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Objective Hypoglycemia, the most common metabolic derangement in the newborn period remains a contentious issue, not only due to various numerical definitions, but also due to limited therapeutical options which either lack evidence to support their efficacy or are increasingly recognized to lead to adverse reactions in this population. This study aimed to investigate neonatologists' current attitudes in diagnosing and managing transient and persistent hypoglycemia in newborns admitted to the Neonatal Intensive Care Unit (NICU). Methods A web-based electronic survey which included 34 questions and a clinical vignette was sent to U.S. neonatologists. Results There were 246 survey responses with most respondents using local protocols to manage this condition. The median glucose value used as the numerical definition of hypoglycemia in first 48 hours of life (HOL) for symptomatic and asymptomatic term infants and preterm infants was 45 mg/dL (2.5 mmol/L; 25–60 mg/dL; 1.4–3.3 mmol/L), while after 48 HOL the median value was 50 mg/dL (2.8 mmol/L; 30–70 mg/dL; 1.7–3.9 mmol/L). There were various approaches used to manage transient and persistent hypoglycemia that included dextrose gel, increasing caloric content of the feeds using milk fortifiers, using continuous feedings, formula or complex carbohydrates, and use of various medications such as diazoxide, glucocorticoids, and glucagon. Conclusion There is still large variability in current practices related to hypoglycemia. Further research is needed not only to provide evidence to support the values used as a numerical definition for hypoglycemia, but also on the efficacy of current strategies used to manage this condition. Key Points Numerical definition of glucose remains variable. Strategies managing transient and persistent hypoglycemia are diverse. There is a need for further research to investigate efficacy of various treatment options. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting KATP channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that KATP channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction. [ABSTRACT FROM AUTHOR]

Inward rectifying potassium channels sensitive to ATP levels (KATP) have been the subject of investigation for several decades. Modulators of KATP channels are well-established treatments for metabolic as well as cardiovascular diseases. Experimental studies have also shown the potential of KATP modulation in neurodegenerative disorders. However, to date, data regarding the effects of KATP antagonists/agonists in experiments related to neurodegeneration remain inconsistent. The main source of confusion in evaluating available data seems to be the choice of experimental models. The present study aims to provide a comprehensive understanding of the effects of both opening and blocking KATP channels in two forms of SH-SY5Y cells. Our results offer valuable insights into the significance of metabolic differences between differentiated and non-differentiated SH-SY5Y cells, particularly in the context of glibenclamide and diazoxide effects under normal conditions and during the initiation of pathological events simulating Parkinson's disease in vitro. We emphasize the analysis of mitochondrial functions and changes in mitochondrial network morphology. The heightened protein expression of KATP channels identified in non-differentiated SH-SY5Y cells seems to be a platform for a more significant impact of KATP modulators in this cell type. The efficiency of rotenone treatment in inducing morphological changes in the mitochondrial network depends on the differentiation status of SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Diazoxide is a commonly used first-line medication for the treatment of hyperinsulinism. Hyperglycemia may occur with diazoxide use. However, hyperglycemic hyperosmolar state (HHS) secondary to diazoxide is an exceedingly rare but potentially life-threatening adverse effect. We present a case of a 2-year-old with Kabuki syndrome and hyperinsulinism on diazoxide. She presented with 4 days of fever, respiratory symptoms, and lethargy. She was influenza B positive. Initial workup indicated HHS, with an elevated serum glucose (47.1 mmol/L [847.8 mg/dL]; reference range 3.9-6.0 mmol/L; 70-108 mg/dL), serum osmolality (357 mmol/kg H2O; reference 282-300 mmol/kg H2O) but absent urine ketones and no metabolic acidosis (venous pH 7.34). Her course was complicated by an acute kidney injury. Management in the hospital included discontinuation of diazoxide and intravenous fluid resuscitation, following which hyperglycemia and hyperosmolarity resolved. No insulin therapy was required. She remained normoglycemic without diazoxide for 2 weeks but subsequently required restarting of diazoxide for hypoglycemia. This case highlights the need for early recognition and prompt management of diazoxide-related HHS to reduce negative outcomes. We present the first case report of a child with Kabuki syndrome and hyperinsulinism with diazoxide-induced HHS. [ABSTRACT FROM AUTHOR]

