para tratamiento de hipoglicemia ni en la alimentación a pecho directo exclusivo al alta entre los grupos. Conclusiones: el gel de dextrosa al 40% en recién nacidos podría ser un tratamiento alternativo para profilaxis de hipoglicemia en recién nacidos con factores de riesgo.

Introduction: neonatal hypoglycemia is a frequent metabolic disorder in neonates, with a higher incidence in those with risk factors such as being children of diabetic mothers, small for gestational age, and late preterm. Methodology: a randomized, placebo controlled analytic trial was conducted to evaluate the efficacy of 40% dextrose gel administration for the prevention of neonatal hypoglycemia in this population. A total of 120 patients were recruited. Results: a lower incidence of neonatal hypoglycemia was found when compared to the incidence reported in the international literature. No statistically significant differences were found in terms of the number of admissions to inpatient areas for hypoglycemia treatment or exclusive direct breastfeeding at discharge between the groups. Conclusions: 40% dextrose gel in newborns could be an alternative treatment for hypoglycemia prophylaxis in newborns with risk factors.

Introdução: a hipoglicemia neonatal é um disturbio metabólico comum em neonatos, com maior incidencia naqueles que apresentam fatores de risco, tais como filhos de mães diabéticas, pequenos para a idade gestacional e prematuros tardios. Metodologia: foi realizado um ensaio analítico randomizado e controlado por placebo para avaliar a eficácia da administração de gel de dextrose a 40% para prevenção de hipoglicemia neonatal nesta população. Um total de 120 pacientes foram recrutados. Resultados: foi encontrada menor incidência de hipoglicemia neonatal quando comparada com a incidência relatada na literatura internacional. Não foram encontradas diferenças estatisticamente significativas relativas ao número de internações em áreas de internação para tratamento de hipoglicemia ou aleitamento materno direto exclusivo para descarga entre os grupos. Conclusões: o gel de dextrose a 40% em recém nascidos pode ser uma alternativa de tratamento para profilaxia de hipoglicemia em recém nascidos com fatores de risco.

Persistent neonatal hypoglycemia secondary to hyperinsulinism/hyperammonemia. Case report

Introduction: Hyperinsulinism/hyperammonemia syndrome (HI/HA) is a rare genetic disease caused by the activation of mutations in the GLUD1 gene. It is characterized by recurrent symptomatic hypoglycemic episodes, poor tolerance to fasting, and requirement for high metabolic fluxes of glucose, with an insulin/ glucose ratio ≥0.3. Case presentation: Preterm male newborn (36 2/7 weeks of gestation) who was delivered by caesarean section due to acute fetal distress. At birth, the patient presented with weak cry, hypotonia, mild respiratory distress, and recurrent episodes of hypoglycemia, thus 10% dextrose and hydrocortisone were administered initially. Treatment with octeoctride was started, but due to the patient's poor response, laboratory tests were performed, reporting the following findings: serum ammonia: 137.6, insulin: 39.1 µIU/mL, blood glucose: 26.06 mg/dL, and insulin/blood glucose ratio: 1.5, leading to the diagnosis of HI/HA syndrome. Treatment with diazoxide was initiated, achieving a progressive improvement in blood glucose levels; however, afterwards, he presented seizures, so midazolam, phenobarbital and valproic acid were added to the treatment regimen. When hypoglycemia and seizure episodes resolved, the patient was discharged at 2 months and 5 days of life, and a treatment based on oral administration of diazoxide, phenobarbital and valproic acid was prescribed. Conclusion: HI/HA syndrome is characterized by recurrent episodes of hypoglycemia and hyperammonemia; therefore, the presence of these two conditions in neonates is highly suggestive of the disease. Timely diagnosis and treatment are required to avoid neurological sequelae, and transdisciplinary assessment is of great importance, as it increases the likelihood of early diagnosis and timely administration of diazoxide to restore normal glucose levels.

