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.

Molecular Characterization and Management of Congenital Hyperinsulinism: A Tertiary Centre Experience

Background: There is limited data from India regarding medical management of congenital hyperinsulinism (CHI). Objective: To study the molecular diagnosis, medical management and outcomes of children with CHI. Study design: Ambispective. Participants: Children with CHI admitted in from December, 2011 till March, 2020 at a tertiary care referral hospital. Outcomes: Clinical and genetic profile, treatment, and response Results: 42 children with a median age of 3 days (range 1 day to 6 years) were enrolled, of which 23 (54.7%) were diazoxideresponsive. Mutations were identified in 28 out of 41 (68.2%) patients. The commonest gene affected was ABCC8 in 22 patients. The pathogenic variant c.331G>A in ABCC8 gene was identified in 6 unrelated cases from one community. Good response to daily octreotide was seen in 13 of the 19 (68.4%) diazoxide-unresponsive patients. Monthly long-acting octreotide was initiated and daily octreotide could be stopped or tapered in 9 patients. Sirolimus was tried with variable response in 6 patients but was discontinued in 5 due to adverse effects. Four patients had focal CHI, of which one underwent partial pancreatic resection. The disease severity reduced with age and neurodevelopment was good in the patients with identifiable genetic defects who were optimally managed. Conclusions: Medical management of CHI is effective, if compliance can be ensured, with good quality of life and neurological outcomes.

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.

Lanreotide and diazoxide have comparable effects on glucose levels in an elderly Japanese insulinoma patient: a case report / Journal of Rural Medicine

An insulinoma is a pancreatic neuroendocrine tumor that causes hypoglycemia. In the elderly, as surgery is not always possible, drugs are an important alternative. However, the effects of lanreotide on insulinomas have not yet been elucidated. We report the case of an 85-year-old Japanese woman who was admitted for loss of consciousness and hypoglycemia, which was resolved after intravenous glucose infusion. Insulin secretion was not inhibited during hypoglycemia. Enhanced computed tomography and OctreoScan scintigraphy revealed a pancreatic tumor (diameter, 13 mm) with radiotracer accumulation. Thus, clinical insulinoma was confirmed. However, the patient refused further examination and surgery. Diazoxide (150 mg/day) therapy resolved hypoglycemia but caused fluid retention. Consequently, we switched to lanreotide (120 mg/6 weeks). Continuous glucose monitoring revealed that both drugs had comparable effects on interstitial glucose normalization. Furthermore, 447 days after the initiation of lanreotide treatment, the patient had no hypoglycemic symptoms. Therefore, lanreotide may be a useful alternative treatment option for inoperable insulinomas in elderly individuals.

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.

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.

Study on the Effect Mechanism of Diazoxide on the Proliferation and Apoptosis of Chondrocytes with Oxidative Injury / 中国药房

OBJECTIVE： To investigate the effect mechanism of diazoxide on the proliferation and apoptosis of chondrocytes with oxidative injury based on endoplasmic reticulum stress （ERS） pathway. METHODS： SD mice were selected for primary culture of articular chondrocytes. The 3rd generation chondrocytes were randomly divided into control group， injury model group and diazoxide group. Control group didn’t receive any treatment. The injury model group was incubated with 300 μmol/L hydrogen peroxide （H2O2） at 37 ℃ for 8 h. Diazoxide group was pretreated with 300 μmol/L diazoxide at 37 ℃ for 0.5 h，and then incubated with 300 μmol/L H2O2 for 8 h. The proliferation of chondrocytes was detected by CCK-8 assay. The apoptosis rate of chondrocytes was detected by flow cytometry. The expression of ERS-related proteins [Caspase-3， Bcl-2-associated X（Bax），C/EBP homologous protein （CHOP）] were detected by Western blotting assay. RESULTS： Compared with control group， the proliferation activity of chondrocytes in injury model group was significantly decreased， while apoptosis rate was increased significantly（P＜0.05）；the protein expression of Caspase-3， Bax and CHOP were increased significantly （P＜0.05）. Compared with injury model group， the proliferation activity of chondrocytes in diazoxide group was increased significantly， while the apoptosis rate was decreased significantly （P＜0.05）； the expression of above related proteins were decreased significantly （P＜0.05）. CONCLUSIONS： Diazoxide can improve the proliferation activity of chondrocytes with oxidative injury and inhibit their apoptosis by inhibiting ERS pathway.