Context Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI). Objective To characterize the clinical and molecular features of HI in children with KS. Design Retrospective cohort study of children with KS and HI evaluated between 1998 and 2023. Setting The Congenital Hyperinsulinism Center of the Children's Hospital of Philadelphia. Patients Thirty-three children with KS and HI. Main Outcome Measure(s) HI presentation, treatment, course, and genotype. Results Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (interquartile range [IQR], 0.6-6.1 months). Median age at KS diagnosis was 5 months (IQR, 2-14 months). Diagnosis of HI preceded KS diagnosis in 20 children (61%). Twenty-four children (73%) had a pathogenic variant in KMT2D , 5 children (15%) had a pathogenic variant in KDM6A , and 4 children (12%) had a clinical diagnosis of KS. Diazoxide trial was conducted in 25 children, 92% of whom were responsive. HI treatment was discontinued in 46% of the cohort at median age 2.8 years (IQR, 1.3-5.7 years). Conclusion Hypoglycemia was recognized at birth in most children with KS and HI, but HI diagnosis was often delayed. HI was effectively managed with diazoxide in most children. In contrast to prior reports, the frequency of variants in KMT2D and KDM6A were similar to their overall prevalence in individuals with KS. Children diagnosed with KS should undergo evaluation for HI, and, because KS features may not be recognized in infancy, KMT2D and KDM6A should be included in the genetic evaluation of HI. [ABSTRACT FROM AUTHOR]

Congenital hyperinsulinism (CHI) is the most common form of persistent hypoglycemia in infants, and diazoxide is the most widely used drug for its treatment. Diazoxide suppresses insulin secretion and attenuates hypoglycemia by binding to sulfonylurea receptor 1 and activating KATP channels. While the short-term side effects of this drug, such as edema and blood cell abnormalities, are well known, the clinical course after its long-term oral administration remains unclear. Furthermore, there are currently no case reports clearly demonstrating a causal relationship between diazoxide and impaired glucose tolerance. We herein describe the case of a 9-year-old girl with CHI complicated with Kabuki syndrome who presented with impaired glucose tolerance due to decreased initial insulin secretion and insulin resistance caused by obesity resulting from diazoxide medication. This is a rare case of the insufficient effects of insulin due to the oral administration of diazoxide, and provides insights for managing the long-term administration of diazoxide to children. [ABSTRACT FROM AUTHOR]

\nIntroduction: To evaluate and describe the diagnostic process, medical, nutritional, and surgical approach, and neurological outcome, we report data from a large Italian cohort of patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed 154 CHI patients admitted to Ospedale Pediatrico Bambino Gesù from 1985 to 2022. Results: Hypoglycemia occurred within the first year of life in 85.5% of patients, median time to diagnosis was 1 day (IQR 14 days). Ninety-two percent of patients were treated with diazoxide: 66.9% were responsive. Octreotide was administered to 28.6% of patients: 61.4% were responsive. Forty percent of patients were off-therapy, mostly from diazoxide. Thirty-four percent of patients carried mutations in ABCC8, 12.6% were syndromic, and 9.2% were transient CHI. Surgery was performed in 23/47 diazoxide-unresponsive and 2/95 diazoxide-responsive patients: 64.0% were focal at histology. Combining data from genetics, pancreatic venous sampling, 18F-DOPA PET/CT, and histology, 80.6% resulted diffuse, 16.7% focal, and 2.8% atypical CHI. Post-surgical diabetes developed in 6 patients. Neurocognitive evaluation revealed developmental delay or intellectual disability in 15.7% of 70 patients, mostly of a mild degree. Epilepsy was documented in 13.7% of 139 patients. Conclusion: Our diagnostic and therapeutic results are mainly consistent with the international indications and the CHI Global Registry data, with relatively low rates of neurological outcomes. Good outcomes were likely associated with early diagnosis and prompt management of patients because the majority of patients were diagnosed within 2 weeks. Remarkably, it is of utmost importance to spread the knowledge and refer CHI patients to multidisciplinary expert centers. We present retrospective data from the largest Italian cohort of patients with congenital hyperinsulinism, in order to evaluate our diagnostic and therapeutic process and the neurological outcome. We focused the discussion on some differences from the literature regarding the timing of molecular analysis performed by the use of virtual panels from clinical exome, regardless of diazoxide responsiveness. We also reported a different approach with the surgical intervention, recording a lower rate of subtotal pancreatectomy in case of diffuse forms unresponsive to medical therapy. Furthermore, we have a different strategy of drug discontinuation to test the remission of disease, without the need of the fasting tolerance test. Despite the mentioned deviations from the recent guidelines, the neurological outcome in our cohort is superimposable and lower than other cohorts. [ABSTRACT FROM AUTHOR]

Neonatal hypoglycemia (NH) is broadly defined as a low plasma glucose concentration that elicits hypoglycemia-induced impaired brain function. To date, no universally accepted threshold (reference range) for plasma glucose levels in newborns has been published, as data consistently indicate that neurologic responses to hypoglycemia differ at various plasma glucose concentrations. Infants at risk for NH include infants of diabetic mothers, small or large for gestational age, and premature infants. Common manifestations include jitteriness, poor feeding, irritability, and encephalopathy. Neurodevelopmental morbidities associated with NH include cognitive and motor delays, cerebral palsy, vision and hearing impairment, and poor school performance. This article offers a timely discussion of the state of the science of NH and recommendations for neonatal providers focused on early identification and disease prevention. [ABSTRACT FROM AUTHOR]

