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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 -
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 -
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 -
Intractable & Rare Diseases Research Feb 2023Prader-Willi syndrome (PWS) is a rare genetic disorder due to lack of genes expression inherited from the paternal chromosome 15q11-q13 region usually from paternal... (Review)
Review
Prader-Willi syndrome (PWS) is a rare genetic disorder due to lack of genes expression inherited from the paternal chromosome 15q11-q13 region usually from paternal deletions, maternal uniparental disomy 15 or imprinting defect. There are two different nutritional stages reported in an individual with PWS; first stage during infancy marked by feeding and growth difficulties and second stage where hyperphagia starts and leads to development of obesity. However, the exact mechanism of hyperphagia development, from having difficulties in feeding during early years to insatiable appetite after they grow is still unknown and is the focused in this review. The keywords used for literature search such as "Prader-Willi syndrome", "hyperphagia", "obesity", and "treatment" were used to create the search strings by using synonyms in order to retrieve the relevant records from PubMed, Scopus and Science Direct. The possible mechanism of hyperphagia can be classed into hormonal abnormalities such as increase in ghrelin and leptin from infancy to adulthood. Low level of hormones was observed in the thyroid, insulin and peptide YY at certain ages. Neuronal abnormalities contributed by Orexin A and brain structure alteration was documented at 4-30 years old. Treatment in the form of drugs such as livoletide, topiramate, and diazoxide could potentially alleviate these abnormalities and make hyperphagia less prominent in PWS. The approaches are important to regulate the hormonal changes and neuronal involvement as potentially controlling hyperphagia and obesity.
PubMed: 36873672
DOI: 10.5582/irdr.2022.01127 -
Biological & Pharmaceutical Bulletin 2023Previous our study found that improvement of skin blood flow associated with neuropathic pain using vasodilators is useful for alleviation of neuropathic pain. In this...
Previous our study found that improvement of skin blood flow associated with neuropathic pain using vasodilators is useful for alleviation of neuropathic pain. In this study, we aimed to elucidate the mechanism underlying enhanced vasorelaxation induced by vasodilators, which increase cAMP and cyclic guanosine monophosphate (cGMP), in chronic constriction injury model rat. We assessed vasorelaxation effect of vasodilators by measurement of isometric contraction in isolated plantar artery from chronic constriction injury of sciatic nerve model rats. Nifedipine, a voltage-dependent Ca channel inhibitor, NS1619, Ca-activated K (BK) channel opener, and diazoxide, an ATP-sensitive potassium channel opener, -induced vasorelaxation in ipsilateral plantar artery was enhanced compared to the these in contralateral plantar artery. Sodium nitroprusside (SNP), a nitric oxide (NO) donor, and substance P, a NK receptor agonist, caused vasorelaxation in both ipsilateral and contralateral artery. The vasorelaxation induced by SNP and substance P in ipsilateral artery is enhanced compared to the these in contralateral artery. Isoprenaline, a β adrenoceptor agonist, and salbutamol, a β adrenoceptor agonist, caused strong vasorelaxation in ipsilateral artery but not in contralateral artery. Iberiotoxin, a BK channel inhibitor, prominently suppressed the enhanced vasorelaxation induced by SNP, substance P, isoprenaline and salbutamol. In summary, the enhanced contraction of arterial smooth muscle cell in skin artery is sensitive to hyperpolarization in chronic constriction injury model rat. Furthermore, β adrenoceptor agonist would be a good drug to improve the decreased skin blood flow because it has selective vasorelaxation to ipsilateral plantar artery.
Topics: Animals; Rats; Substance P; Isoproterenol; Constriction; Arteries; Vasodilator Agents; Nitroprusside; Receptors, Neurokinin-1; Albuterol; Receptors, Adrenergic
PubMed: 36858567
DOI: 10.1248/bpb.b22-00603 -
International Journal of Endocrinology 2023Insulin autoimmune syndrome (IAS) is a rare endocrine disorder characterized by recurrent episodes of severe hypoglycemia, markedly elevated serum insulin, and positive... (Review)
Review
Insulin autoimmune syndrome (IAS) is a rare endocrine disorder characterized by recurrent episodes of severe hypoglycemia, markedly elevated serum insulin, and positive insulin autoantibodies. In recent years, various countries have reported it one after another. It can be seen that we must pay attention to this disease. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. High levels of insulin autoantibodies are found in patients, and C-peptide is not parallel to insulin, which could be diagnostic. IAS is a self-limiting disease with a good prognosis. Its treatment mainly includes symptomatic supportive treatment, such as adjusting the diet and using acarbose and other drugs to delay the absorption of glucose to prevent hypoglycemia. For patients with severe symptoms, available treatments may include drugs that reduce pancreatic insulin secretion (such as somatostatin and diazoxide), immunosuppressants (glucocorticoids, zaprin, and rituximab), and even plasma exchange to remove autoantibodies from the body. This review provides a comprehensive analysis of the epidemiology, pathogenesis, clinical manifestations, diagnosis and identification, and monitoring and treatment management of IAS.
PubMed: 36844104
DOI: 10.1155/2023/1225676