Post-bariatric hypoglycaemia (PBH) has emerged as a significant, underrecognized complication following Roux-en-Y gastric bypass (RYGB) and other weight loss surgeries. The purpose of the study was to characterize the timing, clinical presentation, diagnosis, and management outcomes of PBH in a diverse case series from a multi-specialty center in southern India owing to predominantly high-carbohydrate diet and distinct bariatric phenotype. This was a retrospective observational case series analysis from a multidisciplinary bariatric clinic at a tertiary teaching hospital and in southern India from May 2017 to April 2024. Time to onset of PBH post-surgery, nadir plasma glucose levels, management approach (diet, medication, surgery), complication rates, and patient follow-up duration were evaluated. Nine adults (mean age 41.5 years; both sexes) diagnosed and managed for PBH following RYGB. PBH onset ranged from 1 month to 5 years post-RYGB (mean 17 months). Nadir glucose levels ranged from 16 to 67 mg/dL. Hyperinsulinemia and nesidioblastosis were diagnosed in select cases. Patients received individualized medical nutrition therapy, medication (voglibose, octreotide, diazoxide), and in severe/refractory cases, surgical procedures such as reversal of RYGB or subtotal pancreatectomy was required in 2 patients. Frequent and severe PBH episodes were more common in patients with higher initial BMI and persistent carbohydrate-heavy diets. PBH after bariatric surgery presents with variable onset, severity, and duration, emphasizing the need for long-term multidisciplinary follow-up and individualized management, especially for high-risk populations. Early recognition and tailored intervention can improve clinical outcomes and patient quality of life.

Hyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare metabolic disorder caused by mutations in GLUD1, which encodes the mitochondrial enzyme glutamate dehydrogenase (GDH). This condition is characterized by recurrent hypoglycemia, elevated plasma ammonia, and potential neurological complications. We report the case of a 12-month-old male who presented with episodic hypoglycemia, hyperammonemia, and seizures. Family history was notable for childhood-onset hypoglycemia and seizures in the patient's mother and sister. The patient's laboratory findings during hospitalization were significant for markedly elevated C-peptide level of 4.9 ng/mL (SI: 1.63 nmol/L) (reference range; 1.1-4.4 ng/mL [SI: 0.36-1.46 nmol/L]). Insulin was inappropriately detectable at 20.2 µIU/mL (SI: 124.92 pmol/L) during hypoglycemia (reference range; 4.00-30.00 µIU/mL [SI: 24.0-180.0 pmol/L]). Genetic testing identified c.1491A>G (p.Ile497Met) in GLUD1. Following initiation of diazoxide therapy, he experienced symptomatic improvement with a marked reduction in hypoglycemic episodes. This case expands the literature on autosomal dominant HI/HA syndrome associated with an inherited GLUD1 p.Ile497Met mutation.

Angiotensin II (AngII) plays a pivotal role in body fluid balance through AngII type 1 receptors (Agtr1) expressed in circumventricular organs to stimulate thirst. Blockade of central Agtr1 attenuates thirst to hypotension but not acute hypernatremia. Data in genetic knockout models are limited as systemic AngII does not stimulate thirst in mice, and Agtr1a[-/-] mice are severely hypotensive. Therefore, we generated a novel Agtr1a[-/-] rat using CRISPR-Cas9 to produce an 11-bp frame-shift deletion in exon 3. Baseline mean arterial blood pressure (ABP) was approximately 10 mmHg lower in Agtr1a[-/-] vs. wild-type (WT) rats with no differences in heart rate. Depressor responses to ganglionic blockade, vasopressin receptor blockade, or angiotensin converting enzyme inhibition were not different between strains. Systemic AngII (40 ng/min, IV) significantly increased water intake and mean ABP in WT rats, but these responses were absent in Agtr1a[-/-] rats. Hypotension-induced thirst produced by the vasodilator diazoxide (25 mg/kg, IV) stimulated water intake in WT but not in Agtr1a[-/-] rats. In contrast, water intake stimulated by hypernatremia (2 M NaCl, IV) or overnight water deprivation was not different between strains. These findings support a critical role for Agtr1a in thirst induced by AngII and hypotension but not by hypernatremia or overnight water deprivation.