Introducción. El síndrome hiperinsulinismo/hiperamoniemia (HI/HA) es una enfermedad genética rara causada por la activación de mutaciones en el gen GLUD1. Este síndrome se caracteriza por hipoglucemias sintomáticas recurrentes, poca tolerancia al ayuno y requerimiento de altos flujos metabólicos de glucosa, con un índice insulina/glucosa ≥0.3. Presentación del caso. Recién nacido masculino pretérmino de 36 2/7 semanas de gestación que nació por cesárea debido a sufrimiento fetal agudo. Al nacer, el paciente presentó llanto débil, hipotonia, dificultad respiratoria leve y episodios recurrentes de hipoglicemia, por lo que inicialmente se administró dextrosa 10% e hidrocortisona. Se inició tratamiento con octeoctride, pero ante la pobre respuesta, se realizaron exámenes de laboratorio en los que se reportó lo siguiente: amonio sérico: 137.6 pmol/L, insulina: 39.1 µUl/mL, glucemia: 26.06 mg/dL y relación insulina/glucemia: 1.5, lo que permitió diagnosticarlo con síndrome HI/HA. Se inició tratamiento con diazóxido, lográndose mejora progresiva de la glicemia; pero posteriormente presentó crisis convulsivas, por lo que se agregó midazolam, fenobarbital y ácido valproico al tratamiento. Al resolver la hipoglicemia y las convulsiones, el paciente fue dado de alta a los 2 meses y 5 días de vida, prescribiéndose un tratamiento basado en la administración oral de diazóxido, fenobarbital y ácido valproico. Conclusión. El síndrome HI/HA se caracteriza por hipoglucemias recurrentes e hiperamoniemia; por tanto, la presencia de estas dos condiciones en neonatos es altamente sugestiva de la enfermedad. Su diagnóstico y tratamiento deben ser oportunos para evitar secuelas neurológicas, siendo la valoración transdisciplinaria de gran importancia, pues aumenta las probabilidades de un diagnóstico temprano y administración oportuna de diazóxido para restablecer los niveles normales de glucosa.

Prevalencia de hiperinsulinismo patológico post carga de glucosa y su relación con factores de riesgo cardiovascular, en adultos no diabéticos con insulinemia basal normal / Prevalence of pathologic hyperinsulinism after a glucose load charge: its relation to cardiovascular risk factors

Introducción: 25% de personas con hiperinsulinismo desarrolla diabetes 3-5 años luego del primer diagnóstico y 70% lo hará en el resto de la vida. Intervenir los niveles de glicemia desde que se detecta hiperinsulinemia evita la progresión a diabetes y restaura el metabolismo glicémico. Objetivos: Determinar la prevalencia de hiperinsulinismo patológico post-carga de glucosa (HPPG) y su relación con factores de riesgo cardiovascular en adultos 100 UI/ml a las 2 horas), sexo, hipertensión arterial, dislipidemia, malnutrición por exceso, sedentarismo, tabaquismo, ateromatosis e infarto miocárdico documentado. Con STATA 17 se calculó la prevalencia de variables en población general y según categoría de HPPG y se evaluó la significancia con prueba exacta de Fisher. Se compararon medias con ANOVA y t-test con nivel de significancia <0,05. Se usó regresión binomial para estimar Razón de Prevalencia e intervalos de confianza en variables cuantitativas y cualitativas. Resultados: la prevalencia de HPPG fue 41%. La edad promedio 37,5 años, el sexo masculino 52,9%, la hipertensión-arterial 40,5% y la dislipidemia 74,4%. Al comparar las poblaciones con y sin HPPG existieron diferencia estadísticamente significativa en las variables dislipidemia, hipertensión-arterial, malnutrición por exceso y sexo-masculino. La razón de prevalencia alcanzó a un 62%, 37%, 59% y 20% respectivamente. Conclusión: Se encontró una alta prevalencia de HPPG. Los factores de riesgo asociados a ella fueron dislipidemia, hipertensión arterial, malnutrición por exceso y sexo masculino. Esto sugiere que encontrar HPPG puede ser de utilidad para detectar precozmente a la población con un mayor riesgo de enfermedad cardiovascular.

Introduction: 25% of people with hyperinsulinism develop diabetes 3-5 years after the first diagnosis and 70% will do so in the rest of their lives. To control glycemia levels as soon as hyperinsulinemia is detected, progression to diabetes is prevented and glycemic metabolism is restored. Aim: To determine the prevalence of post-glucose load pathological hyperinsulinism (HPPG) and its relationship with cardiovascular risk factors in adults 100 uIU/ ml at 2 hours), sex, hypertension, dyslipidemia, excess malnutrition due to, sedentary lifestyle, smoking, documented atheromatosis and myocardial infarction. The prevalence of variables in the general population was calculated and, in relation to the HPPG category, significance is evaluated with Fisher's exact test. Finally means are compared with ANOVA and t-test. With significance level <0.05. Binomial regression was used to estimate the prevalence ratio and confidence intervals in quantitative and qualitative variables. Statistical analysis was performed with the STATA 17 software. Results: HPPG prevalence was 41%, mean age 37.5 years, male sex 52.9%, arterial hypertension 40.5% and dyslipidemia 74.4%. Un relation to the presence of HPPG a statistically significant difference in the variables dyslipidemia, arterial hypertension, malnutrition due to excess and male sex was found. The prevalence ratios were 62%, 37%, 59% and 20%, respectively. Conclusion: A high prevalence of HPPG was found. Risk factors associated to HPPG were dyslipidemia, arterial hypertension, malnutrition due to excess and male sex. Thus, HPPG can play a role in the early detection of a higher risk of cardiovascular disease in the general population.

