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Bioscience Reports May 2023Acacia arabica commonly known as 'babul' has been widely used for the treatment of numerous diseases, including diabetes due to their potential pharmacological actions....
Acacia arabica commonly known as 'babul' has been widely used for the treatment of numerous diseases, including diabetes due to their potential pharmacological actions. The aim of the present study was to investigate the insulinotropic and antidiabetic properties of ethanol extract of Acacia arabica (EEAA) bark through in vitro and in vivo studies in high fat-fed (HFF) rats. EEAA at 40-5000 µg/ml significantly increased (P<0.05-0.001) insulin secretion with 5.6 and 16.7 mM glucose, respectively, from clonal pancreatic BRIN BD11 β-cells. Similarly, EEAA at 10-40 µg/ml demonstrated a substantial (P<0.05-0.001) insulin secretory effect with 16.7 mM glucose from isolated mouse islets, with a magnitude comparable to 1 µM glucagon-like peptide-1 (GLP-1). Diazoxide, verapamil, and calcium-free conditions decreased insulin secretion by 25-26%. The insulin secretory effect was further potentiated (P<0.05-0.01) with 200 µM isobutylmethylxanthine (IBMX; 1.5-fold), 200 µM tolbutamide (1.4-fold), and 30 mM KCl (1.4-fold). EEAA at 40 µg/ml, induced membrane depolarization and elevated intracellular Ca2+ as well as increased (P<0.05-0.001) glucose uptake in 3T3L1 cells and inhibited starch digestion, glucose diffusion, dipeptidyl peptidase-IV (DPP-IV) enzyme activity, and protein glycation by 15-38%, 11-29%, 15-64%, and 21-38% (P<0.05, 0.001), respectively. In HFF rats, EEAA (250 mg/5 ml/kg) improved glucose tolerance, plasma insulin, and GLP-1 levels, and lowered DPP-IV enzyme activity. Phytochemical screening of EEAA revealed the presence of flavonoids, tannins and anthraquinone. These naturally occurring phytoconstituents may contribute to the potential antidiabetic actions of EEAA. Thus, our finding suggests that EEAA, as a good source of antidiabetic constituents, would be beneficial for Type 2 diabetes patients.
Topics: Mice; Rats; Animals; Insulin Secretion; Insulin; Diabetes Mellitus, Type 2; Acacia; Diabetes Mellitus, Experimental; Plant Bark; Glucose; Hypoglycemic Agents; Glucagon-Like Peptide 1; Obesity; Ethanol; Diet; Blood Glucose; Dipeptidyl Peptidase 4
PubMed: 37133312
DOI: 10.1042/BSR20230329 -
Endocrine Journal 2016Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension....
Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia.
Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Diazoxide; Drug Monitoring; Drug Resistance; Edema; Female; Heart Failure; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Japan; Male; Middle Aged; Water-Electrolyte Imbalance
PubMed: 26598136
DOI: 10.1507/endocrj.EJ15-0428 -
European Journal of Pharmacology Oct 2021Mitochondrial ATP-sensitive potassium channels (mitoKATP) locate in the inner mitochondrial membrane and possess protective cellular properties. mitoKATP opening-induced...
Pharmacological and molecular docking studies reveal that glibenclamide competitively inhibits diazoxide-induced mitochondrial ATP-sensitive potassium channel activation and pharmacological preconditioning.
Mitochondrial ATP-sensitive potassium channels (mitoKATP) locate in the inner mitochondrial membrane and possess protective cellular properties. mitoKATP opening-induced cardioprotection (using the pharmacological agent diazoxide) is preventable by antagonists, such as glibenclamide. However, the mechanisms of action of these drugs and how mitoKATP respond to them are poorly understood. Here, we show data that reinforce the existence of a mitochondrial sulfonylurea receptor (mitoSUR) as part of the mitoKATP. We also show how diazoxide and glibenclamide compete for the same binding site in mitoSUR. A glibenclamide analog that lacks its cyclohexylurea portion (IMP-A) loses its ability to inhibit diazoxide-induced swelling. These results suggest that the cyclohexylureia portion of glibenclamide is indispensable for mitoKATP inhibition. Moreover, IMP-A did not suppress diazoxide-induced preconditioning (EC50 10.66 μM) in a rat model of a cardiac ischemia/reperfusion. Importantly, glibenclamide inhibited both diazoxide-induced cardioprotection (IC50 86 nM). We suggest that IMP-A must be used with caution since we found this drug possesses significant inhibitory effects on mitochondrial respiration. We characterized the binding of glibenclamide and diazoxide using a molecular simulation (docking) approach. Using the molecular structure of the ATP binding protein ABCB8 (pointed by others as the mitoSUR) we demonstrate that glibenclamide competitively inhibits diazoxide actions. This was reinforced (pharmacologically) in a competitive antagonism test. Taken together, these results bring valuable and novel insights into the pharmacological/biochemical aspects of mitokATP activation and cardioprotection. This study may lead to the discovery of novel therapeutic strategies that may impact ischemia-reperfusion injury.
