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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 -
BMJ Open Diabetes Research & Care Apr 2023Hypoglycemia is listed as an adverse effect in the package inserts of not only hypoglycemic agents but also many other drugs. We aimed to clarify real-world factors...
INTRODUCTION
Hypoglycemia is listed as an adverse effect in the package inserts of not only hypoglycemic agents but also many other drugs. We aimed to clarify real-world factors related to an increased risk of hypoglycemia-related hospitalization (HRH) in Japanese patients with type 2 diabetes (T2D) on non-hypoglycemic agents that have been associated with hypoglycemia.
RESEARCH DESIGN AND METHODS
This cross-sectional study was performed using data from the Medical Data Vision administrative claims database. We identified patients with T2D who were enrolled in the database between April 2014 and October 2019. Logistic regression analyses were performed to identify clinical factors associated with HRH due to non-hypoglycemic agents.
RESULTS
Among 703 745 patients with T2D, 10 376 patients (1.47%) experienced HRH. The use of 332 non-hypoglycemic agents was associated with hypoglycemia. Multivariate analysis was performed to calculate OR for HRH. Seventy-five drugs had an OR greater than 1, and the values were significant. The OR was the highest for diazoxide (OR 15.5, 95% CI 4.87 to 49.3). The OR was higher than 2.0 for methylphenidate (OR 5.15, 95% CI 1.53 to 17.3), disulfiram (OR 4.21, 95% CI 2.05 to 8.62) and hydrocortisone (OR 2.89, 95% CI 1.11 to 7.51).
CONCLUSION
This large retrospective analysis revealed that the risk of HRH from some non-hypoglycemic agents in patients with T2D may be increased. The results of this study are expected to support treatment planning by physicians and healthcare professionals involved in diabetes care.
Topics: Humans; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Retrospective Studies; Cross-Sectional Studies; Hypoglycemia; Hospitalization
PubMed: 37085279
DOI: 10.1136/bmjdrc-2022-003177 -
Journal of Clinical Research in... Apr 2023Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and...
Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and Rabson-Mendenhall syndrome, conditions which are associated with significant morbidity early in life. On the other hand, heterozygous INSR gene mutations result in milder phenotype known as type A insulin resistance syndrome. While presentation in adults with this condition is well reported, phenotypes in infant are less well-characterized. We herein report an infant presenting with hyperinsulinemic hypoglycaemia who did not respond to diazoxide therapy. She was subsequently found to carry heterozygous INSR gene mutation. Our patient was a female infant born at 29 weeks of gestation who developed recurrent hypoglycaemia in early infancy. Workup showed hyperinsulinism and she was started on first-line therapy with diazoxide and high-calorie feeds. However, continuous blood glucose monitoring showed post-prandial hyperglycaemia followed by rapid fall to hypogylcaemia. Whole exome sequencing was performed to investigate for diazoxide-unresponsive hyperinsulinism, which revealed a likely pathogenic mutation in the INSR gene c.1246C>T p. (R416X). This nonsense mutation was inherited from the father. With the molecular diagnosis, diazoxide was stopped and she followed a diet with low glycaemic-index food. Subsequent monitoring showed stable glucose profile. Our case highlights the importance to consider type A insulin resistance syndrome when no mutation could be identified in the ABCC8/KCNJ11 genes in diazoxide-unresponsive hyperinsulinism. With autosomal dominant inheritance, cascade screening should be performed in family members to identify those harbouring the mutation as they are at risk of early onset diabetes.
PubMed: 37074094
DOI: 10.4274/jcrpe.galenos.2023.2022-12-10 -
Frontiers in Endocrinology 2023Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent... (Review)
Review
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent attacks of hypoglycemia due to dysregulated insulin secretion. Timely diagnosis and effective treatment are crucial to prevent severe hypoglycemia that may lead to life-long neurological complications. In pancreatic β-cells, adenosine triphosphate (ATP)-sensitive K (K) channels are a central regulator of insulin secretion vital for glucose homeostasis. Genetic defects that lead to loss of expression or function of K channels are the most common cause of HI (K-HI). Much progress has been made in our understanding of the molecular genetics and pathophysiology of K-HI in the past decades; however, treatment remains challenging, in particular for patients with diffuse disease who do not respond to the K channel activator diazoxide. In this review, we discuss current approaches and limitations on the diagnosis and treatment of K-HI, and offer perspectives on alternative therapeutic strategies.