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.

Therapeutic efficacy analysis of diazoxide in treating 145 cases of congenital hyperinsulinism / 中华胰腺病杂志

Objeetive To analyze the efficacy and safety of diazoxide treatment in patients with congenital hyperinsulinism (CHI).Methods The clinical data of 145 patients diagnosed with CHI hospitalized in Beijing Children's Hospital affiliated to Capital Medical University from February 2002 to January 2016 who received diazoxide treatment were retrospectively analyzed.We conducted a detailed analysis on the efficacy,side effects and prognosis of diazoxide treatment for CHI.Results In 145 patients,there were 89 patients (61.4％) who were responsive to diazoxide and 23 patients (15.9％) unresponsive to diazoxide,and the treatment effect of diazoxide for the other 33 cases (22.8％) was still unclear.In the diazoxide effective group,there were 22 cases (24.7％) of neonatal onset,32 cases (36.0％)of onset from 1-6 months after birth and 35 cases (39.3％) of onset after 6 months of birth,and the birth weight was normal in 67 cases,macrosomia in 16 cases,low in 5 cases and unknown in 1 case.In the diazoxide ineffective group,there were 14 cases (60.8％) of neonatal onset,7 cases (30.4％) of onset from 1-6 months after birth and 2 cases (8.6％)of onset after 6 months of birth,and the birth weight was normal in 9 cases and macrosomia in 14 cases.In the unclear diazoxide effect group,there were 20 cases (60.6％) of neonatal onset,9 cases (27.34％) of onset from 1-6 months after birth and 4 cases (12.1％) of onset after 6 months of birth,and the birth weight was normal in 15 cases and macrosomia in 18 cases.After the application of diazoxide,65 cases (44.8％) had hirsutism,and 43 patients (29.7％) had gastrointestinal side effects.In the diazoxide effective group,the symptom of hypoglycemia was spontaneously alleviated at the age of from 3 months to 7 years old in 20 patients (22.5％),and 33 patients continued to be treated by diazoxide.In the diazoxide ineffective group,the symptom of hypoglycemia was spontaneously alleviated around the age of 1 years old in 4 patients (17.3％),5 patients were treated by octreotide in long term to maintain normal blood sugar level,4 patients received pancreectomy including 3 with normal blood sugar and 1 with occasional hypoglycemia after surgery.In the unclear diazoxide effect group,the symptom of hypoglycemia was spontaneously alleviated at the age of from 10 months to 3 years old in 4 patients (12.1％),2 patients were treated by octreotide in long term to maintain normal blood sugar level,8 patients received pancreatectomy including 5 with controlled blood sugar after surgery.Conclusions Diazoxide is effective in treating CHI children.The efficiency may be higher for the CHI with normal birth weight or whose onset age is after the neonatal period.

Effects of diazoxide in experimental acute necrotizing pancreatitis

OBJECTIVE: We aimed to assess the effects of diazoxide on the mortality, pancreatic injury, and inflammatory response in an experimental model of acute pancreatitis. METHODS: Male Wistar rats (200-400 g) were divided randomly into two groups. Fifteen minutes before surgery, animals received physiological (0.9%) saline (3 mL/kg) (control group) or 45 mg/kg diazoxide (treatment group) via the intravenous route. Acute pancreatitis was induced by injection of 2.5% sodium taurocholate via the biliopancreatic duct. Mortality (n=38) was observed for 72 h and analyzed by the Mantel-Cox Log-rank test. To study pancreatic lesions and systemic inflammation, rats (10 from each group) were killed 3 h after acute pancreatitis induction; ascites volume was measured and blood as well as pancreases were collected. Pancreatic injury was assessed according to Schmidt's scale. Cytokine expression in plasma was evaluated by the multiplex method. RESULTS: Mortality at 72 h was 33% in the control group and 60% in the treatment group (p=0.07). Ascites volumes and plasma levels of cytokines between groups were similar. No difference was observed in edema or infiltration of inflammatory cells in pancreatic tissues from either group. However, necrosis of acinar cells was lower in the treatment group compared to the control group (3.5 vs. 3.75, p=0.015). CONCLUSIONS: Treatment with diazoxide can reduce necrosis of acinar cells in an experimental model of acute pancreatitis, but does not affect the inflammatory response or mortality after 72 h.

