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Peptides May 2022This study aimed to investigate whether the Diminazene Aceturate (DIZE), an angiotensin-converting enzyme 2 (ACE2) activator, can revert cardiac dysfunction in ischemia... (Review)
Review
This study aimed to investigate whether the Diminazene Aceturate (DIZE), an angiotensin-converting enzyme 2 (ACE2) activator, can revert cardiac dysfunction in ischemia reperfusion-induced (I/R) injury in animals and examine the mechanism underlying this effect. Wistar rats systemically received DIZE (1 mg/kg) for thirty days. Cardiac function in isolated rat hearts was evaluated using the Langendorff technique. After I/R, ventricular non-I/R and I/R samples were used to evaluate ATP levels. Mitochondrial function was assessed using cardiac permeabilized fibers and isolated cardiac mitochondria. Cardiac cellular electrophysiology was evaluated using the patch clamp technique. DIZE protected the heart after I/R from arrhythmia and cardiac dysfunction by preserving ATP levels, independently of any change in coronary flow and heart rate. DIZE improved mitochondrial function, increasing the capacity for generating ATP and reducing proton leak without changing the specific citrate synthase activity. The activation of the ACE2 remodeled cardiac electrical profiles, shortening the cardiac action potential duration at 90 % repolarization. Additionally, cardiomyocytes from DIZE-treated animals exhibited reduced sensibility to diazoxide (K agonist) and a higher K current compared to the controls. DIZE was able to improve mitochondrial function and modulate cardiac electrical variables with a cardio-protective profile, resulting in direct myocardial cell protection from I/R injury.
Topics: Adenosine Triphosphate; Angiotensin-Converting Enzyme 2; Animals; Arrhythmias, Cardiac; Diminazene; Myocytes, Cardiac; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury
PubMed: 35033621
DOI: 10.1016/j.peptides.2022.170746 -
Frontiers in Molecular Biosciences 2023Diazoxide is a selective mitochondrial-sensitive potassium channel opening agent that has a definite effect on reducing myocardial ischemia/reperfusion injury (MIRI)....
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. 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. 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/dt 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/dt 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/dt 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. 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.
PubMed: 37304068
DOI: 10.3389/fmolb.2023.1196894 -
Metabolites May 2023The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the... (Review)
Review
The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K-channel at the plasma membrane. The resultant depolarization of the β-cells opens voltage-dependent Ca-channels at the plasma membrane that triggers the exocytosis of insulin secretory granules. The secretory response is biphasic with a first and transient peak followed by a sustained phase. The first phase is reproduced by a depolarization of the β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide (triggering phase); the sustained phase (amplifying phase) depends on the participation of metabolic signals that remain to be determined. Our group has been investigating for several years the participation of the β-cell GABA metabolism in the stimulation of insulin secretion by three different secretagogues (glucose, a mixture of L-leucine plus L-glutamine, and some branched chain alpha-ketoacids, BCKAs). They stimulate a biphasic secretion of insulin accompanied by a strong suppression of the intracellular islet content of gamma-aminobutyric acid (GABA). As the islet GABA release simultaneously decreased, it was concluded that this resulted from an increased GABA shunt metabolism. The entrance of GABA into the shunt is catalyzed by GABA transaminase (GABAT) that transfers an amino group between GABA and alpha-ketoglutarate, resulting in succinic acid semialdehyde (SSA) and L-glutamate. SSA is oxidized to succinic acid that is further oxidized in the citric acid cycle. Inhibitors of GABAT (gamma-vinyl GABA, gabaculine) or glutamic acid decarboxylating activity (GAD), allylglycine, partially suppress the secretory response as well as GABA metabolism and islet ATP content and the ATP/ADP ratio. It is concluded that the GABA shunt metabolism contributes together with the own metabolism of metabolic secretagogues to increase islet mitochondrial oxidative phosphorylation. These experimental findings emphasize that the GABA shunt metabolism is a previously unrecognized anaplerotic mitochondrial pathway feeding the citric acid cycle with a β-cell endogenous substrate. It is therefore a postulated alternative to the proposed mitochondrial cataplerotic pathway(s) responsible for the amplification phase of insulin secretion. It is concluded the new postulated alternative suggests a possible new mechanism of β-cell degradation in type 2 (perhaps also in type 1) diabetes.
