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Journal of Pediatric Endocrinology &... Feb 2024
Topics: Humans; Follow-Up Studies; Congenital Hyperinsulinism; Sulfonylurea Receptors; Heterozygote; Mutation; Diazoxide
PubMed: 38154043
DOI: 10.1515/jpem-2023-0445 -
Biomedicines Dec 2023Modulation of mitochondrial K channels represents a pharmacological strategy to promote cardioprotective effects. Isothiocyanates emerge as molecules capable of...
Modulation of mitochondrial K channels represents a pharmacological strategy to promote cardioprotective effects. Isothiocyanates emerge as molecules capable of releasing hydrogen sulfide (HS), an endogenous pleiotropic gasotransmitter responsible for anti-ischemic cardioprotective effects also through the involvement of mitoK channels. Erucin (ERU) is a natural isothiocyanate resulting from the enzymatic hydrolysis of glucosinolates (GSLs) present in Mill. seeds, an edible plant of the family. In this experimental work, the specific involvement of mitoK channels in the cardioprotective effect induced by ERU was evaluated in detail. An in vivo preclinical model of acute myocardial infarction was reproduced in rats to evaluate the cardioprotective effect of ERU. Diazoxide was used as a reference compound for the modulation of potassium fluxes and 5-hydroxydecanoic acid (5HD) as a selective blocker of K channels. Specific investigations on isolated cardiac mitochondria were carried out to evaluate the involvement of mitoK channels. The results obtained showed ERU cardioprotective effects against ischemia/reperfusion (I/R) damage through the involvement of mitoK channels and the consequent depolarizing effect, which in turn reduced calcium entry and preserved mitochondrial integrity.
PubMed: 38137502
DOI: 10.3390/biomedicines11123281 -
The Journal of Clinical Endocrinology... Jun 2024
Topics: Humans; Diazoxide; Congenital Hyperinsulinism; Infant, Newborn; Drug Resistance
PubMed: 38104245
DOI: 10.1210/clinem/dgad741 -
Neurobiology of Pain (Cambridge, Mass.) 2023Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective...
Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (K) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a K channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of K channels with the K channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of K channels to provide ketogenic diet-related analgesia. This study also identifies K channels as a new target to mimic the antinociceptive effects of a ketogenic diet.
PubMed: 38099277
DOI: 10.1016/j.ynpai.2023.100138 -
Cureus Nov 2023Insulinomas are a rare cause of recurrent hypoglycemia in non-diabetic patients. Diagnosis requires hypoglycemia (plasma glucose <50 mg/dL), neuroglycopenic symptoms,...
Insulinomas are a rare cause of recurrent hypoglycemia in non-diabetic patients. Diagnosis requires hypoglycemia (plasma glucose <50 mg/dL), neuroglycopenic symptoms, and prompt relief of symptoms following the administration of glucose, known as Whipple's triad. The gold standard diagnostic tests are measuring insulin, C-peptide, and glucose during a 72-hour fast. In the preoperative period and in patients with unresectable or metastatic tumors, medical management with diazoxide and octreotide can be considered for recurrent hypoglycemia. We present a case of insulinoma in a 37-year-old woman who initially presented after a seizure-related motor vehicle accident. Upon admission, her initial glucose level was 32 mg/dL, indicating a likely hypoglycemic seizure. During her hospitalization, she had recurrent episodes of fasting and postprandial hypoglycemia, ranging from 32-70 mg/dL. She exhibited the characteristics of Whipple's triad when values dropped below 50 mg/dL. These episodes necessitated continuous infusions of 10% dextrose. Tests for insulin autoantibodies, sulfonylurea screens, and thyroid function yielded unremarkable results. A 72-hour fasting test was initiated to investigate potential endogenous causes of excessive insulin production. Laboratory results from a venous glucose level of 46 mg/dL indicated a notable rise in C peptide and insulin levels, alongside beta hydroxybutyrate suppression, all of which fulfilled the diagnostic criteria for insulinoma. An abdominal magnetic resonance imaging (MRI) unveiled a 1.3 cm mass in the pancreatic tail. This case emphasizes the importance of employing a focused approach when evaluating non-diabetic individuals displaying hypoglycemia with positive Whipple's triad. This targeted method not only enables early detection of this rare condition but also assists in eliminating other common causes of recurrent hypoglycemia in non-diabetic individuals. Moreover, in addition to this diagnosis being rare, it is important to note that patients with insulinomas typically do not exhibit a glucose level low enough to induce seizures during their initial presentation.
