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Journal of the American Heart... Dec 2022Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of... (Review)
Review
Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; =0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; =0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; <0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (<0.01) and maximum change in ventricular pressure during isovolumetric contraction (<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.
Topics: Swine; Animals; Diazoxide; Myocardial Stunning; KATP Channels; Stroke Volume; Ventricular Function, Left; Ischemia; Myocardial Ischemia; Adenosine Triphosphate
PubMed: 36444837
DOI: 10.1161/JAHA.122.026304 -
Pediatrics International : Official... Aug 2014Over the past 20 years, there has been remarkable progress in the diagnosis and treatment of congenital hyperinsulinism (CHI). These advances have been supported by the... (Review)
Review
Over the past 20 years, there has been remarkable progress in the diagnosis and treatment of congenital hyperinsulinism (CHI). These advances have been supported by the understanding of the molecular mechanism and the development of diagnostic modalities to identify the focal form of ATP-sensitive potassium channel CHI. Many patients with diazoxide-unresponsive focal CHI have been cured by partial pancreatectomy without developing postsurgical diabetes mellitus. Important novel findings on the genetic basis of the other forms of CHI have also been obtained, and several novel medical treatments have been explored. However, the management of patients with CHI is still far from ideal. First, state-of-the-art treatment is not widely available worldwide. Second, it appears that the management strategy needs to be adjusted according to the patient's ethnic group. Third, optimal management of patients with the diazoxide-unresponsive, diffuse form of CHI is still insufficient and requires further improvement. In this review, we describe the current landscape of this disorder, discuss the racial disparity of CHI using Japanese patients as an example, and briefly note unanswered questions and unmet needs that should be addressed in the near future.
Topics: Congenital Hyperinsulinism; Humans; Japan
PubMed: 24865345
DOI: 10.1111/ped.12390 -
Veterinary Journal (London, England :... Dec 2015Functional endocrine tumours have long been thought to be rare in guinea pigs, although conditions such as hyperthyroidism and hyperadrenocorticism have been documented... (Review)
Review
Functional endocrine tumours have long been thought to be rare in guinea pigs, although conditions such as hyperthyroidism and hyperadrenocorticism have been documented with increasing frequency so the prevalence of hormonal disorders may have been underestimated. Both the clinical signs and diagnosis of hyperthyroidism in guinea pigs appear to be very similar to those described in feline hyperthyroidism, and methimazole has been proven to be a practical therapy option. Hyperadrenocorticism has been confirmed in several guinea pigs with an adrenocorticotropic hormone stimulation test using saliva as a non-invasive sample matrix; trilostane has been successfully used to treat a guinea pig with hyperadrenocorticism. Insulinomas have only rarely been documented in guinea pigs and one animal was effectively treated with diazoxide.
Topics: Adrenocortical Hyperfunction; Animals; Endocrine Gland Neoplasms; Guinea Pigs; Hyperthyroidism; Insulinoma
PubMed: 26542368
DOI: 10.1016/j.tvjl.2015.08.016 -
American Journal of Physiology. Heart... Jun 2016
Topics: Adenosine Triphosphate; Diazoxide; Ischemic Preconditioning, Myocardial; KATP Channels
PubMed: 27199122
DOI: 10.1152/ajpheart.00309.2016 -
BioRxiv : the Preprint Server For... Aug 2023Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed,...
OBJECTIVE
Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed, and hypoglycemic conditions, yet metabolic regulation of α-cells remains poorly understood. Here, we identified a previously unexplored role for physiological levels of leucine, which is classically regarded as a β-cell fuel, in the intrinsic regulation of α-cell glucagon release.
METHODS
GcgCre:CAMPER and GcgCre:GCaMP6s mice were generated to perform dynamic, high-throughput functional measurements of α-cell cAMP and Ca within the intact islet. Islet perifusion assays were used for simultaneous, time-resolved measurements of glucagon and insulin release from mouse and human islets. The effects of leucine were compared with glucose and the mitochondrial fuels 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH, non-metabolized leucine analog that activates glutamate dehydrogenase), α-ketoisocaproate (KIC, leucine metabolite), and methyl-succinate (complex II fuel). CYN154806 (Sstr2 antagonist), diazoxide (K activator, which prevents Ca-dependent exocytosis from α, β, and δ-cells), and dispersed α-cells were used to inhibit islet paracrine signaling and identify α-cell intrinsic effects.
RESULTS
Mimicking the effect of glucose, leucine strongly suppressed amino acid-stimulated glucagon secretion. Mechanistically, leucine dose-dependently reduced α-cell cAMP at physiological concentrations, with an IC of 57, 440, and 1162 μM at 2, 6, and 10 mM glucose, without affecting α-cell Ca. Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonist or diazoxide, as well as dispersed α-cells, indicating an α-cell intrinsic effect. The effect of leucine was matched by KIC and the glutamate dehydrogenase activator BCH, but not methyl-succinate, indicating a dependence on mitochondrial anaplerosis. Glucose, which stimulates anaplerosis via pyruvate carboxylase, had the same suppressive effect on α-cell cAMP but with lower potency. Similarly to mouse islets, leucine suppressed glucagon secretion from human islets under hypoglycemic conditions.
CONCLUSIONS
These findings highlight an important role for physiological levels of leucine in the metabolic regulation of α-cell cAMP and glucagon secretion. Leucine functions primarily through an α-cell intrinsic effect that is dependent on glutamate dehydrogenase, in addition to the well-established α-cell regulation by β/δ-cell paracrine signaling. Our results suggest that mitochondrial anaplerosis-cataplerosis facilitates the glucagonostatic effect of both leucine and glucose, which cooperatively suppress α-cell tone by reducing cAMP.