Exogenous angiotensin (Ang) (1-7) supplementation and MAS1 receptor activation have been implicated in pain regulation; however, the effects of pharmacological activation of angiotensin-converting enzyme 2 (ACE2), which promotes endogenous Ang (1-7) production, on neuropathic pain remain unclear. In this study, we investigated the antihyperalgesic effects of diminazene aceturate (DIZE), an ACE2 activator, and its underlying mechanisms in chronic constriction injury (CCI) mice. DIZE (15 mg/kg, i.p.) was administered once daily after CCI surgery, and mechanical and thermal sensitivity were assessed using the von Frey and Hargreaves tests, respectively. DIZE significantly attenuated CCI-induced mechanical and thermal hyperalgesia. CCI itself did not alter the expression levels of Ang-generating system components in the dorsal root ganglion or spinal cord, whereas DIZE increased ACE2 expression in the spinal cord. Immunofluorescence analysis showed increased ACE2 expression in the spinal dorsal horn, particularly in laminae I-II. Intrathecal administration of the MAS1 receptor antagonist A779 suppressed the antihyperalgesic effects of DIZE. Pharmacological ATP-sensitive potassium (KATP) channel opening with diazoxide attenuated CCI-induced hyperalgesia, whereas blockade of these channels with glibenclamide induced mechanical and thermal hyperalgesia in naïve mice. DIZE attenuated glibenclamide-induced hyperalgesia, and this effect was reduced by A779. Furthermore, MAS1 receptor immunoreactivity overlapped with that of KATP channel subunits, including SUR1, SUR2A, and Kir6.1, in the spinal dorsal horn. These findings suggest that DIZE attenuates neuropathic pain-related hyperalgesia through activation of the spinal ACE2/MAS1 receptor axis and the involvement of KATP channels.

Functioning pancreatic neuroendocrine carcinoma (pNEC) is relatively less common. Here, we report a middle-aged lady, initially diagnosed as primary ductal carcinoma of the breast with multiple metastases, who was managed with excision biopsy of the breast tumor and palliative chemotherapy elsewhere. She later developed recurrent episodes of hypoglycemia following chemotherapy and was found to have hyperinsulinemic hypoglycemia, clearly suggestive of insulinoma. Ga-68 DOTANOC PET-CT scan showed DOTA-avid primary lesion in pancreas with intense uptake in several sites, including liver, bilateral adnexa, and intra-abdominal lymph nodes, favoring a probable functioning pancreatic neuroendocrine tumor (pNET) with distant metastases. Histopathology of her breast lesion was then re-examined, which showed features of neuroendocrine carcinoma (NEC) that was confirmed with immunohistochemistry (IHC), thus establishing the diagnosis of functioning pNEC. She was treated conservatively with octreotide and diazoxide for recurrent and refractory level 2 and 3 hypoglycemia. She was later discharged at her request on octreotide in a relatively stable condition, but died a week later. Despite being rare, diagnosing insulin-secreting pNEC is quite challenging. However, the diagnosis can be established based on radiological clues, somatostatin receptor expression based on functional imaging, and careful histopathological examination with appropriate IHC.

Glioblastoma (GBM) exhibits profound metabolic plasticity and resistance to conventional therapies, partly driven by mitochondrial adaptability and stress response mechanisms. ONC212, a second-generation imipridone, targets mitochondrial proteostasis, yet determinants of tumour sensitivity remain unclear. This study aimed to investigate whether ATP-sensitive potassium (KATP) channel expression modulates ONC212-induced mitochondrial dysfunction and integrated stress response (ISR) activation in GBM. Human GBM lines (U87, U251, T98G) and non-malignant SVG p12 astrocytes received ONC212 (0.5-80 μM) for 12-48 h. Viability was assessed by CCK-8. KATP subunit expression (Kir6.2, SUR1, CCDC51) was quantified by qRT-PCR and western blot. Mitochondrial ROS quantification, oxygen consumption rate (Seahorse XF), PERK/ATF4/CHOP activation (western blot, immunofluorescence) and apoptosis (caspase-3/7) were evaluated. KATP was modulated pharmacologically (glibenclamide, diazoxide) and via KCNJ11 (Kir6.2) siRNA. ONC212 induced time-dependent and tumour-selective cytotoxicity, with highest sensitivity observed in KATP-high U87 cells. Treatment significantly increased mitochondrial ROS, impaired oxidative phosphorylation and reduced ATP/ADP ratios, indicating bioenergetic collapse. Concurrently, ONC212 robustly activated the PERK/eIF2α/ATF4/CHOP axis and promoted ATF4 nuclear translocation. PERK inhibition attenuated both stress signalling and cytotoxicity, confirming ISR dependency. KATP inhibition enhanced ONC212-induced mitochondrial dysfunction, ISR activation and apoptosis, whereas KATP activation exerted protective effects. Importantly, KCNJ11 silencing markedly potentiated ONC212 sensitivity, amplifying ROS production, mitochondrial impairment and caspase-dependent apoptosis. KATP channel expression may regulate ONC212 responsiveness in GBM by modulating mitochondrial stress and ISR signalling. Targeting KATP channels may enhance imipridone efficacy and represents a promising strategy for metabolically guided GBM therapy.