Manejo anestésico en hipoglucemia hiperinsulinémica del recién nacido / Anesthetic management of hyperinsulinemic hypoglycemia in the newborn

Resumen: La hipoglucemia hiperinsulinémica del recién nacido es una enfermedad hereditaria que cursa con alteraciones en las células pancreáticas; la incidencia estimada es de 1/50,000 nacidos vivos aumentando en casos de consanguinidad. Patología considerada como causa principal de hipoglucemias en este grupo etario con alto riesgo de daño cerebral y retraso mental que impacta significativamente en el neurodesarrollo. La euglucemia y la prevención de lesión cerebral por neuroglucopenia son los principales objetivos del tratamiento médico. Durante el transanestésico de una pancreatectomía, los niveles de glucosa son de utilidad como marcadores; el objetivo del abordaje perioperatorio es mantener estabilidad hemodinámica y euglucemia a través de un adecuado manejo de líquidos. Se presenta el caso de paciente femenino de dos meses de edad con diagnóstico de hipoglucemia hiperinsulinémica con hipoglucemias severas asociadas a crisis convulsivas, ingresa a quirófano para pancreatectomía subtotal.

Abstract: Hyperinsulinemic hypoglycemia of the newborn is a hereditary disease that presents with alterations in pancreatic cells; the estimated incidence is 1/50,000 newly borns increasing in cases of consanguinity. Pathology considered as the main cause of hypoglycemia in this age group with a high risk of brain damage and mental retardation, significantly impacting neurodevelopment. Euglycemia and the prevention of brain injury from neuroglucopenia are the main objectives of medical treatment. During the transanesthetic of a pancreatectomy, the glucose levels are useful as markers; the objective of the perioperative management is to keep hemodynamic stability and euglycemia through proper fluid handling. In this case report we present a two-month-old female patient with a diagnosis of hyperinsulinemic hypoglycemia with severe hypoglycemia associated with seizures that enters the operating room for subtotal pancreatectomy.

Particularidades de la resistencia a la insulina en el síndrome de ovario poliquístico / Particularities of insulin resistance in polycystic ovary syndrome

Introducción: La resistencia a la insulina e hiperinsulinemia son frecuentes en las mujeres con síndrome de ovario poliquístico. Una condición que resulta relevante como factor patogénico principal de las alteraciones metabólicas que acompañan al síndrome y porque condiciona fenotipos con mayor riesgo metabólico y reproductivo. Objetivo: Realizar una revisión bibliográfica sobre la resistencia a la insulina en el síndrome de ovario poliquístico. Métodos: Se realizó una revisión bibliográfica tipo estado del arte. Se consultaron 229 artículos obtenidos de las bases PubMed, Medline, SciELO y Google Académico. Conclusiones: La resistencia a la insulina tiene importancia capital en el síndrome de ovario poliquístico, no sólo por su frecuencia, sino también por el amplio espectro de alteraciones metabólicas y reproductivas que se le asocian. Como en otros trastornos que caracterizan al síndrome, los mecanismos fisiopatogénicos específicos no están del todo claros, pero existe la posibilidad de diagnosticarla y tratarla oportunamente, con lo que pueden prevenirse complicaciones, algunas de importancia vital. Por esto, la educación para la salud desde edades tempranas, que propicie estilos de vida saludable, prevención del sobrepeso corporal y control de otros factores que agravan la resistencia a la insulina, así como la evaluación temprana de la resistencia a la insulina, deben entenderse como cruciales en el manejo de las mujeres con síndrome de ovario poliquístico, con independencia de su peso corporal(AU)

Introduction: Insulin resistance and hyperinsulinemia are frequent in women with polycystic ovary syndrome. This condition is relevant as the main pathogenic factor of the metabolic alterations that accompany the syndrome and because it conditions phenotypes with higher metabolic and reproductive risk. Objective: To perform a literature review on insulin resistance in polycystic ovary syndrome. Methods: A state-of-the-art literature review was performed. The particularities of insulin resistance associated with the syndrome and its clinical expression are described. Conclusions: Insulin resistance is of paramount importance in polycystic ovary syndrome, not only because of its frequency, but also because of the wide spectrum of metabolic and reproductive alterations associated with it. As in other disorders that characterize the syndrome, the specific pathophysiological mechanisms are not entirely clear. However, it is possible to diagnose and treat it in a timely manner, thus preventing complications, some of which are of vital importance. Therefore, and regardless of their body weight, health education from an early age to promote healthy lifestyles, prevention of body overweight and control of other factors that aggravate insulin resistance, including early evaluation of insulin resistance, should be understood as crucial in the management of women with polycystic ovary syndrome(AU)

Analysis on clinical and genetic characteristics of children with ATP-sensitive potassium channel congenital hyperinsulinism / 中华胰腺病杂志