Topics: Humans; Child; Sulfonylurea Receptors; Adenosine Triphosphate; Congenital Hyperinsulinism; Mutation; Insulin Secretion
PubMed: 37056678
DOI: 10.3389/fendo.2023.1161117 -
Pediatric Dermatology 2023Hypertrichosis is defined as excessive hair growth anywhere on the body in either males or females. It may be caused by genetic conditions, endocrinological disorders,...
Hypertrichosis is defined as excessive hair growth anywhere on the body in either males or females. It may be caused by genetic conditions, endocrinological disorders, exposure to specific medications (including phenytoin, minoxidil and diazoxide) and other less frequent causes. We report the case of a 1-year-old boy with a family history of thyroid disease and alopecia areata who presented with generalized hypertrichosis due to secondary exposure to topical minoxidil. We discuss an uncommon cause of hypertrichosis and the importance of considering a wide differential diagnosis.
Topics: Male; Female; Child; Humans; Infant; Minoxidil; Hypertrichosis; Alopecia; Alopecia Areata; Diazoxide; Diagnosis, Differential; Administration, Topical
PubMed: 37042338
DOI: 10.1111/pde.15329 -
Ecotoxicology and Environmental Safety May 2023Heavy metals are ubiquitous environmental pollutants that are extremely dangerous for public health, but the molecular mechanisms of their cytotoxic action are still not...
Modulators of mitochondrial ATP-sensitive potassium channel affect cytotoxicity of heavy metals: Action on isolated rat liver mitochondria and AS-30D ascites hepatoma cells.
Heavy metals are ubiquitous environmental pollutants that are extremely dangerous for public health, but the molecular mechanisms of their cytotoxic action are still not fully understood. In the present work, the possible contribution of the mitochondrial ATP-sensitive potassium channel (mK(ATP)), which is usually considered protective for the cell, to hepatotoxicity caused by heavy metals was investigated using polarography and swelling techniques as well as flow cytometry. Using isolated liver mitochondria from adult male Wistar rats and various potassium media containing or not containing penetrating anions (KNO, KSCN, KAcet, KCl), we studied the effect of mK(ATP) modulators, namely its blockers (5-hydroxydecanoate, glibenclamide, ATP, ADP) and activators (diazoxide, malonate), on respiration and/or membrane permeability in the presence of hepatotoxins such as Cd, Hg, and Cu. It has been shown for the first time that, contrary to Hg and depending on media used, the mK(ATP) modulators affect Cd- and/or Cu-induced alterations in mitochondrial swelling and respiration rates, although differently, nevertheless, in the ways compatible with mK(ATP) participation in both these cases. On rat AS-30D ascites hepatoma cells, it was found that, unlike Cd, an increase in the production of reactive oxygen species was observed with the simultaneous use of Cu and diazoxide; in addition, there was no protective effect of diazoxide against cell death, which also occurred in the presence of Cu. In conclusion, the relationships (functional, structural and/or regulatory) between mK(ATP), components of the mitochondrial electron transport chain (CI, CII-CIII and/or ATP synthase, CV) and mitochondrial permeability transition pores were discussed, as well as the role of these molecular structures in the mechanisms of the cytotoxic action of heavy metals.
Topics: Rats; Male; Animals; Mitochondria, Liver; KATP Channels; Diazoxide; Cadmium; Ascites; Carcinoma, Hepatocellular; Rats, Wistar; Metals, Heavy; Mercury; Liver Neoplasms; Adenosine Triphosphate
PubMed: 36989557
DOI: 10.1016/j.ecoenv.2023.114829 -
Membranes Mar 2023In the inner mitochondrial membrane, several potassium channels that play a role in cell life and death have been identified. One of these channels is the ATP-regulated...