Hypoglycemia in neonates is associated with long-term neurodevelopmental effects. Hyperinsulinemic hypoglycemia (HH) is the most common cause of persistent hypoglycemia in neonatal intensive care units. Diazoxide is the only medication that is currently recommended for treatment of HH in neonates. However, the use of diazoxide in neonates is associated with pulmonary hypertension as an adverse effect. In this article, we review the literature on the mechanism of action and adverse effects with the use of diazoxide in neonatal hyperinsulinism. We then present a case series of neonates treated with diazoxide in our neonatal intensive care unit over a 5-year period. Among 23 neonates who received diazoxide, 4 developed pulmonary hypertension and 1 died. All infants who developed pulmonary hypertension were born preterm at less than 36 weeks gestation and had pre-existing risk factors for pulmonary hypertension. HH in preterm neonates, with pre-existing pulmonary hypertension or with risk factors for pulmonary hypertension requires thoughtful management.

High sodium intake is decisive in the incidence increase and prevalence of hypertension, which has an impact on skeletal muscle functionality. Diazoxide is an antihypertensive agent that inhibits insulin secretion and is an opener of KATP channels (adosine triphosphate sensitive potasium channels). For this reason, it is hypothesized that moderate‐intensity exercise and diazoxide improve skeletal muscle function by reducing the oxidants in hypertensive rats. Male Wistar rats were assigned into eight groups: control (CTRL), diazoxide (DZX), exercise (EX), exercise + diazoxide (EX + DZX), hypertension (HTN), hypertension + diazoxide (HTN + DZX), hypertension + exercise (HTN + EX), and hypertension + exercise + diazoxide (HTN + EX + DZX). To induce hypertension, the rats received 8% NaCl dissolved in water orally for 30 days; in the following 8 weeks, 4% NaCl was supplied to maintain the pathology. The treatment with physical exercise of moderate intensity lasted 8 weeks. The administration dose of diazoxide was 35 mg/kg intraperitoneally for 14 days. Tension recording was performed on the extensor digitorum longus and the soleus muscle. Muscle homogenates were used to measure oxidants using fluorescent probe and the activity of antioxidant systems. Diazoxide and moderate‐intensity exercise reduced oxidants and increased antioxidant defenses. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX)-induced cardiotoxicity is a well known clinical problem, and many investigations have been made of its possible amelioration. We have investigated whether diazoxide (DIA), an agonist at mitochondrial ATP-sensitive potassium channels (mitoKATP), could reverse DOX-induced apoptotic myocardial cell loss, in cultured rat cardiomyocytes. The role of certain proteins in this pathway was also studied. The rat cardiomyocyte cell line (H9c2) was treated with DOX, and also co-treated with DOX and DIA, for 24 h. Distribution of actin filaments, mitochondrial membrane potential, superoxide dismutase (SOD) activity, total oxidant and antioxidant status (TOS and TAS, respectively), and some protein expressions, were assessed. DOX significantly decreased SOD activity, increased ERK1/2 protein levels, and depolarised the mitochondrial membrane, while DIA co-treatment inhibited such changes. DIA co-treatment ameliorated DOX-induced cytoskeletal changes via F-actin distribution and mitoKATP structure. Co-treatment also decreased ERK1/2 and cytochrome c protein levels. Cardiomyocyte loss due to oxidative stress-mediated apoptosis is a key event in DOX-induced cytotoxicity. DIA had protective effects on DOX-induced cardiotoxicity, via mitoKATP integrity, especially with elevated SUR2A levels; but also by a cascade including SOD/AMPK/ERK1/2. Therefore, DIA may be considered a candidate agent for protecting cardiomyocytes against DOX chemotherapy. [ABSTRACT FROM AUTHOR]

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 ± 3.1 weeks. 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 4 months. 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 4 months. [ABSTRACT FROM AUTHOR]

Objective: Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self‐resolving, treatment can be required. Consensus guidelines recommend the lower end of the diazoxide 5–15 mg/kg/day range in THI to reduce the risk of adverse events. We sought to determine if doses <5 mg/kg/day of diazoxide can be effective in THI. Design, Patients, Measurments: Infants with THI (duration <6 months) were treated with low‐dose diazoxide from October 2015 to February 2021. Dosing was based on weight at diazoxide start: 2 mg/kg/day in infants 1000–2000 g (cohort 1), 3 mg/kg/day in those 2000–3500 g (cohort 2) and 5 mg/kg/day in those >3500 g. Results: A total of 73 infants with THI (77% male, 33% preterm, 52% small‐for‐gestational age) were commenced on diazoxide at a median age of 11 days (range 3–43) for a median duration of 4 months (0.3–6.8), with no difference between cohorts. The mean effective diazoxide dose was 3 mg/kg/day (range 1.5–10); 35% (26/73) required an increase from their starting dose, including 60% (9/15) of cohort 1. There was no association between perinatal stress risk factors or treatment‐related characteristics and dose increase. Adverse events occurred in 13 patients (18%); oedema (12%) and hyponatraemia (5%) were the most common. Two infants developed suspected necrotising enterocolitis (NEC); none had pulmonary hypertension. Conclusion: Diazoxide doses <5 mg/kg/day are effective in THI. While the nature of the association between diazoxide and NEC was unclear, other adverse events were mild. We suggest considering starting doses as low as 2–3 mg/kg/day in THI to balance the side effect risk while maintaining euglycaemia. [ABSTRACT FROM AUTHOR]

Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene. The range of clinical manifestations of the ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present two previously unreported paediatric patients with neurodevelopmental challenges, who were diagnosed with missense variants in the ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinaemic hypoglycaemia (HH), a symptom that was not described before in published works. The reason for the occurrence of HH in our proband is not clear, so we try to explain the origin of this symptom in the context of the ZMYND11 syndrome. Thus, this paper contributes to knowledge on the range of possible manifestations of the ZMYND disease and provides further evidence supporting its association with neurodevelopmental challenges. [ABSTRACT FROM AUTHOR]

Background: ABCC8 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). Methods: We enrolled eight Chinese children with HH and analyzed their clinical characteristics, laboratory results, and genetic variations. Results: The 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. Conclusions: Gene 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. [ABSTRACT FROM AUTHOR]

Case summary The patient was a castrated male American Shorthair cat, approximately 14 years old, weighing 3.4 kg. The patient had chronic kidney disease (CKD) (International Renal Interest Society stages 3-4) as an underlying disease. The cat was examined at a hospital for intermittent lethargy and seizures. Hypoglycaemia was repeatedly observed, and the insulin level was 1.78 ng/ml (reference interval 0.27-0.69) when the blood glucose was 49 mg/dl. Although the cat was tentatively diagnosed with insulinoma, surgery was not recommended because of the severe CKD. Although frequent feeding and prednisolone treatment were initially attempted, blood glucose decreased to 24-42 mg/dl. Diazoxide was additionally prescribed at a dose of 5.2 mg/kg q12h. The cat's clinical signs improved, and the blood glucose was in the range of 75-103 mg/dl during the first 2 months. It was maintained at >50 mg/dl until the patient died of renal failure 161 days after the start of diazoxide treatment. With regard to adverse events, vomiting once every 2-3 days without weight loss and non-regenerative anaemia were observed, which might have been at least partially caused by diazoxide treatment. An insulinoma was definitively diagnosed via pathological autopsy. Relevance and novel information This is the first reported case of long-term treatment with diazoxide in a cat with insulinoma. Since it was effective in situations where conventional therapies were unsuccessful, diazoxide could be useful as a new therapeutic option for cats with insulinoma. Since adverse events, such as progression of vomiting frequency and non-regenerative anaemia, were observed, careful monitoring was required during administration. [ABSTRACT FROM AUTHOR]

Abstract High sodium intake is decisive in the incidence increase and prevalence of hypertension, which has an impact on skeletal muscle functionality. Diazoxide is an antihypertensive agent that inhibits insulin secretion and is an opener of KATP channels (adosine triphosphate sensitive potasium channels). For this reason, it is hypothesized that moderate‐intensity exercise and diazoxide improve skeletal muscle function by reducing the oxidants in hypertensive rats. Male Wistar rats were assigned into eight groups: control (CTRL), diazoxide (DZX), exercise (EX), exercise + diazoxide (EX + DZX), hypertension (HTN), hypertension + diazoxide (HTN + DZX), hypertension + exercise (HTN + EX), and hypertension + exercise + diazoxide (HTN + EX + DZX). To induce hypertension, the rats received 8% NaCl dissolved in water orally for 30 days; in the following 8 weeks, 4% NaCl was supplied to maintain the pathology. The treatment with physical exercise of moderate intensity lasted 8 weeks. The administration dose of diazoxide was 35 mg/kg intraperitoneally for 14 days. Tension recording was performed on the extensor digitorum longus and the soleus muscle. Muscle homogenates were used to measure oxidants using fluorescent probe and the activity of antioxidant systems. Diazoxide and moderate‐intensity exercise reduced oxidants and increased antioxidant defenses.

The article discusses the use of low-dose diazoxide therapy in the treatment of hyperinsulinaemic hypoglycaemia (HH), a condition characterized by elevated and unregulated insulin levels leading to low blood glucose concentrations. Diazoxide is the first-line medication for HH but can have side effects such as fluid retention and feeding problems. The study highlights the efficacy and safety of using ≤5 mg/kg/day of diazoxide in small for gestational age (SGA) infants. Another retrospective analysis conducted in London also supports the effectiveness of low-dose diazoxide in managing HH. The study suggests that lower doses of diazoxide should be considered before using higher doses, and regular follow-ups are necessary even at lower doses. [Extracted from the article]