Congenital hyperinsulinism: diagnostic and management challenges in a developing country – case report

Management of congenital hyperinsulinemia of infancy (CHI) is challenging. A 4-month-old female infant with persistent hypoglycemia and elevated insulin levels was diagnosed with CHI. Gallium-68 DOTANOC positron emission tomography/computed tomography (PET/CT) scan (⁶⁸Ga-labeled [1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid]-1-NaI3-octreotide) demonstrated focal disease in the body of the pancreas. Genetic studies indicated paternal inheritance, making focal disease likely. She was started on diazoxide therapy with partial improvement in blood glucose levels. Due to a suboptimal response to diazoxide and the likelihood of focal disease amenable to surgery, a laparoscopic subtotal pancreatectomy with preservation of the head of the pancreas was performed. The biopsy demonstrated diffuse hyperplastic pancreatic islet cells on immunohistochemistry, indicative of diffuse rather than focal disease. Paternal inheritance is a recognized indicator of focal disease. Gallium-68 DOTANOC PET/CT scan is the only available imaging modality in South India as ¹⁸F-L-dihydroxyphenylalanine (DOPA) PET/CT scan is not available at present. A laparoscopic approach reduces the postoperative recovery time and morbidity in such patients. The absence of ¹⁸F-L-DOPA PET/CT scan and the limited supply of diazoxide makes the management of this complex condition more challenging in developing countries.

Clinical characteristics and gene mutations analysis of 56 patients with congenital hyperinsulinism / 中华实用儿科临床杂志

Objective To analyze the clinical characteristics and gene mutations of 56 patients with congenital hyperinsulinism(CHI)and to provide a theoretical basis for clinical diagnosis and treatment of CHI.Methods Fifty-six children who were diagnosed as CHI between February 2002 and January 2016 in Beijing Children's Hospital Affiliated to Capital Medical University were selected as research subjects.A retrospective study was done about the clinical data and the treatment procedures of the 56 patients,such as perinatal conditions,clinical manifestations,laboratory data,treatments,prognosis and so on.Polymerase chain reaction(PCR)-DNA technology or next-generation sequencing technology was used to analyze the CHI relevant genes of the 56 patients.Results Thirty of the 56 patients carried CHI gene mutation.(1)Twenty-three of 56 patients(41.0％)carried ABCC8/KCNJ11 gene mutations:4 of 23 patients carried complex heterozygous mutation,1 of 23 patients carried both ABCC8 and KCNJ11 gene mutation,1 of 23 patients carried maternally inherited ABCC8 gene mutation,12 of 23 patients carried paternally inherited ABCC8 gene mutation,1 of 23 patients carried paternally inherited KCNJ11 gene mutation,3 of 23 patients carried de novo ABCC8 gene mutation,1 of 23 patients had unknown genetic way,19 of 23 patients were treated with Diazoxide,2 of 19 patients were responsive to Diazoxide,7 of 19 patients were unresponsive to Diazoxide and 10 of 19 patients were uncertain to Diazoxide.(2)Five of 56 patients(8.9％)carried GLUD1 gene mutation,4 of 5 patients were treated with Diazoxide and they were all responsive to Diazoxide.(3)One of 56 patients(1.7％)carried de novo GCK gene mutation,responsive to Diazoxide treatment.(4)One of 56 patients(1.7％)carried maternally inherited SLC16A1 gene mutation,responsive to Diazo-xide treatment.Conclusions The ABCC8 gene and GLUD1 gene mutation are the main causative genes of CHI.The GCK gene and SLC16A1 gene mutation are in the minority.Most ABCC8 gene and KCNJ11 gene mutation are unresponsive to Diazoxide treatment.