In the inner mitochondrial membrane, several potassium channels that play a role in cell life and death have been identified. One of these channels is the ATP-regulated potassium channel (mitoK). The ROMK2 potassium channel is a potential molecular component of the mitoK channel. The current study aimed to investigate the pharmacological modulation of the activity of the ROMK2 potassium channel expressed in bacteria. ROMK2 was solubilized in polymer nanodiscs and incorporated in planar lipid bilayers. The impact of known mitoK channel modulators on the activity of the ROMK2 was characterized. We found that the ROMK2 channel was activated by the mitoK channel opener diazoxide and blocked by mitoK inhibitors such as ATP/Mg, 5-hydroxydecanoic acid, and antidiabetic sulfonylurea glibenclamide. These results indicate that the ROMK2 potassium protein may be a pore-forming subunit of mitoK and that the impact of channel modulators is not related to the presence of accessory proteins.
PubMed: 36984747
DOI: 10.3390/membranes13030360 -
Transfusion May 2023Hemorrhagic shock remains a leading cause of death in both military and civilian trauma casualties. While standard of care involves blood product administration,... (Review)
Review
BACKGROUND
Hemorrhagic shock remains a leading cause of death in both military and civilian trauma casualties. While standard of care involves blood product administration, maintaining normothermia, and restoring hemostatic function, alternative strategies to treat severe hemorrhage at or near the point of injury are needed. We reviewed adjunct solutions for managing severe hemorrhage in the prehospital environment.
METHODS
We performed a literature review by searching PubMed with a combination of several keywords. Additional pertinent studies were identified by crossreferencing primary articles. Clinical experience of each author was also considered.
RESULTS
We identified several promising antishock therapies that can be utilized in the prehospital setting: ethinyl estradiol sulfate (EES), polyethylene glycol 20,000 (PEG20K), C1 esterase inhibitors (e.g. Berinert, Cinryze), cyclosporin A, niacin, bortezomib, rosiglitazone, icatibant, diazoxide, and valproic acid (VPA).
CONCLUSION
Several studies show promising adjunct treatment options in the management of severe prehospital hemorrhage. While some are rarely used, many others are readily available and commonly utilized for other indications. This suggests the potential for future use in resourcelimited settings. Human studies and case reports supporting their use are currently lacking.
Topics: Humans; Shock, Hemorrhagic; Hemorrhage; Hemostasis; Warfare; Emergency Medical Services; Wounds and Injuries; Resuscitation
PubMed: 36965171
DOI: 10.1111/trf.17324 -
Clinical Case Reports Mar 2023Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder without a good genotype-phenotype correlation, characterized by tumor predisposition in...
Multiple endocrine neoplasia type 1 familial case in a patient with insulinoma and primary hyperparathyroidism: First report in literature and in the Costa Rican population of the c.1224_1225insGTCC pathogenic variant.
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder without a good genotype-phenotype correlation, characterized by tumor predisposition in the parathyroid gland, anterior pituitary, and pancreatic islet cells. Here, we describe a 37-year-old male with previous history of nephrolithiasis, with a 1-year history of recurrent hypoglycemic episodes. Physical examination revealed the presence of two lipomas. Family history revealed primary hyperparathyroidism (PHPT), hyperprolactinemia, and multiple non-functioning pancreatic neuroendocrine tumors. Initial laboratories revealed hypoglycemia and primary hyperparathyroidism. A fasting test was positive after 3 hours of initiation. An abdominal CT Scan demonstrated a 28 × 27 mm mass in the pancreatic tail and bilateral nephrolithiasis. A distal pancreatectomy was done. After surgery, the patient persisted with hypoglycemic episodes that were managed with diazoxide and frequent feedings. A parathyroid Tc-99 m MIBI scan with SPECT/CT imaging demonstrated two hot uptake lesions compatible with abnormally functioning parathyroid tissue. Surgical treatment was offered; however, the patient decided to postpone the procedure. Direct sequence analysis of gene revealed heterozygosity for a pathogenic insertion c.1224_1225insGTCC (p.Cys409Valfs*41). DNA sequence analysis was done to six of his first-degree relatives. A sister with clinical diagnosis of MEN1 and a pre-symptomatic brother were positive for the same variant. To our knowledge, this is the first report of a genetically confirmed case of MEN1 in our country and is the first report in literature of the c.1224_1225insGTCC variant related to a clinically affected family.
PubMed: 36911651
DOI: 10.1002/ccr3.7041