Objective:To analyze clinical characteristics and genetic characteristics of children with ATP sensitive potassium passage (K ATP-HI). Methods:Forty-five children with genetically confirmed K ATP-HI and their families admitted to Beijing Children′s Hospital of Capital Medical University between February 2002 and December 2018 were selected as the study subjects. A detailed retrospective analysis of the patient's clinical characteristics, diagnosis and treatment process, disease-causing gene carrying status and later follow-up data was performed. ABCC8/KCNJ11 gene was sequenced by second-generation sequencing technology. Results:Among 45 children with K ATP-HI, 34 cases (75.6%) were neonatal onset, the first symptoms of 21 cases (46.7%) were convulsions. 39 cases had been treated with diazoxide, including 12 cases (30.8%) with good efficacy, 16 cases (41%) with poor efficacy and 11 cases with uncertain efficacy. Octreotide was further applied in 18 patients with uncertain or ineffective efficacy after diazoxide treatment, and 13 cases (72.2%) were effective, 3 cases were ineffective, and 2 cases were uncertain. 10 CHI patients who were ineffective to drug treatment or had clearly focal lesions confirmed by 18F-dopa positron emission by computed tomography ( 18F-DOPA PET) scans had undergone surgical treatment, 8 of which underwent partial pancreatectomy and blood glucose returned to normal after the operation; the other 2 cases underwent subtotal pancreatectomy and both had secondary diabetes after operation. Among 45 children with K ATP-HI, 1 case carried both ABCC8 and KCNJ11 mutations, 10 cases carried ABCC8 compound heterozygous mutations, and the remaining 34 cases carried ABCC8/KCNJ11 single genetic mutation. Among them, 21 cases had paternal inheritance, and 3 cases had maternal inheritance, 6 cases were identified with de novo mutations. Conclusions:Diazoxide treatment was ineffective for most K ATP-HI children, but octreotide had a higher effective rate. Partial pancreatectomy for focal type patients had a higher cure rate, and there was a risk of secondary diabetes after subproximal pancreatectomy, so it was very important to clarify the histological type of children before surgery. ABCC8 gene mutations and KCNJ11 gene mutations were the main pathogenic genes of K ATP-HI. Among patients carrying mutations in single ABCC8 or KCNJ11 gene mutation, K ATP-HI inherited by paternity were the majority. Some K ATP-HI children can relieve the hypoglycemia symptoms by themselves.

Hypoglycemia caused by AKT2 gene mutation:a case report and literature review / 中华全科医师杂志

A 15-month-old baby girl presenting with hypoglycemia was admitted in Children′s Hospital of Capital Institute of Pediatrics in October 2019. The blood glucose level was 2.4 mmol/L at admission, she showed asymmetry of left and right limbs. The levels of D-3-hydroxybutyric acid, urinary ketone body and free fatty acid were all decreased during hypoglycemia attack, the hyperglycemic hormone was increased, but insulin level was<0.2 μIU/ml. The whole exon gene testing showed that the patient had heterozygous mutation of AKT2 gene c.49G>A (p.E17K), which was mosaicism; then the patients was diagnosed as hypoinsulinemic hypoketotic hypo-fatty-acidemic hypoglycemia due to mutation of AKT2 gene. Blood glucose levels were dynamically monitored, high carbohydrate diet was administered and raw corn starch supplementation was given before bedtime. After 18 months of treatment, the growth and development of the patient was normal, the frequency of hypoglycemia attacks decreased, and bilateral limb asymmetry improved. The relevant literature was searched from Wanfang Database, CNKI and PubMed from January 1980 to March 2021 by using search term"hypoglycemia"and"AKT2 gene". Five cases of hypoglycemia caused by AKT2 mutation were retrieved, all were reported from other countries, no one case from China. The clinical manifestation of this disease is similar to hyperinsulinemic hypoglycemia, but insulin could not be detected during the attack of hypoglycemia, and the patients may have hemihypertrophy. The study suggests that if the patient has hypoglycemia accompanied by hypoinsulinemia and hemihypertrophy, we should consider the possibility of AKT2 gene mutation, and genetic testing should be recommended.

Insulinoma simulando una epilepsia: reporte de caso / Insulinoma simulating epilepsy: case report

Insulinoma es un tumor neuroendocrino que surge de las células ß del páncreas y produce hiperinsulinemia endógena. Son neoplasias raras con una incidencia reportada de 4 casos por millón de habitantes por año. La presentación clínica típicamente cursa con síntomas adrenérgicos y neuroglucopénicos secundarios a hipoglicemia. Requiere estudios de niveles séricos de insulina, pro-insulina y péptido C, además de imágenes diagnosticas que confirmen los hallazgos. La mayoría de los insulinomas son benignos, su sitio primario más común es el páncreas y pueden extirparse quirúrgicamente. Se presenta el caso de un hombre de 36 años con déficit cognitivo leve y episodios de diaforesis con deterioro neurológico hasta convulsiones tónico clónicas generalizadas que curiosamente resolvían con uso doméstico de "panela molida". Se ingresó a urgencias por ataques recurrentes de hipoglicemia severa con requerimiento de altas dosis de dextrosa al 50% por acceso central, hasta confirmación diagnóstica, intervención y resección de tumor neuroendocrino pancreático bien diferenciado (G1 según clasificación OMS) tipo insulinoma en la cola del páncreas.