Clinical analysis of 194 patients with congenital hyperinsulinism / 中华实用儿科临床杂志

Objective To summarize the clinical data of 194 patients with congenital hyperinsulinism(CHI),in order to provide the theoretical basis for the diagnosis,treatment and prognosis of CHI.Methods One hundred and ninety-four patients with CHI hospitalized in Beijing Children's Hospital Affiliated to Capital Medical University from February 2002 to January 2016 were recruited.Clinical data of 194 patients were collected and clinical characteristics and treatment were retrospectively analyzed.Results One hundred and forty-four cases in 194 patients were treated with Diazoxide,among whom,88 cases were responsive to Diazoxide,23 cases were unresponsive to Diazoxide,and 33 cases were uncertain to Diazoxide.Twenty-six cases in 194 cases were treated with Octreotide,among whom,16 cases were responsive to Octreotide,5 cases were unresponsive to Octreotide,and 5 cases were uncertain to Octreotide.Eleven cases in 194 cases had the 18 Fluoride-L-dihydroxyphenylalanine positron emission computerized tomography scan (18-F-L-DOPA-PET scan),among whom,7 cases were identified as focal lesion and 4 cases were identified as diffuse lesion.Twelve cases in 194 cases were treated with pancreatectomy,among whom,4 cases achieved normal blood glucose levels,4 cases still suffered from persistent hypoglycemia,3 cases had type 1 diabetes mellitus,and 1 case dropped out after the surgery.Forty-five cases in 194 cases had spontaneous remission and the remission time varied from 1 month to 8 years.Conclusions (1) Diazoxide is the first line drug of CHI.The older age onset is,the higher possibility of responsive to Diazoxide shows.(2)Octreotide is used as the second line drug.(3)18-F-L-DOPA-PET scan is the first choice to identify the location of CHI and it is useful in distinguishing between focal and diffuse forms.(4) The outcome of CHI patients after pancreatectomy is very different.A proper surgical method should be selected before the surgery.The blood glucose should be detected after surgery for a long time.(5) Some patients have the tendency of spontaneous remission.

Effects of Diazoxide post conditioning protection on myocardial ischemia-reperfusion injury in non-diabetic rats with stressed hyperglycemia / 中华危重病急救医学