Topics: Animals; Diazoxide; Glyburide; KATP Channels; Molecular Docking Simulation; Rats
PubMed: 34324857
DOI: 10.1016/j.ejphar.2021.174379 -
The Journal of Thoracic and... Jun 2022Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine...
OBJECTIVE
Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine triphosphate potassium sensitive channel openers, such as diazoxide, mimic ischemic preconditioning, prevent cardiomyocyte swelling, preserve myocyte contractility after stress, and provide diastolic protection. We hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection compared with cardioplegia alone during prolonged global ischemia in a large animal model.
METHODS
Twelve pigs were randomized to global ischemia for 2 hours with a single dose of cold blood (4:1) hyperkalemic cardioplegia alone (n = 6) or with diazoxide (500 μmol/L) (n = 6) and reperfused for 1 hour. Cardiac output, myocardial oxygen consumption, left ventricular developed pressure, left ventricular ejection fraction, diastolic function, myocardial troponin, myoglobin, markers of apoptosis, and left ventricular infarct size were compared.
RESULTS
Four pigs in the cardioplegia alone group could not be weaned from cardiopulmonary bypass. There were no differences in myoglobin, troponin, or apoptosis between groups. Diazoxide preserved cardiac output versus control (74.5 vs 18.4 mL/kg/min, P = .01). Linear mixed regression modeling demonstrated that the addition of diazoxide to cardioplegia preserved left ventricular developed pressure by 36% (95% confidence interval, 9.9-61.5; P < .01), dP/dt max by 41% (95% confidence interval, 14.5-67.5; P < .01), and dP/dt min by 33% (95% confidence interval, 8.9-57.5; P = .01). It was also associated with higher (but not significant) myocardial oxygen consumption (3.7 vs 1.4 mL O/min, P = .12).
CONCLUSIONS
Diazoxide preserves systolic and diastolic ventricular function in a large animal model of prolonged global myocardial ischemia. Diazoxide as an adjunct to hyperkalemic cardioplegia may allow safer prolonged ischemic times during increasingly complicated cardiac procedures.
Topics: Animals; Adenosine Triphosphate; Cardioplegic Solutions; Diazoxide; Heart Arrest, Induced; Ischemia; Myocardial Ischemia; Myoglobin; Potassium; Potassium Channels; Stroke Volume; Swine; Troponin; Ventricular Function, Left
PubMed: 32977969
DOI: 10.1016/j.jtcvs.2020.08.069 -
Circulation. Genomic and Precision... Oct 2018In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular...
BACKGROUND
In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target.
METHODS
Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis.
RESULTS
We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide.
CONCLUSIONS
Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
Topics: Adult; Amino Acid Substitution; Child; DNA Mutational Analysis; Exome; Familial Primary Pulmonary Hypertension; Female; Humans; Male; Mutation, Missense; Sulfonylurea Receptors
PubMed: 30354297
DOI: 10.1161/CIRCGEN.118.002087 -
The Journal of Pharmacology and... Sep 2019Glucose-stimulated insulin secretion from pancreatic -cells is controlled by ATP-regulated potassium (K) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1)...
Glucose-stimulated insulin secretion from pancreatic -cells is controlled by ATP-regulated potassium (K) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The K channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular K channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular K channels. VU0071063 induces hyperpolarization of -cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain.
