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Annals of Pediatric Endocrinology &... Dec 2023
PubMed: 35798301
DOI: 10.6065/apem.2244068.034 -
BioRxiv : the Preprint Server For... Mar 2024Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing...
Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.
PubMed: 38585774
DOI: 10.1101/2024.03.27.586949 -
Journal of Nuclear Medicine : Official... Feb 2024Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is...
Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is often difficult to treat. There is currently very limited information about the efficacy of peptide receptor radionuclide therapy (PRRT) for clinical control of hypoglycemia. The aim of this long-term retrospective study was to evaluate the therapeutic efficacy of PRRT for improving hypoglycemia, to evaluate the change of medication after PRRT, and to calculate progression-free survival (PFS) and overall survival (OS). Inclusion criteria were histologically proven somatostatin receptor-positive metastatic malignant insulinoma and at least 2 cycles of [Y]Y-DOTATOC or [Lu]Lu-DOTATOC therapy from early 2000 to early 2022. A semiquantitative scoring system was used to quantify the severity and frequency of hypoglycemic episodes under background antihypoglycemic therapy (somatostatin analog, diazoxide, everolimus, corticosteroids): score 0, no hypoglycemic episodes; score 1, hypoglycemic events requiring additional conservative treatment with optimization of nutrition; score 2, severe hypoglycemia necessitating hospitalization and combined medication or history of hypoglycemic coma. Hypoglycemic score before and after PRRT was analyzed. Time of benefit was defined as a time range of fewer hypoglycemic episodes in the observation period than at baseline. Information on antihypoglycemic medication before and after therapy, PFS, and OS was recorded. Twenty-six of 32 patients with a total of 106 [Y]Y-DOTATOC/[Lu]Lu-DOTATOC cycles were included. The average observation period was 21.5 mo (range, 2.3-107.4 mo). Before therapy, 81% ( = 21) of the patients had a hypoglycemia score of 2 and 19% ( = 5) had a score of 1. After PRRT, 81% of patients ( = 21) had a decreased score, and the remaining 5 patients showed a stable situation. There was temporary worsening of hypoglycemia just after injection of [Y]Y-DOTATOC/[Lu]Lu-DOTATOC in 19% of patients. The average time of benefit in the observation period was 17.2 mo (range, 0-70.2 mo). Antihypoglycemic medication reduction was achieved in 58% ( = 15) of patients. The median OS and PFS after the start of PRRT were 19.7 mo (95% CI, 6.5-32.9 mo) and 11.7 mo (95% CI, 4.9-18.5 mo), respectively. To our knowledge, our study included the largest cohort of patients with malignant insulinoma to be evaluated. Long-lasting symptom control and reduction of antihypoglycemic medications were shown in most patients after late-line PRRT.
Topics: Humans; Retrospective Studies; Insulinoma; Treatment Outcome; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Radioisotopes; Hypoglycemia; Receptors, Peptide; Hypoglycemic Agents; Organometallic Compounds
PubMed: 38164592
DOI: 10.2967/jnumed.123.265894 -
International Journal of Clinical... Jun 2024Malignant insulinoma is a rare neuroendocrine tumor responsible for excessive insulin secretion and life-threatening hypoglycemia episodes. Computed tomography (CT) of...
INTRODUCTION
Malignant insulinoma is a rare neuroendocrine tumor responsible for excessive insulin secretion and life-threatening hypoglycemia episodes. Computed tomography (CT) of the abdomen can identify a pancreatic tumor corresponding to insulinoma. Loco-regional metastases define the metastatic cases. The first-line therapeutic approach is surgery, while other medical treatments like diazoxide and everolimus play also a role. These treatments have shown efficacy in regulating blood glucose and, to some extent, controlling tumor progression.
CASE PRESENTATION
We present the case of a 48-year-old female who was admitted for severe hypoglycemia episodes. She presented neuroglycopenic symptoms without any other clinical features. High levels of C-peptide and insulin during severe hypoglycemia confirmed the presence of endogenous hyperinsulinism. The CT scan of the abdomen confirmed the existence of an insulinoma along with several hepatic metastases. Surgery was proposed as a first-line approach. However, due to the persistent occurrence of severe hypoglycemia episodes, other treatment options were necessary such as diazoxide and everolimus. Diazoxide caused a significant improvement in the patient's blood glucose levels. Nonetheless, glycemic control was unsustainable, obligating the switch to everolimus, which showed better control of blood glucose levels with challenging management due to the appearance of grade 3 stomatitis as a side effect. The patient died 1 year after the diagnosis due to tumor progression.
CONCLUSION
Balancing the benefits of enhanced glycemic control with the difficulties posed by side effect management of everolimus underscores the need to carefully consider both efficacy and potential adverse events.