Objective To observe the protective effects of Diazoxide (DZ) on myocardial ischemia and reperfusion (I/R) in non-diabetic rats with stressed hyperglycemia and to explore its possible mechanism. Methods The stressed hyperglycemia (SHG) myocardical I/R model was prepared by ligation of the left anterior descending branch of the coronary artery for 30 minutes and reperfusion for 120 minutes on the healthy adult Sprague-Dawley (SD) rats. Blood sugar was required up to 10 mmol/L in the qualified animal model after ischemia for 30 minutes. The 48 successful model rats were randomly divided into 4 groups (12 in each group): I/R group, low, medium and high dose DZ treated group (LIPO group, MIPO group, HIPO group). Sham-operated group (sham group) was only threaded without deligation. I/R group, LIPO group, MIPO group and HIPO group were challenged to 0.1% dimethyl sulfoxide (DMSO), DZ (0.1% DMSO dissolved) 4, 7, 10 mg/kg for 2 mL, respectively after ischemia for 25 minutes. Hemodynamics indicators were continuously monitored. After reperfusion for 120 minutes, blood glucose, serum creatine kinase (CK) concentration and lactate dehydrogenase (LDH) activity were detected, myocardial infarction area was analyzed by triphenyltetrazolium chloride (TTC) staining, myocardial ultrastructure was observed by electron microscope, expressions of phosphorylated protein kinase B (p-Akt) and phosphorylated glycogen synthase kinase-3β (p-GSK-3β) were detected by Western Blot. Results Compared with sham group, I/R group had an elevated blood glucose, decreased heart rate (HR), systolic diastolic dysfunction, increased myocardial enzymes. Obvious necrosis of myocardium, myocardial tissue edema, mitochondria swelling, cristae, disappearing glycogen granules were observed under electron microscope with TTC staining. After reperfusion for 120 minutes, comparing with I/R group, blood glucose of HIPO group was significantly increased (mmol/L: 16.93±3.22 vs. 14.65±3.61, P < 0.05); the maximum rate of left ventricle internal pressure drop (-dp/dt max) of LIPO group was improved (mmHg/s: -1 055±16 vs. -982±10, P < 0.05) and the infarct size was evidently shrunk [(32.45±3.54)% vs. (41.30±3.21)%, P < 0.05]; left ventricular systolic pressure (LVSP) of MIPO group and HIPO group [LVSP (mmHg, 1 mmHg = 0.133 kPa): 60±2, 74±4 vs. 54±4], left ventricular end-diastolic pressure [LVEDP (mmHg): 24.6±1.5, 18.9±1.3 vs. 27.9±1.6], the maximum rate of left ventricle internal pressure were increased [+dp/dt max (mmHg/s): 1 049±37, 1 262±75 vs. 975±17], and -dp/dt max (mmHg/s: -1 068±21, -1 321±63 vs. -982±10) were improved in different degrees (all P < 0.05); CK (kU/L: 10.7±0.5, 11.0±1.3 vs. 12.9±1.0), LDH (kU/L: 6.8±0.2, 7.8±0.1 vs. 8.8±0.1) was evidently decreased (all P < 0.05), infarct size was smaller [(31.24±2.45)%, (30.81±2.68)% vs. (41.3±3.21)%, all P < 0.05], electron microscope showed that the myocardial injury was repaired. After reperfusion for 120 minutes, compared with sham group, expressions of p-Akt and p-GSK-3β in I/R group have obviously reduced (grey value: 0 vs. 0.187±0.018, 0.110±0.045 vs. 0.200±0.081, both P < 0.05). Compared with I/R group, expressions of p-Akt in HIPO group and p-GSK-3β in LIPO group, MIPO group and HIPO group were obviously increased (grey value: 0.101±0.009 vs. 0; 0.180±0.057, 0.270±0.062, 0.280±0.039 vs. 0.110±0.045, all P < 0.05). But there were significant increase in MIPO group and HIPO group. There was no significant difference in HR among different treatment groups. Conclusions I/R with SHG can significantly inhibit the activity of PI3K/Akt-GSK-3β signaling pathways, middle and high dose of DZ has a protective effect on I/R myocardium complicating with SHG, and middle dose will not lead to evident increase of blood glucose; DZ may act on GSK-3β through PI3K/Akt-GSK-3β signaling pathways, phosphorylate it and inhibit its activity, so as to develop the cardioprotective effect.

Research on the protective effect of diazoxide pretreatment on the blood-brain barrier of rats after cerebral ischemia/reperfusion injury / 中国医师杂志

Objective To investigate the effect and its mechanism of diazoxide on the blood-brain barrier (BBB) of rats after cerebral ischemia/reperfusion (I/R) injury.Methods Sixty Wistar rats were randomly divided into sham operation group,I/R group,and diazoxide pretreatment groups of low,middle,large dose (5,10,20 mg/kg).The I/R models of rats were performed to undergo middle cerebral artery embolism by thread.BBB permeability was estimated by Evans blue (EB) dyeing,transmission electron microscope (TEM) was used to observe the modification of interendothelial tight junction (TJ) of capillaries.The expression of aquaporin-4 (AQP4) in every rat brain tissues was detected by immunity histochemistry technique.Results (1) Compared to sham operation group,the permeability extent of EB were significantly increased by I/R,which was distinctly attenuated in middle and large dose of diazoxide pretreatment rats,while no obvious changes were found between I/R and low dose groups.(2) TEM showed that TJ of the brain tissue opened after I/R injury and no significant opening of TJ was observed in middle and large dose of diazoxide preconditioning groups.(3) Compared to sham operation group,the expression of AQP4 in the brain tissue of the I/R group was apparently increased (P ＜0.01).Compared to I/R group,the expression of AQP4 was apparently increased in middle and large dose pretreatment groups (P ＜ 0.01),and there were no obvious difference between low dose group and the I/R group.Conclusions Preconditioning of ischemia/reperfusion injury with diazoxide protects the blood-brain barrier,which may due to keep the TJ closed and decrease expression of AQP4 protein.