Insulinoma is a neuroendocrine tumor that arises from the ß cells of the pancreas and produces endogenous hyperinsulinemia. They are rare neoplasms with a reported incidence to 4 cases per million inhabitants per year. The clinical presentation typically presents with adrenergic and neuroglycopenic symptoms secondary to hypoglycemia. It requires studies of serum levels of insulin, pro-insulin and C-peptide, in addition to diagnostic images that confirm the findings. Most insulinomas are benign, their most common primary site is the pancreas, and they can be removed surgically. We present the case of a 36-year-old man with mild cognitive deficits and episodes of diaphoresis with neurological deterioration to generalized clonic tonic seizures that curiously resolved with domestic use of "ground brown sugar". He was admitted to the emergency department due to recurrent attacks of severe hypoglycemia with a high-dose requirement for 50% dextrose through central access, until diagnostic confirmation, intervention, and resection of a welldifferentiated pancreatic neuroendocrine tumor (G1 according to WHO classification) insulinoma in the tail of pancreas.

Hiperinsulinismo congénito: caracterización de pacientes atendidos en un hospital universitario pediátrico en Colombia / Congenital hyperinsulinism: characterization of patients treated in a pediatric university hospital in Colombia

Resumen Introducción: El hiperinsulinismo congénito es una enfermedad del metabolismo de la glucosa, fundamental en la endocrinología pediátrica, ya que se refiere a la producción de mayor cantidad de insulina de la necesaria según la glucemia, lo cual produce hipoglucemias graves persistentes. Esta alteración puede tener importantes secuelas neurológicas debido al daño irreversible que se produce en la neurona por la exposición a la hipoglucemia por cortos periodos de tiempo. Su diagnóstico no es sencillo y requiere un alto índice de sospecha. El tratamiento se establece de manera secuencial, en varias etapas, observando la respuesta a cada uno de los posibles medicamentos empleados. En caso de que falle el manejo farmacológico, se requieren procedimientos quirúrgicos. Serie de casos: Se presentan siete casos de hiperinsulinismo congénito que fueron diagnosticados en los últimos 7 años en el Instituto Roosevelt en Bogotá, Colombia. En este país, el radiotrazador empleado usualmente durante la tomografía por emisión de positrones (PET/TC) no se encuentra disponible. Sin embargo, en uno de los casos descritos fue posible emplear otro radiotrazador alternativo que permitió un adecuado diagnóstico y un tratamiento quirúrgico exitoso. Conclusiones: El hiperinsulinismo congénito es una condición clínica compleja que amerita un correcto diagnóstico y un apropiado manejo, con el objetivo de evitar el daño neurológico que producen las hipoglucemias persistentes. Es posible emplear PET/TC con un radiotrazador adecuado para realizar un diagnóstico oportuno y proporcionar la mejor opción terapéutica disponible.

Abstract Background: Congenital hyperinsulinism is a disease of the glucose metabolism, relevant in pediatric endocrinology because of the elevated production of insulin according to blood glucose level, which leads to persistent severe hypoglycemia. This condition can produce important neurological sequelae in the patient due to the irreversible damage that occurs in the neuron caused by the exposure to hypoglycemia for short periods of time. Congenital hyperinsulinism diagnosis is not simple and it requires a high index of suspicion. The treatment should be established sequentially, in several steps, noticing the response to each possible medication used. If the pharmacological management fails, surgical procedures are required occasionally. Case series report: Seven cases of congenital hyperinsulinism diagnosed in the last seven years at the Instituto Roosevelt in Bogotá, Colombia are presented. In this country, the radiotracer used internationally during positron emission tomography/computed tomography (PET/CT) is not available. However, was possible to use an alternative radiotracer in one of the cases, which led to an adequate diagnosis and a successful surgical treatment. Conclusions: Congenital hyperinsulinism is a complex clinical condition, which requires proper diagnosis and treatment, with the aim of avoiding any neurological damage caused by persistent hypoglycemia. PET/CT can be used with an appropriate radiotracer for a timely diagnosis and to provide the best available therapeutic option.

