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Juntendo Iji Zasshi = Juntendo Medical... 2023The role of autophagy in pancreatic β cells has been reported, but the relationship between autophagy and insulin metabolism is complex and is not fully understood yet.
OBJECTIVES
The role of autophagy in pancreatic β cells has been reported, but the relationship between autophagy and insulin metabolism is complex and is not fully understood yet.
DESIGN
We here analyze the relationship between autophagy and insulin metabolism from a morphological aspect.
METHODS
We observe the morphological changes of β cell-specific Atg7-deficient mice and Atg5-deficient MIN6 cells with electron microscopy.
RESULTS
We find that Atg7-deficient β cells exhibit a marked expansion of the endoplasmic reticulum (ER). We also find that the inhibitory state of insulin secretion causes morphological changes in the Golgi, including ministacking and swelling. The same morphological alterations are observed when insulin secretion is suppressed in Atg5-deficient MIN6 cells.
CONCLUSIONS
The defect of autophagy induces ER expansion, and inhibition of insulin secretion induces Golgi swelling, probably via ER stress and Golgi stress, respectively.
PubMed: 38854847
DOI: 10.14789/jmj.JMJ22-0040-OA -
International Journal of Molecular... Jan 2023Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal... (Review)
Review
Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clinical trials with existing results for the management of obesity and hyperphagia in PWS will be discussed in this review, including treatments such as beloranib, setmelanotide, a diazoxide choline controlled-release tablet (DCCR), an unacylated ghrelin analogue, oxytocin and related compounds, glucagon-like peptide 1 receptor agonists, surgical intervention, and transcranial direct-current stimulation.
Topics: Female; Humans; Prader-Willi Syndrome; Transcranial Direct Current Stimulation; Hyperphagia; Anxiety; Mothers
PubMed: 36768472
DOI: 10.3390/ijms24032150 -
Anatolian Journal of Cardiology Feb 2023Myocardial infarction is associated with the autophagy and apoptosis of cardiomyocytes, and the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway plays a...
BACKGROUND
Myocardial infarction is associated with the autophagy and apoptosis of cardiomyocytes, and the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway plays a crucial role in this mechanism.
METHODS
Acute myocardial infarction rat models were assessed 0.5, 2, 4, and 6 hours after the induction of the myocardial infarction using hematoxylin and eosin staining, triphenyl tetrazolium chloride staining, myocardial enzyme measurements, and levels of autophagic activity. Additionally, diazoxide, 5-hydroxydecanoate, and LY294002 were intraperitoneally administered to rat models at peak myocardial injury to assess their effects on cardiac injury. The expression levels of autophagy-related and apoptosis-related proteins, as well as p-AKT and p-mTOR, were measured. Electron microscopy was used to assess the ultrastructure and the number of autophagosomes in the cardiac tissue.
RESULTS
We demonstrated that the degree of myocardial injury and the level of autophagy were significantly elevated in the experimental cohort compared with the control cohort. In addition, the myocardial infarct size was significantly smaller in diazoxide-treated acute myocardial infarction rats compared with untreated rats. Diazoxide also decreased the levels of myocardial injury markers, autophagy, and apoptosis, while it also induced the levels of AKT and mTOR phosphorylation, decreased the number of autophagosomes, and improved the myocardial ultrastructure of the acute myocardial infarction rats. 5-Hydroxydecanoate treatment resulted in an opposite effect to those observed upon diazoxide treatment. LY294002 was also able to reverse diazoxide treatment effects.
CONCLUSION
Peak levels of myocardial tissue injury and autophagy were observed 2 hours post-acute myocardial infarction induction in rats. Diazoxide treatment inhibited myocardial autophagy and apoptosis while protecting cardiac tissue from ischemic injury, which is likely to have proceeded through activation of the AKT/mTOR pathway.
Topics: Rats; Animals; Proto-Oncogene Proteins c-akt; Signal Transduction; Diazoxide; Rats, Sprague-Dawley; TOR Serine-Threonine Kinases; Myocardial Infarction; Myocytes, Cardiac; Mammals
PubMed: 36747448
DOI: 10.14744/AnatolJCardiol.2022.2406 -
Frontiers in Endocrinology 2022Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and... (Review)
Review
Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.
Topics: Humans; Child; Hyperinsulinism; Hypoglycemia; Phosphotransferases (Phosphomutases)
PubMed: 36726472
DOI: 10.3389/fendo.2022.1102307 -
Clinical Medicine Insights. Case Reports 2023Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We...
Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We reported a 37-week-old boy with the diagnosis of hypoglycemia. We started a dextrose infusion, but we used oral diazoxide, due to hypoglycemia episodes despite the increase in dextrose intake. The newborn had a normoglycemic condition after gradually increasing the diazoxide dose to 15 mg/kg/day. He was fully breastfed and discharged at 14 days of age with ongoing diazoxide. In weekly serial clinical follow-ups, the parents noticed an increase in the growth of forehead and facial hair that was diagnosed as diazoxide-induced hypertrichosis. Diazoxide was gradually tapered, and hypertrichosis continued until 1 month after dioxide discontinuation. Diazoxide use in NICU settings has increased over time. Diazoxide has many side effects, one of which is hypertrichosis. Many diazoxide side effects have been reported in adults or children and few studies have reported the prevalence of these adverse effects of diazoxide in neonates and infants.
PubMed: 36726424
DOI: 10.1177/11795476231151330 -
ACG Case Reports Journal Jan 2023Pancreatic neuroendocrine tumors are rare neoplasms characterized into nonfunctioning (NF-PNET) and functioning (F-PNET) subtypes. F-PNETs typically involve overt...
