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PloS One 2022In folklore, Heritiera fomes (H. fomes) has been extensively used in treatment of various ailments such as diabetes, cardiac and hepatic disorders. The present study...
In folklore, Heritiera fomes (H. fomes) has been extensively used in treatment of various ailments such as diabetes, cardiac and hepatic disorders. The present study aimed to elucidate the antidiabetic actions of hot water extract of H. fomes (HWHF), including effects on insulin release from BRIN BD11 cells and isolated mouse islets as well as glucose homeostasis in high-fat-fed rats. Molecular mechanisms underlying anti-diabetic activity along with isolation of active compounds were also evaluated. Non-toxic concentrations of HWHF stimulated concentration-dependent insulin release from isolated mouse islets and clonal pancreatic β-cells. The stimulatory effect was potentiated by glucose and isobutyl methylxanthine (IBMX), persisted in presence of tolbutamide or a depolarizing concentration of KCl but was attenuated by established inhibitors of insulin release such as diazoxide, verapamil, and Ca2+ chelation. HWHF caused depolarization of the β-cell membrane and increased intracellular Ca2+. The extract also enhanced glucose uptake and insulin action in 3T3-L1 differentiated adipocytes cells and significantly inhibited in a dose-dependent manner starch digestion, protein glycation, DPP-IV enzyme activity, and glucose diffusion in vitro. Oral administration of HWHF (250 mg/5ml/kg b.w.) to high-fat fed rats significantly improved glucose tolerance and plasma insulin responses and it inhibited plasma DPP-IV activity. HWHF also decreased in vivo glucose absorption and intestinal disaccharidase activity while increasing gastrointestinal motility and unabsorbed sucrose transit. Compounds were isolated from HWHF with similar molecular weights to quercitrin (C21 H20 O11) ranging from 447.9 to 449.9 Da which stimulated the insulin release in vitro and improved both glucose tolerance and plasma insulin responses in mice. In conclusion, H. fomes and its water-soluble phytochemicals such as quercitrin may exert antidiabetic actions mediated through a variety of mechanisms which might be useful as dietary adjunct in the management of type 2 diabetes.
Topics: Animals; Mice; Rats; Blood Glucose; Calcium; Coriolaceae; Diabetes Mellitus, Type 2; Glucose; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin, Regular, Human; Islets of Langerhans; Malvaceae; Plant Bark; Water
PubMed: 35239729
DOI: 10.1371/journal.pone.0264632 -
The Pan African Medical Journal 2020Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates... (Review)
Review
Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates and children. Prompt diagnosis and management of the underlying hypoglycemia disorder is critical for preventing brain damage and improving outcomes. Congenital hyperinsulinism (CHI) is the most common and severe cause of persistent hypoglycemia in neonates and children, it represents a group of clinically, genetically and morphologically heterogeneous disorders characterised by dysregulation of insulin secretion from pancreatic β-cells. It is extremely important to recognize this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, CHI is divided mainly into two types focal and diffuse disease. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localized to a small region of the pancreas. Recent discoveries of the genetic causes of CHI have improved our understanding of the pathophysiology, but its management is complex and requires the integration of clinical, biochemical, molecular, and imaging findings to establish the appropriate treatment according to the subtype. Here we present a case of sever congenital hyperinsulinism in a girl admitted for lethargy, irritability and general seizures accompanied with profound hypoglycemia, in spite of aggressive medical treatment, she died because of sever congenital hyperinsulinism diazoxide unresponsive.
Topics: Congenital Hyperinsulinism; Diazoxide; Fatal Outcome; Female; Humans; Infant, Newborn; Seizures; Severity of Illness Index
PubMed: 32537058
DOI: 10.11604/pamj.2020.35.53.16604 -
The Journal of Endocrinology Jul 2021The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High...
The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High insulin and low GH levels are often observed in obesity, contributing to reduced energy expenditure and further fat accumulation. Although suppression of hyperinsulinemia is proposed as a treatment for obesity, changes in GH secretion and energy metabolism following this treatment are not thoroughly studied. This leaves unexplained observations, such as unchanged lean mass following insulin reduction. In this study, high-fat diet-induced obese (DIO) and normal chow-fed lean mice on a C57BL/6J background were treated for 7 weeks with diazoxide (1250 mg/kg in food), a KATP channel opener that suppressed insulin secretion. Diazoxide treatment for 10 days was sufficient to increase pulsatile GH secretion in DIO mice before any significant body weight change. The restored insulin-GH balance in DIO mice was followed by improvement in substrate and energy metabolism in a prolonged treatment period (4-6 weeks), including reduced fat mass, increased lipid oxidation and energy expenditure, as well as improved insulin sensitivity and metabolic flexibility. These metabolic benefits occurred along with the changes in the expression level of genes regulated by the insulin-GH balance. When applying diazoxide to normal chow-fed normoinsulinemic lean mice, none of the above metabolic effects was observed, suggesting that the metabolic changes following diazoxide treatment were mediated through the suppression of hyperinsulinemia. These results suggest that suppression of hyperinsulinemia by diazoxide restores GH secretion and improves substrate and energy metabolism in DIO mice.