Clinical and pathogenic gene mutation analysis of 21 cases of congenital hyperinsulinemia / 中国新生儿科杂志

Objective To study the clinical and genetic characteristics of congenital hyperinsulinism (CHI).Method From November 2016 to November 2018,a cohort of 21 patients with CHI were retrospectively reviewed in our hospital.The second generation sequencing was performed on Ion torrent platform to identify the genetic etiology of this disease.Result The average birth weight was 3 748 g.Overall,11 of the 21 patients (52.4％) were large for gestational age (＞ Pg0),and 90.5％ (19/21) onset within 3 days after birth.Seizures occurred in 7 cases (33.3％).Diazine was effective in alleviation in 6 patients,octreotide was effective in 8 patients,and diazine and octreotide were ineffective in 7 patients.11 patients underwent 18-fluoro-l-dopa PET-CT scan,indicating focal islet cell proliferation in 8 patients and diffuse islet cell proliferation in 3 patients.8 focal cases accepted the partial pancreatectomy (7 cases who failed to respond to drug therapy,1 case who received octreotide had significant liver damage),and all of these 8 cases were confirmed with focal islet cell proliferation by postoperative pathology.7 cases had normal glucose level after surgery,while 1 case developed insulin-dependent diabetes.Patients of 3 cases with diffuse islet cell proliferation had no consent for surgery.Gene mutations were identified in 61.9％ (13/21) of patients (12 cases of ABCC8 gene and 1 case of KCNJ11 gene).15 sequence changes were identified (14 in ABCC8 and 1 in KCNJ11).3 new ABCC8 gene mutations (exon13:c.1822C ＞ T,p.Q608X;exon22:c.2691delC,p.W898Gfs*5;exon33:c.4039C ＞T,p.Q1347X),and 1 new KCNJJ11 gene mutation (exon1:c.629T ＞ A,p.H315Y) were firstly reported.Conclusion Partial pancreatectomy is an effective treatment for those CHI not responsive to drug,however,with an attendant risk of developing diabetes.Mutations of ABCC8 gene and KCNJJ11 gene are the main pathogenic genes of CHI.Patients with different gene mutations may have different responses to drug treatment.Therefore,it is necessary to improve gene testing in clinical practice to guide treatment and prognosis.3 new ABCC8 gene mutations and 1 new KCNJJ11 gene mutation were first reported,which expand the spectra of gene mutation.

Clinical and genetic characteristics analysis of Chinese children with glutamate dehydrogenase type of congenital hyperinsulinemia / 中华胰腺病杂志

Objective@#To analyze the clinical features and genetic characteristics of Chinese children with glutamate dehydrogenase type of congenital hyperinsulinism (GDH-HI).@*Methods@#Pedigrees with 10 GDH-HI children admitted to Beijing Children′s Hospital from February 2008 to December 2018 were selected as subjects. Clinical features, the detection of pathogenic genes and follow-up data were retrospectively analyzed. Polymerase chain reaction DNA (PCR-DNA) direct sequencing method and second generation sequencing technique were used to analyze the GLUD1 genetic sequences of 10 GDH-HI children and their relatives.@*Results@#Of the 10 GDH-HI children, 9 had normal birth weight and 1 was a giant. Nine patients were accompanied by asymptomatic hyperammonemia, and one had normal blood ammonia. 9 had ever been treated with diazoxide, which was all effective. All 10 children carried GLUD1 gene mutations, 5 patients carried c. 965C>T (p.R322H) GLUD1 gene mutation, and the remaining 5 cases carried c. 1388A>T (p.N463I), c. 1495C>A(p.G499C), c. 1493C>T(p. S498L), c. 1519G>A(p.H507Y) and c. 1388A>G(p.N463S), respectively. 9 cases (90%) had de novo mutations, and 1 case had paternal autosomal dominant inheritance. 8 children were followed up in long term. One child had spontaneous remission in 8 years after being diagnosed, and seven patients required long-term oral diazoxide to maintain normal blood glucose levels, two of whom had epilepsy.@*Conclusions@#The birth weight of children with GDH-HI in China was usually normal. A small number of GDH-HI children had normal serum ammonia levels. Most of the GLUD1 gene mutations in GDH-HI children in China were de novo mutations, among which the GDH p. R322H mutation was a hot spot mutation in Chinese children with GDH-HI. Most of GDH-HI children were diazoxide-responsive. As the disease progresses, some children may have epilepsy, and a few children have a tendency to relieve by themselves.

