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Endocrinology, Diabetes & Metabolism... May 2023Neonatal hypoglycemia is a serious condition that can have a major impact on the growing neonatal brain. The differential diagnosis of neonatal hypoglycemia is broad and...
SUMMARY
Neonatal hypoglycemia is a serious condition that can have a major impact on the growing neonatal brain. The differential diagnosis of neonatal hypoglycemia is broad and includes hyperinsulinism as well as panhypopituitarism. The FOXA2 gene has been involved in the development of the pancreas as well as the pituitary gland. Six cases have been reported thus far with FOXA2 mutations presenting with variable degrees of hypopituitarism, and only two patients had permanent hyperinsulinism; other cases have been reported with microdeletions in 20p11, the location that encompasses FOXA2, and those patients presented with a wider phenotype. A full-term female infant presented with severe hypoglycemia. Critical sampling showed an insulin of 1 mIU/mL, suppressed beta-hydroxybutyric acids, and suppressed free fatty acids. Blood glucose responded to glucagon administration. Growth hormone (GH) stimulation test later showed undetectable GH in all samples, and cortisol failed to respond appropriately to stimulation. Gonadotropins were undetectable at 1 month of life, and MRI showed ectopic posterior pituitary, interrupted stalk, hypoplastic anterior pituitary, cavum septum pellucidum, and diminutive appearance of optic nerves. Whole-exome sequencing revealed a likely pathogenic de novo c.604 T>C, p.Tyr202His FOXA2 mutation. We expand the known phenotype on FOXA2 mutations and report a likely pathogenic, novel mutation associated with hyperinsulinism and panhypopituitarism.
LEARNING POINTS
FOXA2 has been shown to play an important role in the neuroectodermal and endodermal development. FOXA2 mutation may lead to the rare combination of hyperinsulinism and panhypopituitarism. Patients reported so far all responded well to diazoxide. Dysmorphology may be subtle, and liver functions should be monitored.
PubMed: 37219505
DOI: 10.1530/EDM-22-0355 -
Evidence-based Complementary and... 2023is used in traditional medicine for the prevention and self-treatment of a variety of illnesses, including diabetes mellitus, obesity, and hypertension. The present...
is used in traditional medicine for the prevention and self-treatment of a variety of illnesses, including diabetes mellitus, obesity, and hypertension. The present study aims to investigate the , , and hypoglycemic and hypotensive effects of the lyophilized aqueous extract of . seeds (CV) on submitted to hypercaloric diet and physical inactivity (HCD/PI) for 12 weeks. This diet induces a type 2 diabetes/metabolic syndrome phenotype with hypertension. Furthermore, HCD/PI decreased aorta contraction due to noradrenaline, enhanced L-arginine, and depressed insulin-evoked relaxation, while the relaxing effects of the NO donor SNAP and of diazoxide were unchanged. experiments showed that the oral administration of the CV extract (50 mg/kg b.wt) for 3 consecutive weeks significantly attenuated the development of type 2 diabetes, obesity, dyslipidemia, and hypertension. These effects may involve the improvement of lipid metabolism, insulin sensitivity, systolic arterial pressure, and urine output. Additionally, and investigations revealed that CV treatment improved vascular contraction to noradrenaline, induced a slight aorta relaxation in response to carbachol, increased the vasorelaxation effect evoked by insulin, and depressed the L-arginine evoked relaxation. However, CV did not change the endothelium-independent vasorelaxation response evoked by SNAP or diazoxide. Hence, the present study provides useful information and supports the traditional use of CV in the prevention and self-treatment of numerous ailments. Overall, it can be concluded that . seed extracts might be useful in the management of type 2 diabetes and hypertension.
PubMed: 37215635
DOI: 10.1155/2023/3081102 -
Frontiers in Cellular Neuroscience 2023Recent pharmacological studies demonstrate a role for zinc (Zn) in shaping intracellular calcium (Ca) dynamics and vice versa in excitable cells including neurons and...
Recent pharmacological studies demonstrate a role for zinc (Zn) in shaping intracellular calcium (Ca) dynamics and vice versa in excitable cells including neurons and cardiomyocytes. Herein, we sought to examine the dynamic of intracellular release of Ca and Zn upon modifying excitability of primary rat cortical neurons using electric field stimulation (EFS) . We show that exposure to EFS with an intensity of 7.69 V/cm induces transient membrane hyperpolarization together with transient elevations in the cytosolic levels of Ca and Zn ions. The EFS-induced hyperpolarization was inhibited by prior treatment of cells with the K channel opener diazoxide. Chemical hyperpolarization had no apparent effect on either Ca or Zn. The source of EFS-induced rise in Ca and Zn seemed to be intracellular, and that the dynamic inferred of an interplay between Ca and Zn ions, whereby the removal of extracellular Ca augmented the release of intracellular Ca and Zn and caused a stronger and more sustained hyperpolarization. We demonstrate that Zn is released from intracellular vesicles located in the soma, with major co-localizations in the lysosomes and endoplasmic reticulum. These studies further support the use of EFS as a tool to interrogate the kinetics of intracellular ions in response to changing membrane potential .