Topics: Animals; Body Composition; Diazoxide; Diet, High-Fat; Energy Metabolism; Growth Hormone; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity
PubMed: 34156345
DOI: 10.1530/JOE-20-0616 -
Frontiers in Endocrinology 2022Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in... (Review)
Review
Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in isolation, or present as a feature of syndromic disease. Establishing the underlying aetiology of the hyperinsulinism is critical for guiding medical management of this condition especially in children with diazoxide-unresponsive hyperinsulinism where the underlying genetics determines whether focal or diffuse pancreatic disease is present. Disease-causing single nucleotide variants affecting over 30 genes are known to cause persistent hyperinsulinism with mutations in the KATP channel genes ( and ) most commonly identified in children with severe persistent disease. Defects in methylation, changes in chromosome number, and large deletions and duplications disrupting multiple genes are also well described in congenital hyperinsulinism, further highlighting the genetic heterogeneity of this condition. Next-generation sequencing has revolutionised the approach to genetic testing for congenital hyperinsulinism with targeted gene panels, exome, and genome sequencing being highly sensitive methods for the analysis of multiple disease genes in a single reaction. It should though be recognised that limitations remain with next-generation sequencing with no single application able to detect all reported forms of genetic variation. This is an important consideration for hyperinsulinism genetic testing as comprehensive screening may require multiple investigations.
Topics: Child; Congenital Hyperinsulinism; Diazoxide; Humans; Insulin; KATP Channels; Mutation
PubMed: 35872984
DOI: 10.3389/fendo.2022.873254 -
Cell & Bioscience 2020Openers of mitochondrial adenosine triphosphate-dependent potassium (mKATP) channels like diazoxide increase reactive oxygen species (ROS) production in cardiac cells...
BACKGROUND
Openers of mitochondrial adenosine triphosphate-dependent potassium (mKATP) channels like diazoxide increase reactive oxygen species (ROS) production in cardiac cells and reduce Ca elevations produced by ischemia-reperfusion, protecting the heart from damage. In this study we tested the hypothesis that opening mKATP channels regulates expression of the major components of store-operated Ca entry (SOCE) STIM1 and Orai1.
RESULTS
Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot experiments showed that diazoxide increased expression of STIM1 and Orai1 at the mRNA and protein levels, respectively, in adult rat cardiomyocytes. Immunofluorescence analyses revealed that diazoxide also disrupted the striated distribution pattern of STIM1. These effects were prevented by the ROS scavenger -acetyl cysteine (NAC), the mKATP channel antagonist 5-hydroxydecanoate (5-HD), or the protein synthesis inhibitor cycloheximide (CHX). Confocal microscopy revealed that diazoxide also led to nuclear translocation of the transcription factors c-Fos and NFκB, which was also blocked by NAC or 5-HD. Finally, the MAPK pathway inhibitor UO126 attenuated diazoxide-induced upregulation of STIM1 and Orai1 expression.
CONCLUSIONS
Our results suggest that opening mitochondrial potassium ATP channels with diazoxide upregulates the expression of STIM1 and Orai1 by de novo synthesis by a mechanism that involves NFkB, c-Fos, and ROS via MAPK/ERK signaling.
PubMed: 32817784
DOI: 10.1186/s13578-020-00460-w -
ChemMedChem Apr 2021Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII...
Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition and their effect on cancer cells for the first time. A 15-fold increase in CII inhibition was achieved over diazoxide, albeit with micromolar IC values. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with much greater antineoplastic effect than diazoxide, the most potent of which possesses an IC of 2.93±0.07 μM in a cellular model of triple-negative breast cancer, with high selectivity over nonmalignant cells and more than double the potency of the clinical agent 5-fluorouracil. No correlation between cytotoxicity and CII inhibition was found, thus indicating an as-yet-undefined mechanism of action of this scaffold. The derivatives described herein represent valuable hit compounds for therapeutic discovery in triple-negative breast cancer.