Pancreatic neuroendocrine tumors are rare neoplasms characterized into nonfunctioning (NF-PNET) and functioning (F-PNET) subtypes. F-PNETs typically involve overt symptoms related to excessive hormone secretion but may rarely present first as NF-PNETs with delayed transformation. We present a patient with known NF-PNET with liver metastases who developed hypoglycemia 2 years after initial diagnosis due to malignant insulinoma. Hypoglycemia was refractory to continuous dextrose but improved temporarily after diazoxide and hepatic artery embolization. Malignant insulinomas are usually metastatic at presentation and portend poor prognosis. Hypoglycemia may be medically managed with steroids, somatostatin analogues, and diazoxide, along with therapies to reduce tumor burden.
PubMed: 38445216
DOI: 10.14309/crj.0000000000000954 -
Frontiers in Pharmacology 2022To evaluate the efficacy of different pharmacologic treatment for severe hypertension during pregnancy. Two reviewers searched Ovid MEDLINE, Ovid EMbase, and the...
To evaluate the efficacy of different pharmacologic treatment for severe hypertension during pregnancy. Two reviewers searched Ovid MEDLINE, Ovid EMbase, and the Cochrane Library for randomized clinical trials from the establishment of the database to 15 July 2021 that were eligible for inclusion and analyzed the pharmaceuticals used for severe hypertension in pregnancy. 29 relevant trials with 2,521 participants were involved. Compared with diazoxide in rate of achieving target blood pressure, other pharmaceuticals, including epoprostenol (RR:1.58, 95%CI:1.01-2.47), hydralazine\dihydralazine (RR:1.57, 95%CI:1.07-2.31), ketanserin (RR:1.67, 95%CI:1.09-2.55), labetalol (RR:1.54, 95%CI:1.04-2.28), nifedipine (RR:1.54, 95%CI:1.04-2.29), and urapidil (RR:1.57, 95%CI:1.00-2.47), were statistically significant in the rate of achieving target blood pressure. According to the SUCRA, diazoxide showed the best therapeutic effect, followed by nicardipine, nifedipine, labetalol, and nitroglycerine. The three pharmaceuticals with the worst therapeutic effect were ketanserin, hydralazine, and urapidil. It is worth noting that the high ranking of the top two pharmaceuticals, including diazoxide and nicardipine, comes from extremely low sample sizes. Other outcomes were reported in the main text. This comprehensive network meta-analysis demonstrated that the nifedipine should be recommended as a strategy for blood pressure management in pregnant women with severe hypertension. Moreover, the conventional pharmaceuticals, including labetalol and hydralazine, showed limited efficacy. However, it was important to note that the instability of hydralazine reducing blood pressure and the high benefit of labetalol with high dosages intakes should also be of concern to clinicians.
PubMed: 36699058
DOI: 10.3389/fphar.2022.1092501 -
Children (Basel, Switzerland) Dec 2022Hypoglycemia in neonates is associated with long-term neurodevelopmental effects. Hyperinsulinemic hypoglycemia (HH) is the most common cause of persistent hypoglycemia... (Review)
Review
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.
PubMed: 36670556
DOI: 10.3390/children10010005 -
The Journal of Clinical Endocrinology... Jun 2023Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region,... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled.
OBJECTIVE
The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones.
METHODS
In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo.
RESULTS
DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant).
CONCLUSION
DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.
Topics: Humans; Prader-Willi Syndrome; Diazoxide; COVID-19; Obesity; Hyperphagia
PubMed: 36639249
DOI: 10.1210/clinem/dgad014 -
Cureus Dec 2022Background and objective Neonatal hypoglycemia (NH) is one of the most common causes of admission to the neonatal intensive care unit (NICU). Persistent NH despite...
Background and objective Neonatal hypoglycemia (NH) is one of the most common causes of admission to the neonatal intensive care unit (NICU). Persistent NH despite adequate feeding and intravenous dextrose may often require medications to maintain normal blood glucose levels (BGL). Several medications are used in the management of persistent NH, such as glucagon, diazoxide, and octreotide. In this study, we aimed to determine the factors that predict the need for medications to treat persistent NH. Methods This was a retrospective cohort study conducted at the Sultan Qaboos University Hospital (SQUH), Muscat, Oman. Infants admitted to the NICU between 2015 and 2019 with hypoglycemia (capillary blood glucose <2.6 mmol/l) were eligible to be included in the study. A prespecified dataset was collected from electronic patient records, including birth weight (BW), APGAR scores, gestational age, BGL, maternal risk factors such as diabetes mellitus (DM), hypertension, or antenatal use of medications, and the NICU management during admission. Data analysis was performed using SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, NY). Results A total of 89 neonates were admitted due to NH during the study period. Of them, 10 (11.2%) patients had received medication (diazoxide). Use of medication for persistent NH was significantly associated with maternal gestational diabetes/diabetes mellitus (GDM/DM) status (p=0.041), higher BW (p=0.001), and large for gestational age [LGA (defined as BW >90th percentile)] (p=0.014), severe hypoglycemia (mean glucose level of 1-1.5 mmol/l) at two hours of life and at admission, and elevated maximum glucose infusion rate (GIR). GIR for the medication-requiring cohort was 12.95 mg/kg/min and that for the non-medication-requiring cohort was 6.77 mg/kg/min (p<0.001). Conclusion Based on our findings, the need for using certain medications to treat persistent NH, such as diazoxide in neonates admitted with NH, can be predicted by factors such as maternal GDM/DM status, BW >90th percentile, very low BGL at two hours of age and on admission, and elevated GIR. Elevated maximum GIR was a leading indicator for using medications in the treatment of NH.
PubMed: 36620829
DOI: 10.7759/cureus.32197