PubMed: 38074057
DOI: 10.7759/cureus.48514 -
Journal of Diabetes Investigation Mar 2024This report describes a patient who developed recurrent hypoglycemia episodes after 23 days of antiplatelet therapy with clopidogrel for left subclavian artery stent... (Review)
Review
This report describes a patient who developed recurrent hypoglycemia episodes after 23 days of antiplatelet therapy with clopidogrel for left subclavian artery stent implantation. The patient suffered from palpitation, profuse sweating and weakness on the 23rd day of clopidogrel treatment. The minimum plasma glucose was 2.2 mmol/L, and the hypoglycemia was associated with significantly elevated levels of insulin. A diagnosis of insulin autoimmune syndrome (IAS) was made with the presence of insulin autoantibody and a comprehensive differential diagnosis of other conditions related with hypoglycemia. Clopidogrel was stopped, and the patient was treated with acarbose and had frequent low-carbohydrate meals; his hypoglycemia did not occur within 10 days. To date, seven cases of IAS induced by clopidogrel have been reported. Most reported cases were male aged in their 70s, and the hypoglycemic attack appeared 1-4 weeks after exposure to clopidogrel, characterized by severe hyperinsulinemia hypoglycemia with high titers of insulin autoantibodies. Most IAS cases can resolve spontaneously when they stop using the trigger medicine. Severe cases had been treated with drugs that reduce pancreatic insulin secretion (such as somatostatin and diazoxide), immunosuppressants (glucocorticoids, azathioprine and rituximab) and even immunoadsorption to remove the insulin autoantibody from the body. Considering the hypoglycemic attack might increase the risk of cardiovascular events among patients taking clopidogrel, we recommend that doctors should be aware of IAS as a rare severe adverse effect of clopidogrel, and be vigilant for the symptoms related with hypoglycemia in clopidogrel users.
Topics: Humans; Male; Female; Clopidogrel; Hypoglycemia; Hypoglycemic Agents; Insulin; Hyperinsulinism; Autoimmune Diseases; Autoantibodies
PubMed: 38063248
DOI: 10.1111/jdi.14110 -
Clinical Endocrinology Feb 2024Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self-resolving, treatment can be...
OBJECTIVE
Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self-resolving, treatment can be required. Consensus guidelines recommend the lower end of the diazoxide 5-15 mg/kg/day range in THI to reduce the risk of adverse events. We sought to determine if doses <5 mg/kg/day of diazoxide can be effective in THI.
DESIGN, PATIENTS, MEASURMENTS
Infants with THI (duration <6 months) were treated with low-dose diazoxide from October 2015 to February 2021. Dosing was based on weight at diazoxide start: 2 mg/kg/day in infants 1000-2000 g (cohort 1), 3 mg/kg/day in those 2000-3500 g (cohort 2) and 5 mg/kg/day in those >3500 g.
RESULTS
A total of 73 infants with THI (77% male, 33% preterm, 52% small-for-gestational age) were commenced on diazoxide at a median age of 11 days (range 3-43) for a median duration of 4 months (0.3-6.8), with no difference between cohorts. The mean effective diazoxide dose was 3 mg/kg/day (range 1.5-10); 35% (26/73) required an increase from their starting dose, including 60% (9/15) of cohort 1. There was no association between perinatal stress risk factors or treatment-related characteristics and dose increase. Adverse events occurred in 13 patients (18%); oedema (12%) and hyponatraemia (5%) were the most common. Two infants developed suspected necrotising enterocolitis (NEC); none had pulmonary hypertension.
CONCLUSION
Diazoxide doses <5 mg/kg/day are effective in THI. While the nature of the association between diazoxide and NEC was unclear, other adverse events were mild. We suggest considering starting doses as low as 2-3 mg/kg/day in THI to balance the side effect risk while maintaining euglycaemia.
Topics: Infant; Female; Infant, Newborn; Humans; Male; Diazoxide; Hypoglycemia; Infant, Small for Gestational Age; Risk Factors; Hyperinsulinism; Congenital Hyperinsulinism
PubMed: 38059644
DOI: 10.1111/cen.14987 -
Clinical Endocrinology Feb 2024
Topics: Humans; Diazoxide; Hyperinsulinism; Hypertension, Pulmonary
PubMed: 38059616
DOI: 10.1111/cen.14996 -
Clinical Endocrinology Feb 2024
Topics: Humans; Diazoxide; Hyperinsulinism; Hypoglycemia; Congenital Hyperinsulinism
PubMed: 38059613
DOI: 10.1111/cen.14991 -
Frontiers in Endocrinology 2023Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study...
OBJECTIVE
Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations.
METHODS
We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (K) channel variants were assessed using patch clamp recording and Western blot.
RESULTS
Nine of 13 (69%) patients with ten different pathogenic variants (7 in , 2 in and 1 in ) were identified by the combined sequencing. The variant p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F K channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C K channels were defective in trafficking. One patient had a dominant mutation in the gene (p.I211F), and WES revealed mosaicism of this variant from another patient.
CONCLUSION
Pathogenic variants in K channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the gene is highly suggestive of a founder effect. The I211F mutation in the gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) K channels are also associated with the diazoxide-unresponsive phenotype.
Topics: Humans; Child; Diazoxide; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors; Congenital Hyperinsulinism; Genetic Association Studies; Adenosine Triphosphate
PubMed: 38033998
DOI: 10.3389/fendo.2023.1283907