PubMed: 37577685
DOI: 10.1101/2023.07.31.551113 -
Gene Aug 2023The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in...
The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding K channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.
Topics: Humans; Infant; Male; Congenital Hyperinsulinism; Diazoxide; Heterozygote; Insulin; Mutation; Sulfonylurea Receptors
PubMed: 37336273
DOI: 10.1016/j.gene.2023.147576 -
Reviews in Endocrine & Metabolic... Oct 2022Maturity-Onset Diabetes of the Youth (MODY) diabetes remains commonly misdiagnosed. A monogenic form should be suspected in individuals presenting hyperinsulinemic... (Review)
Review
Maturity-Onset Diabetes of the Youth (MODY) diabetes remains commonly misdiagnosed. A monogenic form should be suspected in individuals presenting hyperinsulinemic hypoglycemia (HH) associated with, either later development of MODY (hypoglycemia-remission-diabetes sequence), or with first/second-degree family history of diabetes. Herein, we aimed to describe this individual or family monogenic association between HH and diabetes, and identify potential genotype-phenotype correlations. We conducted a systematic review of 26 studies, including a total of 67 patients with this association resulting from variants in GCK (n = 5 cases), ABCC8 (n = 29), HNF1A (n = 5), or HNF4A (n = 28). A family history of hypoglycemia and/or diabetes was present in 91% of cases (61/67). Median age at first hypoglycemia was 24 h after birth. Diazoxide was initiated in 46 children (46/67-69%); responsiveness was found in 91% (42/46). Median HH duration was three years (1 day-25 years). Twenty-three patients (23/67-34%) later developed diabetes (median age: 13 years; range: 8-48); more frequently in those untreated with diazoxide. This association was most commonly inherited in an autosomal dominant manner (43/48-90%). Some genes were associated with less severe initial hypoglycemia (HNF1A), shorter duration of HH (HNF4A), and more maternal (ABCC8) or paternal (HNF4A) transmission. This study illustrates that the same genotype can give a biphasic phenotype in the same person or a reverse phenotype in the same family. Wider awareness of this association is necessary in pediatrics to establish annual monitoring of patients who have presented HH, and during maternity to screen diabetes and optimize genetic counseling and management of pregnancy, childbirth, and the newborn.PROSPERO registration: CRD42020178265.
Topics: Child; Congenital Hyperinsulinism; Diabetes Mellitus, Type 2; Diazoxide; Female; Humans; Mutation; Phenotype; Pregnancy
PubMed: 35996042
DOI: 10.1007/s11154-022-09749-2 -
European Journal of Pharmacology Dec 2015Gap junctions (GJs) channels provide the basis for intercellular communication in the cardiovascular system for maintenance of the normal cardiac rhythm, regulation of... (Review)
Review
Gap junctions (GJs) channels provide the basis for intercellular communication in the cardiovascular system for maintenance of the normal cardiac rhythm, regulation of vascular tone and endothelial function as well as metabolic interchange between the cells. They allow the transfer of small molecules and may enable slow calcium wave spreading, transfer of "death" or of "survival" signals. In the cardiomyocytes the most abundant isoform is Connexin 43 (Cx43). Alterations in Cx43 expression and distribution were observed in myocardium disease; i.e. in hypertrophic cardiomyopathy, heart failure and ischemia. Recent reports suggest the presence of Cx43 in the mitochondria as well, at least in the inner mitochondrial membrane, where it plays a central role in ischemic preconditioning. In this review, the current knowledge on the relationship between the remodeling of cardiac gap junctions and cardiac diseases are summarized.
Topics: Animals; Cardiovascular Diseases; Connexin 43; Humans
PubMed: 26499977
DOI: 10.1016/j.ejphar.2015.10.030 -
Pharmacological Research Sep 2019Progressive neuronal death is the key pathogenic event leading to clinical symptoms in neurodegenerative disorders (NDDs). Neuroprotective treatments are virtually... (Review)
Review
Progressive neuronal death is the key pathogenic event leading to clinical symptoms in neurodegenerative disorders (NDDs). Neuroprotective treatments are virtually unavailable, partly because of the marked internal heterogeneity of the mechanisms underlying pathology. Targeted neuroprotection would require deep mechanistic knowledge across the entire aetiological spectrum of each NDD and the development of tailored treatments. Although ideal, this strategy appears challenging, as it would require a degree of characterization of both the disease and the patient that is currently unavailable. The alternate strategy is to search for commonalities across molecularly distinct NDD forms and exploit these for the development of drugs with broad-spectrum efficacy. In this view, mounting evidence points to ionic mechanisms (IMs) as targets with potential therapeutic efficacy across distinct NDD subtypes. The scope of this review is to present clinical and preclinical evidence supporting the link between disruption of IMs and neuronal death in specific NDDs and to critically revise past and ongoing attempts of harnessing IMs for the development of neuroprotective treatments.
Topics: Animals; Cell Death; Humans; Neurodegenerative Diseases; Neurons; Retinal Diseases
PubMed: 31279830
DOI: 10.1016/j.phrs.2019.104343 -
Diabetes Sep 2023Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can...
UNLABELLED
Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.
ARTICLE HIGHLIGHTS
Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.
Topics: Animals; Mice; Antibodies; Blood Glucose; Congenital Hyperinsulinism; Diazoxide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperinsulinism; Mutation; Sulfonylurea Receptors
PubMed: 37358194
DOI: 10.2337/db22-1039