PubMed: 37180947
DOI: 10.3389/fncel.2023.1118335 -
Frontiers in Pharmacology 2023ATP-sensitive-K+ channels (KATP) are involved in diseases, but their role in cancer is poorly described. Pituitary macroadenoma has been observed in Cantu' syndrome...
ATP-sensitive-K+ channels (KATP) are involved in diseases, but their role in cancer is poorly described. Pituitary macroadenoma has been observed in Cantu' syndrome (C.S.), which is associated with the gain-of-function mutations of the and genes. We tested the role of the /Sur1, /Sur2A/B, /Kir6.2, and /Kir6.1 genes experimentally in a minoxidil-induced renal tumor in male rats and in the female canine breast cancer, a spontaneous animal model of disease, and in the pharmacovigilance and omics databases. We performed biopsies from renal tissues of male rats ( = 5) following a sub-chronic high dosing topical administration of minoxidil (0.777-77.7 mg/kg/day) and from breast tissues of female dogs for diagnosis ( = 23) that were analyzed by immunohistochemistry. Pharmacovigilance and omics data were extracted from EudraVigilance and omics databases, respectively. An elevated immunohistochemical reactivity to Sur2A-mAb was detected in the cytosol of the Ki67+/G3 cells other than in the surface membrane in the minoxidil-induced renal tumor and the breast tumor samples. , and genes are upregulated in cancers but is downregulated. The Kir6.2-Sur2A/B-channel opener minoxidil showed 23 case reports of breast cancer and one case of ovarian cancer in line with omics data reporting, respectively, and the negative and positive prognostic roles of the gene in these cancers. Sulfonylureas and glinides blocking the pancreatic Kir6.2-Sur1 subunits showed a higher risk for pancreatic cancer in line with the positive prognostic role of the gene but low risks for common cancers. Glibenclamide, repaglinide, and glimepiride show a lower cancer risk within the KATP channel blockers. The Kir6.2-Sur1 opener diazoxide shows no cancer reactions. An elevated expression of the Sur2A subunit was found in proliferating cells in two animal models of cancer. Immunohistochemistry/omics/pharmacovigilance data reveal the role of the Kir6.1/2-Sur2A/B subunits as a drug target in breast/renal cancers and in C.S.
PubMed: 37180726
DOI: 10.3389/fphar.2023.1115543 -
The Journal of Biological Chemistry Jun 2023Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell K channels, results in dysregulated insulin secretion...
Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell K channels, results in dysregulated insulin secretion and persistent hypoglycemia. Children with K-HI are unresponsive to diazoxide, the only FDA-approved drug for HI, and utility of octreotide, the second-line therapy, is limited because of poor efficacy, desensitization, and somatostatin receptor type 2 (SST2)-mediated side effects. Selective targeting of SST5, an SST receptor associated with potent insulin secretion suppression, presents a new avenue for HI therapy. Here, we determined that CRN02481, a highly selective nonpeptide SST5 agonist, significantly decreased basal and amino acid-stimulated insulin secretion in both Sur1 (a model for K-HI) and wild-type mouse islets. Oral administration of CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle in Sur1 mice. During a glucose tolerance test, CRN02481 significantly increased glucose excursion in both WT and Sur1 mice compared to the control. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from healthy, control human islets similar to the effects observed with SS14 and peptide somatostatin analogs. Moreover, CRN02481 significantly decreased glucose- and amino acid-stimulated insulin secretion in islets from two infants with K-HI and one with Beckwith-Weideman Syndrome-HI. Taken together, these data demonstrate that a potent and selective SST5 agonist effectively prevents fasting hypoglycemia and suppresses insulin secretion not only in a K-HI mouse model but also in healthy human islets and islets from HI patients.
Topics: Animals; Child; Humans; Infant; Mice; Adenosine Triphosphate; Amino Acids; Glucose; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Mutation; Potassium Channels, Inwardly Rectifying; Receptors, Somatomedin
PubMed: 37178920
DOI: 10.1016/j.jbc.2023.104816 -
Frontiers in Cardiovascular Medicine 2023Diazoxide is a powerful cardioprotective agent that activates mitochondrial ATP-dependent K-channels and stimulates mitochondrial respiration. Diazoxide reduced infarct...