Descripción de la experiencia en pacientes diagnosticados con insulinoma. Estudio multicéntrico en Medellín, Colombia / Description of the experience with patients with insulinoma diagnosis. Multicentric study in Medellín, Colombia

RESUMEN Objetivo: describir la experiencia de los pacientes con insulinoma, diagnosticados y tratados entre los años 2002 y 2017 en tres hospitales de la ciudad de Medellín, Colombia. Métodos: estudio descriptivo y retrospectivo de pacientes con criterios bioquímicos para hipoglucemia hiperinsulínica y confirmación histopatológica de insulinoma. Resultados: se estudiaron 19 casos, 10 eran mujeres (52,6 %), la edad media al diagnóstico fue 43 años (D.E 15,5). Hubo cuatro casos de insulinoma multifocal (21,1 %), tres asociados con NEM-1 (15,8 %) y dos malignos (10,6 %). Todos presentaron hipoglucemia en ayunas y 63,2 % posprandial. En la prueba de ayuno, el nadir de glucemia sucedió antes de 48 horas en todos los casos, en promedio 9 horas (D.E 8,0). El diagnóstico bioquímico fue realizado con hipoglucemia e insulina elevada en todos los casos, aunque el péptido C fue reportado en nueve pacientes (47,3 %) y las sulfonilureas en dos (11,1 %). La localización preoperatoria se hizo por imágenes en 12 individuos (68,5 %) y las pruebas invasivas fueron necesarias en seis (31,5 %). Las pruebas diagnósticas fueron positivas en un 83 % para resonancia, 50 % para ecografía endoscópica y prueba de estímulo intraarterial con calcio y 100 % para ecografía intraoperatoria. La cirugía se realizó en 18 casos (94,7 %). La mortalidad (15,8 %) fue derivada de complicaciones en el posoperatorio temprano; la curación se logró en todos los casos. Conclusiones: el insulinoma en nuestro medio tiene características demográficas y clínicas similares a otras series. Existen limitaciones locales para el acceso a los estudios bioquímicos y en el rendimiento diagnóstico de las pruebas de localización.

SUMMARY Objective: The objective of the study was to describe the characteristics of patients with insulinoma in three hospitals in Medellín, Colombia, between 2002 and 2017. Methods: A retrospective analysis of patients with hyperinsulinemic hypoglycemia and histologic confirmation of insulinoma was conducted. Results: A total of 19 cases were identified. Ten women (52.6 %) and 9 males (47.4 %). The mean age at diagnosis was 43 years (S.D: 15.5). Four cases had multifocal insulinoma (21.1%), 3 cases were secondary to multiple endocrine neoplasia type 1 (15.8 %), and 2 of them were malignant (10.6 %). All patients presented fasting hypo-glycemia, and 63.2% presented post-prandial hypoglycemia. Glucose nadir in the fasting test occurred in the first 48 hours in all cases, with a mean time to hypoglycemia of 9 hours (S.D 8.0). The biochemical diagnosis was done with increased insulin in the presence of hypoglycemia. C-peptide was done in 9 patients (47.3 %), and sulfonylureas in 2 cases (11.1 %). Preoperative localization was done by imaging in 12 cases (68.5 %), and invasive tests were required in 6 cases (31.5 %). Localization tests were positive as follows: magnetic resonance imaging in 83%, endoscopic ultrasound in 50%, selective intra-arterial calcium injection in 50 %, and intraoperative ultrasound in 100%. Eighteen patients (94. 7%) underwent surgery. Mortality (15.8 %) was secondary to early post-operative complications. Conclusions: The characteristics of patients with insulinoma in Medellín are similar to other series. However, there are important local limitations for proper biochemical testing and imaging localization. This is the largest study in our country.

Hiperinsulinismo congénito por mutación del gen ABCC8 / Congenital hyperinsulinism due to the ABCC8 gene mutation / Hiperinsulinismo congênito causado por mutação do gen ABCC8

Resumen: El hiperinsulinismo congénito es la causa más común de hipoglucemia persistente en el recién nacido y la infancia, con un alto riesgo de daño neurológico irreversible. En los últimos años, gracias a los avances en el conocimiento de la genética molecular, se ha avanzado y profundizado en sus bases genéticas; sin embargo, el diagnóstico se sigue realizando en muchas ocasiones demasiado tarde, dada la heterogeneidad que presenta esta enfermedad. Se detalla a continuación el caso de una paciente con hipoglicemias de difícil control desde el nacimiento, secundaria a hiperinsulinismo congénito y en cuyo estudio genético se evidenció mutación del gen ABCC8.

Summary: Congenital hyperinsulinism (CH) is the most common cause of persistent hypoglycemia in newborns and children at a high risk of irreversible neurological damage. In spite of the recent progress made by the molecular genetics' genetic base, diagnosis is still often late, given the heterogeneity of this disease. We hereby report the case of a patient ranging from secondary and difficult to control hypoglycemia to congenital hyperinsulinemia. Her genetic test showed ABCC8 gene mutation.

Resumo: O hiperinsulinismo congênito (HC) é a causa mais comum de hipoglicemia persistente em recém-nascidos e crianças com alto risco de dano neurológico irreversível. Apesar dos recentes progressos realizados pela base genética da genética molecular, o diagnóstico ainda é frequentemente realizado tarde demais, dada a heterogeneidade dessa doença. Relatamos o caso duma paciente que varia de hipoglicemia secundária e de difícil controle a hiperinsulinemia congênita. Seu teste genético mostrou mutação no gene ABCC8.