Effects of insulin intervention and diazoxide after-treatment on myocardial ischemia/reperfusion injury in diabetic rats / 中华危重病急救医学

Objective To study the effect and possible mechanism of diazoxide on myocardial ischemia/reperfusion (I/R) injury in diabetic rats, and the influence of insulin intervention which aims to maintain blood sugar levels within the normal range on the protective function of cardiomyocytes. Methods 126 health male Sprague-Dawley (SD) rats were intraperitoneally injected with one dose of 60 mg/kg streptozotocin (STZ) to reproduce diabetic model. The diabetic rats were randomly divided into seven groups, with 18 rats in each group. Myocardial I/R model was established by 30 minutes ligation of the left anterior descending branch of the coronary artery, and 120 minutes blood circulation recover. Sham group was only threaded without ligation. Rats in I/R group, diazoxide group (DZ group), and Ottawa vine penicillin (WNT) group were infused intravenously with 2 mL of 0.1% dimethyl sulphoxide (DMSO), DZ (7 mg/kg), and WNT (15 μg/kg), respectively, after 25 minutes of ischemia. Sham group was only injected with 2 mL of 0.1% DMSO. DZ+WNT group was infused with WNT 5 minutes before the injection of DZ. Insulin intervention (RI) group received a continuous insulin infusion to maintain the blood sugar at the level of 4-6 mmol/L. RI+DZ group was infused with DZ after ischemia for 25 minutes based on blood sugar control. Hemodynamic parameters in each group were monitored continuously. The pathological changes of myocardium were observed with hematoxylin and eosin (HE) staining. The expressions of phosphorylated protein kinase B (p-Akt) and phosphorylated glycogen synthase kinase-3β (p-GSK-3β) were determined by Western Blot. Results Compared with sham group, the cardiac functions of the intervention groups were significantly decreased, and severe myocardial injury was observed. Compared with I/R group, the cardiac functions of intervention groups were not obviously improved. However, after insulin intervention by which blood sugar was maintained within normal range, the cardiac function and myocardial injury were further aggravated. Compared with sham group (the expression value of sham group was set as 1), the expressions of p-Akt in other groups including I/R group, DZ group, RI group, and RI+DZ group showed no statistically significant difference (gray value: 1.07±0.09, 1.03±0.07, 1.07±0.07, 1.02±0.08 vs. 1.00, all P > 0.05). However, the expressions of p-Akt were decreased in WNT group and DZ+WNT group as compared with those of sham group and I/R group (gray value: 0.54±0.06, 0.51±0.05 vs. 1.00 and 1.07±0.09, all P 0.05). However, the expression of pGSK-3β was increased in RI group, RI+DZ group as compared with sham group and I/R group (gray value: 1.68±0.08, 1.70±0.05 vs. 1.00 and 0.97±0.08, all P < 0.05), and it was significantly higher in RI+DZ group than that of DZ group (gray value: 1.70±0.05 vs. 1.00±0.11, P < 0.05). Conclusions Diazoxide after myocardial injury could not protect the myocardium from I/R injury in diabetic rats, and did not trigger the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Insulin intervention by which blood sugar was maintaine d within the normal range exacerbates myocardial I/R injury in diabetic rats.

Genetic pathogenesis and current trends in diagnosis and therapy of ATP-sensitive potassium channel congenital hyperinsulinism / 中华实用儿科临床杂志

ATP-sensitive potassium channel congenital hyperinsulinism (KATP-HI) is the most common and most severe type of congenital hyperinsulinism,accounting for 40％-45％.It is due to the inactivating mutations of the ABCC8 and KCNJ11 gene which encode the ATP-sensitive potassium channel.Diazoxide is the main and preferred therapy for KATP-HI.For KATP-HI children who are unresponsive to medical therapy usually need different degrees of pancreatectomy to maintain normal blood sugar level.

Hyperinsulinemic Hypoglycemia in Infancy: Current Concepts in Diagnosis and Management.