PubMed: 37367856
DOI: 10.3390/metabo13060697 -
JFMS Open Reports 2022A 5.5 month-old intact male Maine Coon cat was presented to a referral hospital for a history of muscle fasciculations, lethargy and seizures associated with refractory...
CASE SUMMARY
A 5.5 month-old intact male Maine Coon cat was presented to a referral hospital for a history of muscle fasciculations, lethargy and seizures associated with refractory hypoglycemia. Diagnostic testing for hypothyroidism, hyposomatotropism or hypoadrenocorticism, inborn errors of metabolism (ie, storage diseases and urea cycle disorders), infection or iatrogenic hypoglycemia were negative. An inappropriately high serum insulin level was noted in the face of marked hypoglycemia. The insulin:glucose ratio was 0.44 (<0.3) and the amended insulin:glucose ratio was 1268 (<30). Thoracic radiography and abdominal ultrasonography did not identify a cause for this elevated insulin level. Stabilization with a low, but adequate, blood glucose occurred with corticosteroid therapy, with further significant improvement with the addition of diazoxide. Peripheral neuropathy developed several months later, and concerns for quality of life led to humane euthanasia approximately 1 year after the initial diagnosis. Insulin levels remained high at the time of euthanasia. Necropsy found no gross lesions, though microscopic degeneration of the sciatic nerve and subjectively mildly increased size and number of pancreatic islets was noted. These findings were consistent with a diagnosis of congenital hyperinsulinism.
RELEVANCE AND NOVEL INFORMATION
This is the first reported case of congenital hyperinsulinism in a cat and may parallel the diffuse form of hypoglycemic hyperinsulinism reported in humans and a single dog. It should be considered a differential diagnosis in kittens presenting for refractory hypoglycemia.
PubMed: 36458207
DOI: 10.1177/20551169221136473 -
Cardiovascular Drugs and Therapy Feb 2023Doxorubicin-induced cardiotoxicity (DIC) is a common side effect of doxorubicin chemotherapy, and a major mechanism of DIC is inflammation. However, no effective method...
PURPOSE
Doxorubicin-induced cardiotoxicity (DIC) is a common side effect of doxorubicin chemotherapy, and a major mechanism of DIC is inflammation. However, no effective method exists to prevent DIC. In the present study, we investigated the cardioprotective effects of nicorandil against DIC using multiparametric cardiac magnetic resonance (CMR) imaging and elucidated the anti-inflammatory properties of nicorandil in rat models.
METHODS
Male Sprague-Dawley rats received four weekly intraperitoneal doxorubicin doses (4 mg/kg/injection) to establish the DIC model. After treatment with or without nicorandil (3 mg/kg/day) or diazoxide (10 mg/kg/day) orally, all the groups underwent weekly CMR examinations, including cardiac function and strain assessment and T2 mapping, for 6 weeks. Additionally, blood samples and hearts were collected to examine inflammation and histopathology.
RESULTS
According to our results, the earliest DIC CMR parameter in the doxorubicin group was T2 mapping time prolongation compared with the DIC rats treated with nicorandil (doxorubicin+nicorandil group) at week 2. Subsequently, the left ventricular ejection fraction (LVEF) and global peak systolic myocardial strain in the doxorubicin group were significantly reduced, and nicorandil effectively inhibited these effects at week 6. Our results were confirmed by histopathological evaluations. Furthermore, nicorandil treatment had a protective effect against the doxorubicin-induced inflammatory response. Interestingly, similar protective results were obtained using the K channel opener diazoxide.
CONCLUSION
Collectively, our findings indicate that nicorandil application ameliorates DIC in rats with significantly higher cardiac function and myocardial strain and less fibrosis, apoptosis and inflammatory cytokine production. Nicorandil prevents T2 abnormalities in the early stages of DIC, showing a high clinical value for early nicorandil treatment in chemotherapy patients.