Hipoglucemia por hiperinsulinismo endógeno / Endogenous hyperinsulinism hypoglycemia

RESUMEN La hipoglucemia por hiperinsulinismo endógeno constituye un reto terapéutico. Se describen las características clínicas, bioquímicas e imagenológicas de pacientes con diagnóstico de hiperinsulinismo endógeno atendidos en el Instituto Nacional de Endocrinología en el periodo 2004-2018(AU)

ABSTRACT Hypoglycemia due to endogenous hyperinsulinism constitutes a therapeutic challenge. The clinical, biochemical and imaging characteristics of patients diagnosed with endogenous hyperinsulinism treated at the National Endocrinology Institute from 2004 to 2018 are described(AU)

Hypoglycemia caused by co-secretion of insulin from lung tumor and cardia cancer: first case report

ABSTRACT CONTEXT: Non-islet-cell-tumor-induced hypoglycemia (NICTH) is caused on rare occasions by secretion of insulin from tumor cells that are reported to have a single tissue origin. CASE REPORT: A 67-year-old male patient had cardia adenocarcinoma and concomitant lung adenocarcinoma with extensive metastases and repeated episodes of intractable hypoglycemia. Immunohistochemical staining for insulin showed that lung adenocarcinoma stained positive and gastric cardia adenocarcinoma stained weakly positive. These results indicate that tumor cells of different tissue origins co-secreted insulin. CONCLUSIONS: This is the first report on intractable hypoglycemia due to co-secretion of insulin from two kinds of primary tumor cells in a single patient.

Gene mutation and treatment of neonatal congenital hyperinsulinism / 中国新生儿科杂志

Objective To summarize the gene mutation,treatment and prognosis of neonatal congenital hyperinsulinism (CHI) cases.Method The gene mutation and treatment of newborn infants who were admitted to the neonatal center of Beijing Children's Hospital between February 2015 and February 2018 with confirmed CHI diagnosis and whole exome sequencing (WES) results were retrospectively summarized.Result Totally 8 infants (5 boys and 3girls) were included.The onset age was (13.2±6.1) h (2 h ～ 2 d).The main clinical presentations were inactivity,seizures and poor feeding.Among the 8 patients,3 were positively responded to diazoxide,5 were negative and then been treated by octreotide.Among these 5 cases,3 were positively responded to octreotide (with stable blood glucose level after discharged home and till 6 months of age) and 2 were negative to both diazoxide and octreotide (1 had partial pancreatectomy afterwards but still had 1～2 episodes pf hypoglycemia till 6 months post-operational periods,another 1 died with unknown detail information soon after the parents quit further medical intervention).All 8 cases had heterozygous gene mutations.7 out of the 8 cases were ABCC8 gene (encoding islet beta-cell potassium channel protein sulfonylurea receptor protein SUR1) mutation on different sites including c.4414G＞A,c.221G＞A,c.1773C＞G,c.4352T＞C,c.2924-9C＞T,c.4198+ 1G＞T,c.2509C＞T,c.2331G＞A,c.4316A＞G and c.47G＞C.Among these 7 cases,3 were complicated heterozygous mutations with completely no response to diazoxide (2 out of the 3 were positively responded to octreotide,1 out of the 3 was negative to octreotide)and the other 4 were simple heterozygous mutations (2 out of the 4 were positively responded to diazoxide,1 out of the 4 was negative to diazoxide but positive to octreotide,and 1 out of the 4 was negative to both diazoxide and octreotide).1 out of the 8 cases was heterozygous GLUD1 gene mutation at c.1388A＞T site and had positive therapeutic responses to diazoxide.All 5 out of the 8 cases with negative therapeutic response to diazoxide had ABCC8 gene mutation.Conclusion ABCC8 gene encoding islet beta-cellpotassium channel protein sulfonylurea receptor protein SUR1 is the most common gene to have mutation io CHI.Mutations at multiple sites of this gene may cause CHI.Various therapeutic responses to medications might be related to different types of gene mutation.

Tracer Accumulation in Relation to Venous Thrombus on ¹⁸F-DOPA PET/CT in a Case of Persistent Hyperinsulinemic Hypoglycemia of Infancy / 대한핵의학회잡지

¹⁸F-DOPA PET/CT is commonly done in patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) to look for any focal lesion in the pancreas.We present the findings in a 20-day-old neonate with PHHI who underwent ¹⁸F-DOPA PET/CT. The scan showed diffuse uptake in the pancreas with no focal lesion, physiologic excretion into the genito-urinary system, and interestingly tracer accumulation was seen in the inferior vena cava and ilio-femoral veins which is a non-physiological site for tracer accumulation. The uptake corresponded to a large venous thrombus which was confirmed by a venous Doppler.