Topics: Antineoplastic Agents; Benzothiadiazines; Cell Proliferation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Halogenation; Humans; Molecular Structure; Structure-Activity Relationship
PubMed: 33331124
DOI: 10.1002/cmdc.202000729 -
Gynecological Endocrinology : the... Jun 2022Safety information on diazoxide for pregnant and lactating women with hypoglycemia is limited. In this case report, we assessed diazoxide concentrations in maternal and...
Safety information on diazoxide for pregnant and lactating women with hypoglycemia is limited. In this case report, we assessed diazoxide concentrations in maternal and infant blood, cord blood, and breast milk. We described a 30-year-old pregnant woman diagnosed with hypoglycemia due to nesidioblastosis at 4 months of age. Before becoming pregnant, she was treated with oral diazoxide (75-375 mg). All medications were discontinued after she was discovered to be pregnant. During gestational week 25, diazoxide treatment was resumed at 150-175 mg daily for repeated hypoglycemic episodes. Diazoxide administration was continued in combination with diet treatment until delivery. Glucose levels were well controlled. During gestational week 40, a male infant weighing 3069 g was delivered spontaneous vaginal delivery with no pregnancy or neonatal complications. Diazoxide concentrations detected in maternal serum at 2.5-11.6 h after oral treatment ranged from 12.4 to 32.7 µg/mL. In cord blood, the diazoxide concentration was 18.5 µg/mL at 7.2 h after the last dose. During lactation, no hypoglycemia or hyperglycemia was observed. The approximate calculated ratio of diazoxide in breast milk and maternal serum was 0.09. The calculated daily infant dose was 0.47 mg/kg/day. The relative infant dose breast milk ranged from 3.1% to 5.9%. Diazoxide transferred from maternal blood to the fetus across the placenta. It also transferred into breast milk, but there were no harmful effects on the infant.
Topics: Adult; Diazoxide; Female; Fetal Blood; Humans; Hypoglycemia; Infant; Infant, Newborn; Lactation; Male; Milk, Human; Pregnancy
PubMed: 35403531
DOI: 10.1080/09513590.2022.2061453 -
Toxicology Oct 2023Bleomycin (BLM), a frequently employed chemotherapeutic agent, exhibits restricted clinical utility owing to its pulmonary toxicity. Meanwhile, baicalin (BA)-an active...
Bleomycin (BLM), a frequently employed chemotherapeutic agent, exhibits restricted clinical utility owing to its pulmonary toxicity. Meanwhile, baicalin (BA)-an active ingredient extracted from the roots of Scutellaria baicalensis Georgi -has been shown to alleviate BLM-induced pulmonary fibrosis (PF). Hence, the objective of this study was to examine the protective effects of BA in the context of BLM-induced early PF in mice and elucidate the underlying mechanism(s). We established an in vivo BLM (3.5 mg/kg)-induced PF murine model and in vitro BLM (35 μM)-damaged MLE-12 cell model. On Day 14 of treatment, the levels of fibrosis and apoptosis were evaluated in mouse lungs via hydroxyproline analysis, western blotting (COL1A1, TGF-β, Bax, Bcl-2, cleaved caspase-3), and Masson, immunohistochemical (α-SMA, AIF, Cyto C), and TUNEL staining. Additionally, in vitro, apoptosis was assessed in MLE-12 cells exposed to BLM for 24 h using the Annexin V/PI assay and western blotting (Bax, Bcl-2, cleaved caspase-3, AIF, Cyto C). To elucidate the role of the mitochondrial ATP-sensitive potassium channel (mitoKATP) in the protective effect of BA, we utilised diazoxide (DZX)-a mitoKATP agonist-and 5-hydroxydecanoate sodium (5-HD)-a mitoKATP inhibitor. Results revealed the involvement of mitoKATP in the protective effect of BA in BLM-induced PF. More specifically, mitoKATP activation can attenuate BLM-induced PF progression and mitigate alveolar epithelial type II cell death by reducing mitochondrial ROS, maintaining the mitochondrial membrane potential, and impeding the mitochondrial apoptotic pathway. Collectively, the findings offer pharmacological support to use BA for the treatment or prevention of BLM-induced PF and suggest that mitoKATP might serve as an effective therapeutic target for this condition.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Caspase 3; bcl-2-Associated X Protein; Signal Transduction; Proto-Oncogene Proteins c-bcl-2
PubMed: 37783230
DOI: 10.1016/j.tox.2023.153638 -
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 -
Clinical Pediatrics Jul 2021
Topics: Congenital Hyperinsulinism; Diazoxide; Gastrointestinal Agents; Humans; Infant; Infant, Newborn; Male; Octreotide; Pancreas; Treatment Outcome
PubMed: 33971777
DOI: 10.1177/00099228211013648