INTRODUCTION
Diazoxide is a powerful cardioprotective agent that activates mitochondrial ATP-dependent K-channels and stimulates mitochondrial respiration. Diazoxide reduced infarct size in isolated rodent heart preparations and upon pretreatment in juvenile pigs with coronary occlusion/reperfusion. We aimed to study the use of diazoxide in a more realistic adult pig model of reperfused acute myocardial infarction when diazoxide was administered just before reperfusion.
METHODS AND RESULTS
In a first approach, we pretreated anaesthetised adult Göttingen minipigs with 7 mg kg diazoxide ( = 5) or placebo ( = 5) intravenously over 10 min and subjected them to 60 min coronary occlusion and 180 min reperfusion; blood pressure was maintained by use of an aortic snare. The primary endpoint was infarct size (triphenyl tetrazolium chloride staining) as a fraction of area at risk; no-reflow area (thioflavin-S staining) was the secondary endpoint. In a second approach, diazoxide ( = 5) was given from 50 to 60 min coronary occlusion, and blood pressure was not maintained. There was a significant reduction in infarct size (22% ± 11% of area at risk with diazoxide pretreatment vs. 47% ± 11% with placebo) and area of no-reflow (14% ± 14% of infarct size with diazoxide pretreatment vs. 46% ± 20% with placebo). With diazoxide from 50 to 60 min coronary occlusion, however, there was marked hypotension, and infarct size (44% ± 7%) and area of no-reflow were not reduced (35% ± 25%).
CONCLUSIONS
Cardioprotection by diazoxide pretreatment was confirmed in adult pigs with reperfused acute myocardial infarction but is not feasible when diazoxide is administered in a more realistic scenario before reperfusion and causes hypotension.
PubMed: 37153458
DOI: 10.3389/fcvm.2023.1173462 -
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 -
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 -
World Journal of Clinical Cases Apr 2023Neonatal hyperinsulinism can result from perinatal stress, genetic disorders, or syndromes, which can lead to persistent or intractable hypoglycemia in newborns....
BACKGROUND
Neonatal hyperinsulinism can result from perinatal stress, genetic disorders, or syndromes, which can lead to persistent or intractable hypoglycemia in newborns. Mutations in the gene result in abnormal functioning of potassium channel proteins in pancreatic β-cells, leading to an overproduction of insulin and congenital hyperinsulinemia.
CASE SUMMARY
We report a case of a high-birth-weight infant with postnatal hypoglycemia and hyperinsulinemia, whose mother had pregestational diabetes mellitus with poor glycemic control and whose sister had a similar history at birth. Whole-exome sequencing revealed a new mutation in the gene in exon 8 (c.1257T>G), which also occurred in his sister and mother; thus, the patient was diagnosed with neonatal hyperinsulinism with an mutation. With oral diazoxide treatment, the child's blood glucose returned to normal, and the pediatrician gradually discontinued treatment because of the child's good growth and development.
CONCLUSION
We report a new mutation locus in the gene. This mutation locus warrants attention for genetic disorders and long-term prognoses of hypoglycemic children.
PubMed: 37122528
DOI: 10.12998/wjcc.v11.i10.2254 -
Life (Basel, Switzerland) Apr 2023The mitochondrial splice variant of the sulfonylurea receptor (SUR2A-55) is associated with protection from myocardial ischemia-reperfusion (IR) injury, increased...
The mitochondrial splice variant of the sulfonylurea receptor (SUR2A-55) is associated with protection from myocardial ischemia-reperfusion (IR) injury, increased mitochondrial ATP sensitive K channel activity (mitoK) and altered glucose metabolism. While mitoK channels composed of CCDC51 and ABCB8 exist, the mitochondrial K pore regulated by SUR2A-55 is unknown. We explored whether SUR2A-55 regulates ROMK to form an alternate mitoK. We assessed glucose uptake in mice overexpressing SUR2A-55 (TG) compared with WT mice during IR injury. We then examined the expression level of ROMK and the effect of ROMK modulation on mitochondrial membrane potential (Δψm) in WT and TG mice. TG had increased glucose uptake compared to WT mice during IR injury. The expression of ROMK was similar in WT compared to TG mice. ROMK inhibition hyperpolarized resting cardiomyocyte Δψm from TG mice but not from WT mice. In addition, TG and ROMK inhibitor treated WT isolated cardiomyocytes had enhanced mitochondrial uncoupling. ROMK inhibition blocked diazoxide induced Δψm depolarization and prevented preservation of Δψm from FCCP perfusion in WT and to a lesser degree TG mice. In conclusion, cardio-protection from SUR2A-55 is associated with ROMK regulation, enhanced mitochondrial uncoupling and increased glucose uptake.
PubMed: 37109544
DOI: 10.3390/life13041015