Topics: Animals; Ductus Arteriosus; Glucose; HEK293 Cells; Humans; Insulin Secretion; Insulin-Secreting Cells; Ion Channel Gating; Mice; Potassium Channels, Inwardly Rectifying; Structure-Activity Relationship; Sulfonylurea Receptors; Vasodilation; Xanthines
PubMed: 31201216
DOI: 10.1124/jpet.119.257204 -
PloS One 2019Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adolescent; Basal Metabolism; Body Composition; Child; Delayed-Action Preparations; Diazoxide; Double-Blind Method; Female; Humans; Hyperinsulinism; Hyperphagia; Male; Obesity; Pilot Projects; Prader-Willi Syndrome; Safety; Waist Circumference; Young Adult
PubMed: 31545799
DOI: 10.1371/journal.pone.0221615 -
ACS Applied Materials & Interfaces Aug 2022Here, we present multifunctional fluorescent nanodiamonds (FNDs) for simultaneous drug delivery and free radical detection. For this purpose, we modified FNDs containing...
Here, we present multifunctional fluorescent nanodiamonds (FNDs) for simultaneous drug delivery and free radical detection. For this purpose, we modified FNDs containing nitrogen vacancy (NV) centers with a diazoxide derivative. We found that our particles enter cells more easily and are able to deliver this cancer drug into HeLa cells. The particles were characterized by infrared spectroscopy, dynamic light scattering, and secondary electron microscopy. Compared to the free drug, we observe a sustained release over 72 h rather than 12 h for the free drug. Apart from releasing the drug, with these particles, we can measure the drug's effect on free radical generation directly. This has the advantage that the response is measured locally, where the drug is released. These FNDs change their optical properties based on their magnetic surrounding. More specifically, we make use of a technique called relaxometry to detect spin noise from the free radical at the nanoscale with subcellular resolution. We further compared the results from our new technique with a conventional fluorescence assay for the detection of reactive oxygen species. This provides a new method to investigate the relationship between drug release and the response by the cell via radical formation or inhibition.
Topics: Dynamic Light Scattering; HeLa Cells; Humans; Microscopy, Fluorescence; Nanodiamonds; Nitrogen
PubMed: 35984747
DOI: 10.1021/acsami.2c11688 -
Acta Endocrinologica (Bucharest,... 2021Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic...
Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic hypoglycemia, in addition to persistently elevated plasma ammonia levels. First-line treatment is diazoxide, and most patients respond well to this agent, however side effects may be observed. The most frequent side effect of diazoxide is fluid retention and hypertrichosis, while hyperuricemia and hematologic side effects are observed less often. Herein, we report a case who had a heterozygous mutation of GLUD1 gene and who developed diazoxide related neutropenia 8 years after the start of treatment. On follow-up, leucopenia and mild neutropenia persisted and the treatment was changed to somatostatin analogues. However, she developed persistent severe symptomatic hypoglycemia and required diazoxide retreatment. A lower dose of diazoxide (6 mg/kg/day) successfully controlled hypoglycemia and cell counts increased even though they were not normalized. Neutropenia in current case presented after a long period of time of diazoxide use and this period is the longest defined in the literature. Long-term endocrine and hematologic follow-up of this patient up to 18 years old will also be presented.
PubMed: 35342475
DOI: 10.4183/aeb.2021.383 -
Clinical Pediatric Endocrinology : Case... 2021Hyperglycemia and hyperosmolar hyperglycemic syndrome (HHS) are the rare adverse effects of diazoxide. Furosemide has been reported to worsen glucose tolerance and cause...
Hyperglycemia and hyperosmolar hyperglycemic syndrome (HHS) are the rare adverse effects of diazoxide. Furosemide has been reported to worsen glucose tolerance and cause HHS. A 5-yr-old girl presented to the emergency department with complaints of tachycardia, polyuria, and lethargy for 1 wk prior to hospitalization. She was treated with two diuretics for aortic valve reflux disease and diazoxide for congenital hyperinsulinemia. She was diagnosed with HHS based on her serum glucose level of 529 mg/dL and serum osmotic pressure of 357 mOsm/kg. There were no findings suggestive of new-onset diabetes mellitus. She had fever on admission and, was diagnosed with a urinary tract infection. The blood diazoxide level at the time of hospitalization was 25 µg/dL. Diazoxide use, even in patients with low diazoxide levels, may cause hyperglycemia. Patients on diuretics and diazoxide must be carefully monitored, considering the risk of developing HHS.
PubMed: 34285456
DOI: 10.1297/cpe.30.139