Topics: Rats; Male; Animals; Nicorandil; Diazoxide; Cardiotoxicity; Stroke Volume; Rats, Sprague-Dawley; Ventricular Function, Left; Doxorubicin; Magnetic Resonance Imaging; Inflammation
PubMed: 34595611
DOI: 10.1007/s10557-021-07252-5 -
Cureus Mar 2023A low blood glucose level (less than 55 mg/dL) associated with autonomic and neuroglycopenic signs and symptoms that resolve after glucose administration establishes...
A low blood glucose level (less than 55 mg/dL) associated with autonomic and neuroglycopenic signs and symptoms that resolve after glucose administration establishes Whipple's triad, indicating the presence of a hypoglycemic disorder. Insulinoma remains the most common cause of endogenous hyperinsulinemia. We present the case of a 73-year-old male who was brought to the emergency department after losing consciousness. On initial assessment, severe hypoglycemia was identified and treated. No abnormalities were detected on the physical examination, initial blood tests, abdominal ultrasound and computed tomography (CT) thorax, and abdomen and pelvis. The patient had another episode of symptomatic hypoglycemia, and the blood tests performed were compatible with endogenous hyperinsulinism. The patient was started on diazoxide to prevent further hypoglycemia episodes. Magnetic resonance imaging (MRI) showed a nodular area in the cephalic region of the pancreas, and the patient was discharged with diazoxide and flash glucose monitoring. In the follow-up appointment, he presented with signs and symptoms of congestive heart failure. Endoscopic ultrasound was requested, but the patient was at high risk for complications while undergoing the procedure under anesthesia due to congestive heart failure. A Gallium-DOTA-NOC positron emission tomography and computed tomography (PET-CT) was requested and confirmed the presence of a nodular area in the cephalic region of the pancreas. He was referred to general surgery for definitive treatment. Insulinoma is still a challenging medical condition. Therefore, management by a multidisciplinary team is essential. This case highlights the impact that side effects of medication used to treat this condition can have. Diazoxide was initiated to stop severe recurrent hypoglycemia; however, the patient developed congestive heart failure and was unable to undergo an endoscopic ultrasound to localize the lesion, resulting in a delay in diagnosis and definitive treatment. Diazoxide is a potent hyperglycemic drug but it can also cause fluid retention, nausea, hypertrichosis, neutropenia, and thrombocytopenia.
PubMed: 37123740
DOI: 10.7759/cureus.36804 -
Clinical Endocrinology Mar 2021Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin...
OBJECTIVE
Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin release. Syndromic conditions like Beckwith-Wiedemann (BWS), Kabuki (KS) and Turner (TS) are known to be associated with a higher risk for HH. This systematic review of children with HH referred to a tertiary centre aims at estimating the frequency of a syndromic/multisystem condition to help address stratification of genetic analysis in infants with HH.
METHODS
We performed a retrospective study of 69 patients with syndromic features and hypoglycaemia in a specialist centre from 2004 to 2018.
RESULTS
Biochemical investigations confirmed HH in all the cases and several genetic diagnoses were established. Responsiveness to medications and the final outcome following medical treatment or surgery were studied.
CONCLUSIONS
This study highlights the association of HH with a wide spectrum of syndromic diagnoses and that children with features suggestive of HH-associated syndromes should be monitored for hypoglycaemia. If hypoglycaemia is documented, they should also be screened for possible HH. Our data indicate that most syndromic forms of HH are diazoxide-responsive and that HH resolves over time; however, a significant percentage continues to require medications years after the onset of the disease. Early diagnosis of hyperinsulinism and initiation of treatment is important for preventing hypoglycaemic brain injury and intellectual disability.
Topics: Child; Congenital Hyperinsulinism; Diazoxide; Follow-Up Studies; Humans; Infant; Retrospective Studies; Syndrome
PubMed: 33345357
DOI: 10.1111/cen.14393 -
Angewandte Chemie (International Ed. in... Jul 2022Benzoxathiazine dioxide, as a bioisostere of the clinically widely used diazoxide, exhibits interesting biological activity. However, limited success has been achieved...