Background and objective Congenital hyperinsulinemic hypoglycemia (CHH) is the leading cause of persistent hypoglycemia in neonates and infants. In high-resource settings, diagnosis and management depend on rapid genetic testing and advanced imaging to differentiate focal from diffuse disease. However, in low-resource settings, limited diagnostic capacity and lack of access to medications often necessitate early surgical intervention. This study aimed to evaluate the clinical features, surgical intervention, and outcomes in infants undergoing pancreatectomy for congenital hyperinsulinism at Al Ribat University Hospital, Sudan. Methods A retrospective descriptive study was conducted, involving all pediatric patients who underwent pancreatectomy for CHH from January 2019 to December 2024. Data were extracted from operative logs and medical records, including demographics, diagnostic investigations, medical therapy, surgical procedures, postoperative complications, histopathology, and one-year outcomes. Descriptive statistics and appropriate inferential statistical tests were used for the analysis. Results Thirty-two patients were included, of whom 19 (59.4%) were female. The majority were diagnosed during the first week of life (n = 19, 59.4%). Diazoxide was administered to 30 (93.75%) patients, with only eight (26.7%) showing a therapeutic response. Restricted access to genetic testing (n = 8, 25%) and imaging (n = 6, 18.8%) resulted in the predominance of near-total pancreatectomy (n = 31, 96.9%). Intraoperative complications were minimal, with bleeding occurring in two cases (6.25%) and vascular injury in one case (3.1%). Early postoperative hypoglycemia was noted in 13 patients (40.6%), whereas hyperglycemia was noted in one patient (3.1%). Surgical complications included wound infection in seven patients (21.9%) and intestinal obstruction in one patient (3.1%). Histopathology confirmed CHH in all cases, with diffuse disease in 27 patients (84.4%). During a one-year follow-up period, three patients (9.4%) died, including two (6.3%) due to recurrent hypoglycemia. Conclusions Near-total pancreatectomy remains a practical and life-saving option for infants with medically unresponsive CHH in low-resource settings where diagnostic and pharmacologic limitations restrict individualized care. Despite limited access to preoperative localization and the predominance of diffuse disease, surgical outcomes were acceptable, with low intraoperative morbidity and manageable rates of postoperative complications. Persistent postoperative hypoglycemia and late mortality highlight the need for structured endocrine follow-up and improved access to medical therapy. Strengthening diagnostic capacity, ensuring medication availability, and establishing coordinated multidisciplinary care pathways are essential to improving long-term outcomes for children with CHH in resource-limited environments.

KCNJ11 mutations can cause congenital hyperinsulinism or diabetes mellitus. In children, seizures are typically associated with stress-induced hyperglycemia (150-200 mg/dL [8.3-11.1 mmol/L]; reference range, 73-109 mg/dL [4.1-6.1 mmol/L]). We report a 7-year-old boy with complex febrile status epilepticus who was incidentally found to have severe hypoglycemia (20 mg/dL [1.1 mmol/L]). On admission, plasma glucose was 157 mg/dL (8.7 mmol/L) after intravenous glucose administration, with an insulin level of 14.7 μU/mL (88.2 pmol/L; reference range, 2.19-9.89 μU/mL [13.1-59.3 pmol/L]) and suppressed ketones (3-hydroxybutyrate 65 μmol/L [0.065 mmol/L]; reference range, 0-74 μmol/L [0-0.074 mmol/L]). Retrospective review revealed neonatal hyperinsulinemic hypoglycemia (plasma glucose 34 mg/dL [1.9 mmol/L], insulin 5.2 μU/mL [31.2 pmol/L]). At ages 4 and 5 years, prolonged febrile seizures occurred with lower-than-expected glucose levels (103 mg/dL [5.7 mmol/L] and 127 mg/dL [7.0 mmol/L]). The mother had gestational diabetes mellitus followed by type 2 diabetes. Genetic testing identified a novel heterozygous nonsense pathogenic variant in KCNJ11 (p.Trp90Ter). A fasting study showed no hypoglycemia, and diazoxide was not initiated. KCNJ11 mutations can cause hypoglycemia beyond infancy, highlighting the need for genetic evaluation in atypical pediatric presentations.