Topics: Humans; Female; Everolimus; Insulinoma; Middle Aged; Pancreatic Neoplasms; Hypoglycemia; Antineoplastic Agents; Liver Neoplasms; Blood Glucose; Fatal Outcome; Diazoxide; Treatment Outcome
PubMed: 38431828
DOI: 10.5414/CP204503 -
Pediatrics and Neonatology Sep 2023
Topics: Humans; Infant; Diazoxide; Trichlormethiazide; Trisomy 13 Syndrome; Body Water; Treatment Outcome
PubMed: 37225554
DOI: 10.1016/j.pedneo.2023.04.003 -
Diabetes Jun 2024Glucagon is critical for the maintenance of blood glucose, however nutrient regulation of pancreatic α-cells remains poorly understood. Here, we identified a role for...
Glucagon is critical for the maintenance of blood glucose, however nutrient regulation of pancreatic α-cells remains poorly understood. Here, we identified a role for leucine, a well-known β-cell fuel, in the α-cell intrinsic regulation of glucagon release. In islet perifusion assays, physiological concentrations of leucine strongly inhibited alanine and arginine-stimulated glucagon secretion from human and mouse islets under hypoglycemic conditions. Mechanistically, leucine dose-dependently reduced α-cell cAMP, independently of Ca2+, ATP/ADP, or fatty acid oxidation. Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonists or diazoxide, compounds that limit paracrine signaling from β/δ-cells. Studies in dispersed mouse islets confirmed an α-cell intrinsic effect. The inhibitory effect of leucine on cAMP was mimicked by glucose, α-ketoisocaproate, succinate, and the glutamate dehydrogenase activator BCH, and blocked by cyanide, indicating a mechanism dependent on mitochondrial metabolism. Glucose dose-dependently reduced the impact of leucine on α-cell cAMP, indicating an overlap in function, however leucine was still effective at suppressing glucagon secretion in the presence of elevated glucose, amino acids, and the incretin GIP. Taken together, these findings show that leucine plays an intrinsic role in limiting α-cell secretory tone across the physiological range of glucose levels, complementing the inhibitory paracrine actions of β/δ-cells.
PubMed: 38870025
DOI: 10.2337/db23-1013 -
Genes Feb 2024Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main...
Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the gene. The range of clinical manifestations of the ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present two previously unreported paediatric patients with neurodevelopmental challenges, who were diagnosed with missense variants in the gene. It should be noted that one of the individuals manifested with hyperinsulinaemic hypoglycaemia (HH), a symptom that was not described before in published works. The reason for the occurrence of HH in our proband is not clear, so we try to explain the origin of this symptom in the context of the syndrome. Thus, this paper contributes to knowledge on the range of possible manifestations of the disease and provides further evidence supporting its association with neurodevelopmental challenges.
Topics: Child; Humans; Abnormalities, Multiple; Cell Cycle Proteins; Co-Repressor Proteins; DNA-Binding Proteins; Intellectual Disability; Mutation, Missense; Phenotype; Syndrome
PubMed: 38397245
DOI: 10.3390/genes15020256 -
Oxford Medical Case Reports Jun 2024Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hypoglycaemia. We discuss a 91-year-old Caucasian lady who presented with syncope and episodic...
Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hypoglycaemia. We discuss a 91-year-old Caucasian lady who presented with syncope and episodic adrenergic and neuroglycopenic symptoms. Despite significantly elevated insulin, C-peptide, and proinsulin levels with the presence of anti-insulin antibodies, a pancreatic mass was not identified. Serum immunoelectrophoresis demonstrated monoclonal gammopathy of undetermined significance (MGUS). Treatment involved high-dose steroids, diazoxide, corn starch and acarbose, however the patient passed away four months later due to worsening co-morbidities. The management of IAS in the setting of MGUS is challenging.
PubMed: 38860020
DOI: 10.1093/omcr/omae054 -
Internal Medicine (Tokyo, Japan) May 2024We herein report a case in which diazoxide was effective in treating reactive hypoglycemia caused by late dumping syndrome in a patient with end-stage renal disease...
We herein report a case in which diazoxide was effective in treating reactive hypoglycemia caused by late dumping syndrome in a patient with end-stage renal disease (ESRD). A 50-year-old man with ESRD and a history of gastrectomy underwent hemodialysis. Although he was administered voglibose to treat recurrent reactive hypoglycemia caused by late dumping syndrome, he had difficulty continuing treatment because of gastrointestinal side effects. When he began diazoxide treatment, the reactive hypoglycemia improved. The dose was gradually increased with no apparent side effects, and the hypoglycemic attacks disappeared one year after the start of treatment.
Topics: Humans; Diazoxide; Male; Middle Aged; Hypoglycemia; Kidney Failure, Chronic; Gastrectomy; Dumping Syndrome; Treatment Outcome; Renal Dialysis
PubMed: 37813619
DOI: 10.2169/internalmedicine.1704-23 -
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