We describe initial manifestations, approach to diagnosis, and treatment of a patient with congenital disorder of glycosylation type 1b (CDG 1b), previously managed as acetylcarnitine deficiency. A 9-year-old girl initially diagnosed with and treated for acetylcarnitine deficiency at an outside hospital presented with recurrent hypoglycemia, failure to thrive, poor weight gain, and short stature. She had discontinued levocarnitine therapy because of lack of response, and testing with us demonstrated a normal carnitine and acyl carnitine panel and hyperinsulinemic hypoglycemia during a diagnostic fast. Oral diazoxide and hydrochlorothiazide were initiated with resolution of hypoglycemia. She had iron deficiency anemia, but an upper gastrointestinal evaluation was normal. Genetic testing confirmed a diagnosis of CDG 1b caused by deficiency of mannose phosphate isomerase. Oral mannose was started with gradual reduction in and eventual discontinuation of the diazoxide dose. Hypoglycemia in the pediatric age group needs a systematic approach. It is important to raise awareness of CDG 1b, which can present as persistent hyperinsulinemic hypoglycemia. Mannose supplementation can ameliorate clinical symptoms and biochemical abnormalities. [ABSTRACT FROM AUTHOR]

Islet transplantation offers improved glycemic control in individuals with type 1 diabetes mellitus. However, in vitro islet culture is associated with islet apoptosis and eventually will lose their functionality prior to transplantation. In this study, we examined the effects of mesenchymal stem cells (MSCs) secretome preconditioned with diazoxide (DZ) and trimetazidine (TMZ) on rat islet cells during pre-transplant culture. With and without preconditioned hAD-MSCs' concentrated conditioned media (CCM) were added to the culture medium containing rat islets every 12 h for 24 and 48 h, after testing for selected cytokine concentrations (interleukin (IL)-4, IL-6, IL-13). Insulin content, glucose-stimulated insulin secretion, islet cell apoptosis, and mRNA expression of pro-apoptotic (BAX, BAK-1, and PUMA) and anti-apoptotic factors (BCL-2, BCL-xL, and XIAP) in rat islets were assessed after 24 and 48 h of culture. The protein level of IL-6 and IL-4 was significantly higher in TMZ-MSC-CM compared to MSC-non-CM. In rat isolated islets, normalized secreted insulin in the presence of 16.7 mM glucose was significantly higher in treated islet groups compared to control islets at both 24 and 48 h cultivation. Also, the percentage of apoptotic islet cells TMZ-MSC-CCM-treated islets was significantly lower compared to MSC-CM and MSC-CCM-treated islets in both 24 and 48 h cultivation. Consistent with the number of apoptotic cells, after 24 h culture, the expression of BCL-2 and BCL-xL genes in the control islets was lower than all treatment islet groups and in 48 h was lower than only TMZ-MSC-CM-treated islets. Also, the expression of the XIAP gene in control islets was significantly lower compared to the TMZ-MSC-CCM-treated islets at both at 24 and 48 h. In addition, mRNA level of the BAX gene in TMZ-MSC-CCM-treated islets was significantly lower compared to other groups at 48 h. Our findings revealed that TMZ proved to be more effective than DZ and could enhance the potential of hAD-MSCs-CM to improve the function and viability of islets prior to transplantation. [ABSTRACT FROM AUTHOR]

Diazoxide is a potential candidate for the treatment of transitional hypoglycaemia in infants. A clinical trial is currently underway to investigate whether low-dose oral diazoxide is beneficial for severe or recurrent transitional neonatal hypoglycaemia (the NeoGluCO Study, registration ANZCTR12620000129987). The present study aimed to develop and validate the parameters for quantifying diazoxide from neonatal plasma samples, and to assess the stability of extemporaneously prepared diazoxide suspensions to support the NeoGluCO Study. To determine the plasma concentration of diazoxide, a protein precipitation mediated extraction protocol was developed, which demonstrated >94% diazoxide extraction recoveries from all samples. The method was linear over the range of 0.2–40 μg/mL (R2 > 0.9994) with a limit of quantification of 0.2 μg/mL. Accuracy of the method was within 97–106% with relative standard deviation

The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome can be potentially life-threatening. The diagnosis is sometimes difficult since the clinical manifestations may be incomplete or non-specific. Insulinoma is a rare functioning neuroendocrine tumor (NET) of the pancreas. Medical therapy may be needed when surgery is contraindicated, delayed or refused. Diazoxide is widely used to control hypoglycemia in patients with insulinoma. We report a clinical case of an insulinoma in a 85-year-old patient treated with diazoxide with a fatal outcome due to a delayed diagnosis of a DRESS syndrome. This is the first case of DRESS syndrome reported after using diazoxide for insulinoma treatment in our knowledge.