Antiseizure medications (ASMs) have traditionally been characterized by their modulation of neuronal ion channels and synaptic processes; however, accumulating evidence indicates that numerous ASMs also directly modulate mitochondrial function. Specifically, several ASMs interact with ion channels located in both the inner and outer mitochondrial membranes, including the voltage-dependent anion channel (VDAC), the mitochondrial calcium uniporter (MCU), the mitochondrial Na+/Ca2+ exchanger (NCLX), the mitochondrial permeability transition pore (mPTP), and mitochondrial ATP-sensitive potassium channels (mitoKATP). Modulation of these channels regulates critical processes in epilepsy, including Ca2+ homeostasis, ATP synthesis, redox equilibrium, and susceptibility to neuronal apoptosis. Phenytoin and carbamazepine reduce voltage-dependent anion channel isoform 1 (VDAC1)-associated mitochondrial permeability by modulating the Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 protein (Bcl-2) ratio; ethosuximide limits mitochondrial Ca2+ overload through modulation of the MCU complex; valproic acid stabilizes NCLX function and prevents mPTP opening via antioxidant mechanisms; levetiracetam contributes to preserving intracellular Ca2+ handling; and mitoKATP activators, including diazoxide and retigabine, promote mitochondrial membrane potential stability and reduce seizure-induced reactive oxygen species (ROS) generation. The mitochondrial effects vary according to epilepsy subtype, contributing to the attenuation of hippocampal apoptosis in temporal lobe epilepsy and thalamocortical network modulation in generalized epilepsies. In this narrative review we examine the experimental and molecular evidence demonstrating how ASMs modulate mitochondrial ion channels and how these interactions contribute to their anticonvulsant mechanisms, thereby broadening the understanding of mitochondria as key functional components in antiseizure pharmacology.

Insulinomas and functional pancreatic neuroendocrine tumours (pNETs) are rare but important causes of endogenous hyperinsulinaemic hypoglycaemia whose neuroglycopenic manifestations can closely mimic neurological disorders, leading to considerable diagnostic delay. We present the case of a 74-year-old man with epilepsy, seizure-free for 11 years on carbamazepine, and a background of metastatic well-differentiated grade 3 pNET (Ki-67: 40-50%), who was admitted with a 2-3-week history of nocturnal confusion, cold sweats, nightmares, increasing agitation, and an episode of abnormal limb movements. The presentation was initially attributed to possible seizure recurrence or delirium. Routine investigations, including CT brain, carbamazepine levels, and type 1 antineuronal nuclear autoantibody antibody testing, were unremarkable, and blood glucose on admission was normal. The correct diagnosis was reached only during a witnessed ward episode on day two, when capillary blood glucose was found to be critically low and symptoms resolved immediately with intravenous dextrose. Subsequent biochemical evaluation demonstrated markedly elevated serum insulin (42 µU/L; reference: 2-24 µU/L), C-peptide (2,464 pmol/L; reference: <90 pmol/L), and on formal supervised 72-hour fast, which provoked symptomatic hypoglycaemia after just three hours, insulin was 180 µU/L, proinsulin was 730 pmol/L (reference: <10 pmol/L), and C-peptide was 2,136 pmol/L, with a negative sulphonylurea screen, fulfilling the diagnostic criteria for endogenous hyperinsulinaemia. Somatostatin receptor scintigraphy (single-photon emission computed tomography-computed tomography) identified multifocal hepatic metastases and focal uptake in the pancreatic tail, confirming an insulin-secreting primary. The patient was managed with diazoxide and monthly lanreotide but experienced rapid deterioration and died on palliative care. This case underscores the need to consider a functional pNET as a cause of seizure-like episodes even in patients with established epilepsy, and highlights that capillary blood glucose measurement during any witnessed neurological episode is a simple but potentially life-saving clinical step that should never be omitted.