Purpose: Molecular basis of various forms of hyperinsulinemic hypoglycemia, involving defects in key genes regulating insulin secretion, are being increasingly reported. However, the management of medically unresponsive hyperinsulinism still remains a challenge as current facilities for genetic diagnosis and appropriate imaging are limited only to very few centers in the world. We aim to provide an overview of spectrum of clinical presentation, diagnosis and management of hyperinsulinism. Methods: We searched the Cochrane library, MEDLINE and EMBASE databases, and reference lists of identified studies. Conclusions: Analysis of blood samples, collected at the time of hypoglycemic episodes, for intermediary metabolites and hormones is critical for diagnosis and treatment. Increased awareness among clinicians about infants “at-risk” of hypoglycemia, and recent advances in genetic diagnosis have made remarkable contribution to the diagnosis and management of hyperinsulinism. Newer drugs like lanreotide (long acting somatostatin analogue) and sirolimus (mammalian target of rapamycin (mTOR) inhibitor) appears promising as patients with diffuse disease can be treated successfully without subtotal pancreatectomy, minimizing the long-term sequelae of diabetes and pancreatic insufficiency. Newer insights in understanding the molecular and histological basis and improvements in imaging and surgical techniques will modify the approach to patients with congenital hyperinsulinism.

Effect of mitochondrial potassium channel on the renal protection mediated by sodium thiosulfate against ethylene glycol induced nephrolithiasis in rat model

Purpose: Sodium thiosulfate (STS) is clinically reported to be a promising drug in preventing nephrolithiasis. However, its mechanism of action remains unclear. In the present study, we investigated the role of mitochondrial KATP channel in the renal protection mediated by STS. Materials and Methods: Nephrolithiasis was induced in Wistar rats by administrating 0.4% ethylene glycol (EG) along with 1% ammonium chloride for one week in drinking water followed by only 0.75% EG for two weeks. Treatment groups received STS, mitochondrial KATP channel opener and closer exclusively or in combination with STS for two weeks. Results: Animals treated with STS showed normal renal tissue architecture, supported by near normal serum creatinine, urea and ALP activity. Diazoxide (mitochondria KATP channel opening) treatment to the animal also showed normal renal tissue histology and improved serum chemistry. However, an opposite result was shown by glibenclamide (mitochondria KATP channel closer) treated rats. STS administered along with diazoxide negated the renal protection rendered by diazoxide alone, while it imparted protection to the glibenclamide treated rats, formulating a mitochondria modulated STS action. Conclusion: The present study confirmed that STS render renal protection not only through chelation and antioxidant effect but also by modulating the mitochondrial KATP channel for preventing urolithiasis.

Role of atp-dependent k channels in the effects of erythropoietin in renal ischaemia injury.

Background & objectives: Erythropoietin (EPO) has cytoprotective and anti-apoptotic effects in pathological conditions, including hypoxia and ischaemia-reperfusion injury. One of the targets to protect against injury is ATP-dependent potassium (KATP ) channels. These channels could be involved in EPO induced ischaemic preconditoning like a protective effect. We evaluated the cell cytoprotective effects of EPO in relation to KATP channel activation in the renal tubular cell culture model under hypoxic/normoxic conditions. Methods: Dose and time dependent effects of EPO, KATP channel blocker glibenclamide and KATP channel opener diazoxide on cellular proliferation were evaluated by colorimetric assay MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] under normoxic and hypoxic conditions in human renal proximal tubular cell line (CRL-2830). Evaluation of the dose and time dependent effects of EPO, glibenclamide and diazoxide on apoptosis was done by caspase-3 activity levels. Hypoxia inducible factor-1 alpha (HIF-1 α) mRNA levels were measured by semi-quantative reverse transcription polymerase chain reaction (RT)-PCR. Kir 6.1 protein expresion was evalutaed by western blot. Results: Glibenclamide treatment decreased the number of living cells in a time and dose dependent manner, whereas EPO and diazoxide treatments increased. Glibenclamide (100 μM) treatment significantly blocked the anti-apoptotic effects of EPO (10 IU/ml) under both normoxic and hypoxic conditions. EPO (10 IU/ml) and diazoxide (100 μM) treatments significantly increased (p<0.01) whereas glibenclamide decreased (p<0.05) HIF-1 α mRNA expression. Glibenclamide significantly (p<0.01) decreased EPO induced HIF-1 α mRNA expression when compared with the EPO alone group. Interpretation & conclusions: Our results showed that the cell proliferative, cytoprotective and anti-apoptotic effects of EPO were associated with KATP channels in the renal tubular cell culture model under hypoxic/normal conditions.