Introduction: Given that reports on severe diazoxide (DZX) toxicity are increasing, we aimed to understand if the short-term clinical outcomes of small-for-gestational-age (SGA) infants with hyperinsulinemic hypoglycemia (HH) managed primarily by supportive care, termed watchful waiting (WW), are different from those treated with DZX. Method: A real-life observational cohort study was conducted from 1 September 2014 to 30 September 2020. The WW or DZX management decision was based on clinical and biochemical criteria. We compared central line duration (CLD), postnatal length of stay (LOS), and total intervention days (TIDs) among SGA-HH infants treated with DZX versus those on a WW approach. Fasting studies determined the resolution of HH. Result: Among 71,836 live births, 11,493 were SGA, and 51 SGA infants had HH. There were 26 and 25 SGA-HH infants in the DZX and WW groups, respectively. Clinical and biochemical parameters were similar between groups. The median day of DZX initiation was day 10 of life (range 4-32), at a median dose of 4 mg/kg/day (range 3-10). All infants underwent fasting studies. MedianCLD [DZX, 15 days (6-27) vs.WW, 14 days (5-31), P = 0.582] and postnatal LOS [DZX, 23 days (11-49) vs. WW, 22 days (8-61), P = 0.915] were comparable. Median TID was >3-fold longer in the DZX than theWWgroup [62.5 days (9-198) vs. 16 days (6-27), P < 0.001]. Conclusion: CLD and LOS are comparable between WW and DZX groups. Since fasting studies determine the resolution of HH, physicians should be aware that clinical intervention of DZX-treated SGA-HH patients extends beyond the initial LOS. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more insidious symptoms can rarely occur, such as manifestations of hypoglycemia in newborns with congenital hyperinsulinism hypoglycemia, especially when a variant of the KDM6A gene is found. In those cases, a treatment with diazoxide can be started and can be replaced with lanreotide if a satisfying glycemic control is not achieved. We report the case of a female patient born at 37 weeks of gestational age, without any obvious facial dysmorphic features, after a non‐complicated pregnancy, that presented with feeding difficulties, drowsiness, and irritability revealing a hyperinsulinemic hypoglycemia. Further testing at 6 months old found a KDM6A mutation. The patient was initially treated by diazoxide alone, but its dosage had to be lowered because of the occurrence of treatment side effects, and lanreotide had been added to maintain acceptable blood sugar levels. A congenital hyperinsulinemia hypoglycemia revealed heterozygous truncating variant in the KDM6A gene, also known as X‐linked Kabuki syndrome in a newborn. In cases of neonatal hypoglycemia, the first‐line therapy is diazoxide. Our report shows that analogues of somatostatin such as lanreotide should be considered if the diazoxide regimen is not tolerated. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Phosphomannomutase 2 deficiency (PMM2-CDG) is a disorder of protein N-glycosylation with a wide clinical spectrum. Hypoglycemia is rarely reported in PMM2-CDG. In this study, we evaluated cause, treatment options and outcomes in cases with hypoglycemia in the course of PMM2-CDG. METHODS: Clinical records of patients followed with PMM2-CDG within the last two decades were reviewed. Medical data of patients with hypoglycemia were evaluated in more detail. Demographic and clinical findings, organ involvement and laboratory investigations at time of hypoglycemia were recorded. Time of first attack of hypoglycemia, cause, treatment modalities, duration of hypoglycemia (permanent/transient), and duration of treatment, as well as outcome were also recorded. Other published cases with PMM2-CDG and hypoglycemia are also reviewed in order to elucidate characteristics as well as pathophysiology of hypoglycemia. RESULTS: Nine patients with PMM2-CDG were reviewed, and hypoglycemia was present in three cases. All three had hyperinsulinism as the cause of hypoglycemia. In the first two cases reported here, serum insulin level concurrent with hypoglycemic episodes was elevated, and glucose response was exaggerated during glucagon test, favoring hyperinsulinism. However, in the third case, the serum insulin level at time of hypoglycemia was not so high but hypoglycemia responded well to diazoxide. Hyperinsulinism was permanent in two of these three cases. No genotype-phenotype correlation was observed with respect to hyperinsulinism. DISCUSSION AND CONCLUSION: The main cause of hypoglycemia in PMM2-CDG appears to be hyperinsulinism. Although insulin levels at the time of hypoglycemia may not be very high, hypoglycemia in patients with PMM2 responds well to diazoxide.

I investigated the effects of diazoxide, a mitochondrial potassium channel opener, on streptozotocin (STZ) induced pancreatic β cell damage via the HSP70/HSP90/TLR4/AMPK signaling pathways in vitro. I used the pancreatic β cell line, 1.1B4, to create four groups: control, STZ treated, diazoxide treated, STZ + diazoxide treated. The STZ treated cells were exposed to 20 µM STZ for 2 h with or without 100 µM diazoxide for 24 h. Total antioxidant status (TAS), total oxidant status (TOS), cell viability and mitochondrial membrane potential (MMP) were measured. Expression of ATP-sensitive potassium channel (KATP) subunits, heat shock protein-70 (HSP70), heat shock protein-90 (HSP90), toll-like receptor 4 (TLR4), AMP-activated protein kinase (AMPK) and some apoptotic proteins were detected using western blotting. Apoptosis was assessed using TUNEL staining. STZ increased TOS and OSI in the pancreatic β cells; however, diazoxide failed to improve oxidative stress. Also, STZ increased tunnel positive cells in the pancreatic β cells. Diazoxide decreased the tunnel positive cells in the STZ treated β cell. STZ decreased MMP; however, diazoxide did not normalize MMP in the STZ induced β cells. Diazoxide increased the HSP70:HSP90 protein expression ratio. STZ decreased expression of AMPK and subunits of KATP channel and increased the expression of caspase-3 and TLR4 protein; diazoxide normalized the expression of all proteins studied. KATP channel opening by diazoxide protects pancreatic β cells against STZ toxicity via HSP70/HSP90/TLR4/AMPK signaling. [ABSTRACT FROM AUTHOR]

Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. To generate cardiac-specific Cx43-deficient (cCx43−/−) mice, Cx43flox/flox mice were crossed with α-MHC (Myh6)-cre+/− mice. The resulting offspring, Cx43flox/flox/Myh6-cre+/− mice (cCx43−/− mice) and their littermates (cCx43+/+ mice), were used. Trabeculae were dissected from the right ventricles of mouse hearts. Cardiomyocytes were enzymatically isolated from the ventricles of mouse hearts. Force was measured with a strain gauge in trabeculae (22°C). To assess arrhythmia susceptibility, the minimal extracellular Ca2+ concentration ([Ca2+]o,min), at which arrhythmias were induced by electrical stimulation, was determined in trabeculae. ROS production was estimated with 2′,7′-dichlorofluorescein (DCF), mitochondrial membrane potential with tetramethylrhodamine methyl ester (TMRM), and Ca2+ spark frequency with fluo-4 and confocal microscopy in cardiomyocytes. ROS production within the mitochondria was estimated with MitoSoxRed and mitochondrial Ca2+ with rhod-2 in trabeculae. Diazoxide was used to activate mitochondrial KATP. Most of cCx43−/− mice died suddenly within 8 weeks. Cx43 was present in the inner mitochondrial membrane in cCx43+/+ mice but not in cCx43−/− mice. In cCx43−/− mice, the [Ca2+]o,min was lower, and Ca2+ spark frequency, the slope of DCF fluorescence intensity, MitoSoxRed fluorescence, and rhod-2 fluorescence were higher. TMRM fluorescence was more decreased in cCx43−/− mice. Most of these changes were suppressed by diazoxide. In addition, in cCx43−/− mice, antioxidant peptide SS-31 and N-acetyl-L-cysteine increased the [Ca2+]o,min. These results suggest that Cx43 deficiency activates Ca2+ leak from the SR, probably due to depolarization of mitochondrial membrane potential, an increase in mitochondrial Ca2+, and an increase in ROS production, thereby causing triggered arrhythmias, and that Cx43 hemichannel deficiency may be compensated by activation of mitochondrial KATP channels in mouse hearts. [ABSTRACT FROM AUTHOR]

Aim/Introduction: Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Hyperglycemia causes dyslipidemia and stimulates oxidative damage, leading to the main symptoms, such as fatigue and culminates in diabetic complications. Previous studies have shown that ATP-sensitive potassium channels counteract muscle fatigue and metabolic stress in healthy mouse models. To determine the effect of diazoxide on muscle strength development during diabetes, we tested the effect of diazoxide in streptozotocin-diabetic rats in muscle function, lipid profile and oxidative stress biomarkers. Materials and methods: Wistar rats were divided into 4 groups of six animals each: (1) Control group, (2) diabetes group, (3) Control group + diazoxide, and (4) Diabetic + diazoxide (DB + DZX). 4 weeks after rats were sacrificed, soleus and extensor digitorum longus muscles (EDL) were extracted to prepare homogenates and serum was obtained for biochemical measurements. Oxidative damage was evaluated by the thiobarbituric acid method and the fluorescent for reactive oxygen species (ROS) probe 2,4-H2DCFDA, respectively. Results: Diabetic rats with diazoxide administration showed an increase in the development of muscle strength in both muscles; in turn, the onset of fatigue was longer compared to the group of diabetic rats without treatment. Regarding the lipid profile, diazoxide decreased total cholesterol levels in the group of diabetic rats treated with diazoxide (x̅46.2 mg/dL) compared to the untreated diabetic group (x̅=104.4 mg/dL); secondly, diazoxide decreased triglyceride concentrations (x̅=105.3 mg/dL) compared to the untreated diabetic rats (x̅=412.2 mg/dL) as well as the levels of very low-density lipoproteins (x̅=20.4 mg/dL vs. x̅=82.44 mg/dL). Regarding the various markers of oxidative stress, the diabetic group treated with diazoxide was able to reduce the concentrations of TBARS and total reactive oxygen species as well as preserve the concentrations of reduced glutathione. Conclusion: Diazoxide administration in diabetic rats increases muscle strength development in EDL and soleus muscle, decreases fatigue, reduces cholesterol and triglyceride concentrations and improves oxidative stress parameters such as TBARS, ROS, and glutathione status. [ABSTRACT FROM AUTHOR]