Benzoxathiazine dioxide, as a bioisostere of the clinically widely used diazoxide, exhibits interesting biological activity. However, limited success has been achieved in terms of its concise and direct synthesis. We report herein a facile electrochemical migratory cyclization of N-acylsulfonamides to access a diverse array of benzoxathiazine dioxides. The inclusion of electrochemistry is crucial for realizing such a novel transformation, which is substantiated both by the experiments and density-functional-theory calculations.
Topics: Cyclization; Electrochemistry
PubMed: 35606293
DOI: 10.1002/anie.202206058 -
The Journal of Biological Chemistry Jan 2020MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well as in plasma of...
MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well as in plasma of diabetic patients. Here we investigated how miR-199 expression is regulated in β-cells by assessing expression of miR-199 precursors (primiR-199a1, primiR-199a2, and primiR-199b) and mature miR-199 (miR-199-3p and miR-199-5p) and promoter transcriptional activity assays in mouse islets and mouse insulinoma cells (MIN6) under different stimuli. We found that mouse islets equally express miR-199-3p and miR-199-5p. However, the primiRNA expression levels differed; although primiR-199a1 expression was about 30% greater than that of primiR-199a2, primiR-199b is barely detected in islets. We observed a 2-fold increase in primiR-199a1 and primiR-199a2 mRNA levels in mouse islets cultured in 10 mm glucose compared with 5.5 mm glucose. Similar responses to glucose were observed in MIN6 cells. Exposure to 30 mm KCl to induce membrane depolarization and calcium influx increased expression of primiR-199a2 but not of primiR-199a1 in MIN6 cells, indicating that calcium influx was involved. Transcriptional activity studies in MIN6 cells also revealed that primiR-199a2 promoter activity was enhanced by glucose and reduced by 2-deoxy-D-glucose-induced starvation. KCl and the potassium channel blocker tolbutamide also stimulated primiR-199a2 promoter activity. Calcium channel blockade by nifedipine reduced primiR-199a2 promoter activity in MIN6 cells, and diazoxide-mediated calcium influx inhibition blunted glucose up-regulation of miR-199-3p in islets. In conclusion, we uncover that glucose acutely up-regulates miR-199 family expression in β-cells. Glucose metabolism and calcium influx are involved in primiR-199a2 expression but not primiR-199a1 expression.
Topics: Animals; Calcium; Cell Line; Cell Membrane; Female; Glucose; Insulin-Secreting Cells; Male; Mice; MicroRNAs; Up-Regulation
PubMed: 31882540
DOI: 10.1074/jbc.RA119.010356 -
Journal of Clinical Research in... Mar 2022Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects...
OBJECTIVE
Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects behind hyperinsulinism and its complications provides clues to timely diagnosis and management. The aim of this study was to evaluate the underlying genetic aetiology of a specific Iranian pediatric cohort with CHI.
METHODS
A total of 44 unrelated children, 20 girls and 24 boys, with an initial diagnosis or history of CHI from all regions of Iran were recruited between 2016 and 2019. Targeted next generation sequencing (tNGS) was performed for the genes found in about half of CHI patients.
RESULTS
Mutations were identified in 24 cases (55%). Patients with a confirmed genetic cause were mainly diagnosed below age of one year old (p=0.01), had fewer other syndromic features, excluding seizure, (p=0.03), were less diazoxide responsive (p=0.04) and were more diazoxide unresponsive leading to pancreatectomy (p=0.007) compared to those with no identified mutations. Among 24 patients with identified genetic mutations, 17 (71%) had a mutation in , 3 (12%) in , 3 (12%) in , and 1 patient had a mutation in . These included five novel mutations in , and .
CONCLUSION
This is the biggest genetic study of CHI in Iran. A high frequency of recessive forms of CHI, especially HADH mutations, in our study could be due to a high rate of consanguineous marriage. We recommend tNGS to screen for all the CHI genes.
Topics: Child; Congenital Hyperinsulinism; Diazoxide; Female; Humans; Infant; Iran; Male; Mutation; Sulfonylurea Receptors
PubMed: 34927408
DOI: 10.4274/jcrpe.galenos.2021.2021.0071