Key Clinical Message Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more insidious symptoms can rarely occur, such as manifestations of hypoglycemia in newborns with congenital hyperinsulinism hypoglycemia, especially when a variant of the KDM6A gene is found. In those cases, a treatment with diazoxide can be started and can be replaced with lanreotide if a satisfying glycemic control is not achieved. We report the case of a female patient born at 37 weeks of gestational age, without any obvious facial dysmorphic features, after a non‐complicated pregnancy, that presented with feeding difficulties, drowsiness, and irritability revealing a hyperinsulinemic hypoglycemia. Further testing at 6 months old found a KDM6A mutation. The patient was initially treated by diazoxide alone, but its dosage had to be lowered because of the occurrence of treatment side effects, and lanreotide had been added to maintain acceptable blood sugar levels. A congenital hyperinsulinemia hypoglycemia revealed heterozygous truncating variant in the KDM6A gene, also known as X‐linked Kabuki syndrome in a newborn. In cases of neonatal hypoglycemia, the first‐line therapy is diazoxide. Our report shows that analogues of somatostatin such as lanreotide should be considered if the diazoxide regimen is not tolerated.

IntroductionGiven that reports on severe diazoxide (DZX) toxicity are increasing, we aimed to understand if the short-term clinical outcomes of small-for-gestational-age (SGA) infants with hyperinsulinemic hypoglycemia (HH) managed primarily by supportive care, termed watchful waiting (WW), are different from those treated with DZX.MethodA real-life observational cohort study was conducted from 1 September 2014 to 30 September 2020. The WW or DZX management decision was based on clinical and biochemical criteria. We compared central line duration (CLD), postnatal length of stay (LOS), and total intervention days (TIDs) among SGA-HH infants treated with DZX versus those on a WW approach. Fasting studies determined the resolution of HH.ResultAmong 71,836 live births, 11,493 were SGA, and 51 SGA infants had HH. There were 26 and 25 SGA-HH infants in the DZX and WW groups, respectively. Clinical and biochemical parameters were similar between groups. The median day of DZX initiation was day 10 of life (range 4–32), at a median dose of 4 mg/kg/day (range 3–10). All infants underwent fasting studies. Median CLD [DZX, 15 days (6–27) vs. WW, 14 days (5–31), P = 0.582] and postnatal LOS [DZX, 23 days (11–49) vs. WW, 22 days (8–61), P = 0.915] were comparable. Median TID was >3-fold longer in the DZX than the WW group [62.5 days (9–198) vs. 16 days (6–27), P < 0.001].ConclusionCLD and LOS are comparable between WW and DZX groups. Since fasting studies determine the resolution of HH, physicians should be aware that clinical intervention of DZX-treated SGA-HH patients extends beyond the initial LOS.

Background: Diazoxide is a selective mitochondrial-sensitive potassium channel opening agent that has a definite effect on reducing myocardial ischemia/reperfusion injury (MIRI). However, the exact effects of diazoxide postconditioning on the myocardial metabolome remain unclear, which might contribute to the cardioprotective effects of diazoxide postconditioning.Methods: Rat hearts subjected to Langendorff perfusion were randomly assigned to the normal (Nor) group, ischemia/reperfusion (I/R) group, diazoxide (DZ) group and 5-hydroxydecanoic acid + diazoxide (5-HD + DZ) group. The heart rate (HR), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and maximum left ventricular pressure (+dp/dtmax) were recorded. The mitochondrial Flameng scores were analysed according to the ultrastructure of the ventricular myocardial tissue in the electron microscopy images. Rat hearts of each group were used to investigate the possible metabolic changes relevant to MIRI and diazoxide postconditioning.Results: The cardiac function indices in the Nor group were better than those in the other groups at the end point of reperfusion, and the HR, LVDP and +dp/dtmax of the Nor group at T2 were significantly higher than those of the other groups. Diazoxide postconditioning significantly improved cardiac function after ischaemic injury, and the HR, LVDP and +dp/dtmax of the DZ group at T2 were significantly higher than those of the I/R group, which could be abolished by 5-HD. The HR, LVDP and +dp/dtmax of the 5-HD + DZ group at T2 were significantly lower than those of the DZ group. The myocardial tissue in the Nor group was mostly intact, while it exhibited considerable damage in the I/R group. The ultrastructural integrity of the myocardium in the DZ group was higher than that in the I/R and 5-HD + DZ groups. The mitochondrial Flameng score in the Nor group was lower than that in the I/R, DZ and 5-HD + DZ groups. The mitochondrial Flameng score in the DZ group was lower than that in the I/R and 5-HD + DZ groups. Five metabolites, namely, L-glutamic acid, L-threonine, citric acid, succinate, and nicotinic acid, were suggested to be associated with the protective effects of diazoxide postconditioning on MIRI.Conclusion: Diazoxide postconditioning may improve MIRI via certain metabolic changes. This study provides resource data for future studies on metabolism relevant to diazoxide postconditioning and MIRI.

INTRODUCTION:Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS. METHOD:This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period. RESULTS:Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide. CONCLUSION:DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.