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Reviews in Endocrine & Metabolic... Dec 2023The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses... (Review)
Review
The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses drug-related hypoglycemia, but it misses a focus on drug-induced hyperinsulinemic hypoglycemia (DHH). Here we reviewed the association existing between drugs and hyperinsulinemic hypoglycemia. We primarily selected on the main electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) the reviews on drug-induced hypoglycemia. Among the drugs listed in the reviews, we selected the ones linked to an increase in insulin secretion. For the drugs missing a clear association with insulin secretion, we investigated the putative mechanism underlying hypoglycemia referring to the original papers. Our review provides a list of the most common agents associated with hyperinsulinemic hypoglycemia (HH), in order to facilitate both the recognition and the prevention of DHH. We also collected data about the responsiveness of DHH to diazoxide or octreotide.
Topics: Humans; Hypoglycemia; Hyperinsulinism; Diazoxide; Insulin Secretion
PubMed: 37552352
DOI: 10.1007/s11154-023-09828-y -
Endocrinology, Diabetes & Metabolism... Nov 2022A 52-year-old female presented with recurrent episodes of fasting or post-absorptive hypoglycemia. A 72-h fasting test confirmed endogenous hyperinsulinemia....
SUMMARY
A 52-year-old female presented with recurrent episodes of fasting or post-absorptive hypoglycemia. A 72-h fasting test confirmed endogenous hyperinsulinemia. Conventional imaging was unremarkable. Selective pancreatic arterial calcium stimulation and hepatic venous sampling showed a maximum calcium-stimulated insulin concentration from several pancreatic areas, mainly the proximal splenic artery and the proximal gastroduodenal artery, suggesting the presence of one or more occult insulinoma(s) in the region of the pancreatic body. 68Ga-DOTA-exendin-4 PET/CT showed however generalized increased uptake in the pancreas and a diagnosis of nesidioblastosis was therefore suspected. The patient has been since successfully treated with dietetic measures and diazoxide. Treatment efficacy was confirmed by a flash glucose monitoring system with a follow-up of 7 months.
LEARNING POINTS
Adult nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia. The distinction between insulinoma and nesidioblastosis is essential since the therapeutic strategies are different. 68Ga-DOTA-exendin-4 PET/CT emerges as a new noninvasive diagnostic tool for the localization of an endogenous source of hyperinsulinemic hypoglycemia. Medical management with dietetic measures and diazoxide need to be considered as a valuable option to treat patients with adult nesidioblastosis. Flash glucose monitoring system is helpful for the evaluation of treatment efficacy.
PubMed: 36448840
DOI: 10.1530/EDM-22-0325 -
The Journal of Clinical Endocrinology... Jul 2022Congenital hyperinsulinism (HI) results in severe, persistent hypoglycemia and is associated with high risk of neurodevelopmental deficits. Sixty percent of HI cases are...
CONTEXT
Congenital hyperinsulinism (HI) results in severe, persistent hypoglycemia and is associated with high risk of neurodevelopmental deficits. Sixty percent of HI cases are unresponsive to diazoxide, the only Food and Drug Administration-approved drug. Somatostatin analogs are used off-label as second-line treatment; the long-acting somatostatin analogue, lanreotide, has been used to treat HI over the past decade. Existing reports are limited to small case series.
OBJECTIVE
To assess the effectiveness and safety of lanreotide in individuals with HI.
DESIGN
Retrospective cohort study of individuals with HI treated with lanreotide between 2015 and 2020.
SETTING
The Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia.
PATIENTS
Fifty-four individuals with hyperinsulinism treated with lanreotide.
MAIN OUTCOME MEASURES
Fasting duration with plasma glucose > 70 mg/dL; frequency of lanreotide-associated side effects.
RESULTS
The median duration of lanreotide therapy was 28.7 (2.8-64.5) months. Thirty-four patients (63%) had HI due to inactivating mutations of the adenosine 5'-triphosphate (ATP) sensitive potassium channel (KATP-HI), and 39% had undergone a pancreatectomy. Of 52 patients receiving other HI therapies, 22 (42%) were able to discontinue other treatments and were managed on lanreotide alone. Fasting duration with plasma glucose > 70 mg/dL was significantly longer during therapy with lanreotide compared to prior to lanreotide initiation (8.6 ± 6.5 vs 5.1 ± 4.7 hours, P = 0.001). The most common side effects were subcutaneous nodules (26%) and gallstones (11%).
CONCLUSIONS
Lanreotide is a well-tolerated treatment for patients with HI. It results in a longer duration of fasting and a simplification of treatment regimens.
Topics: Blood Glucose; Child; Congenital Hyperinsulinism; Humans; Hyperinsulinism; Peptides, Cyclic; Retrospective Studies; Somatostatin
PubMed: 35587448
DOI: 10.1210/clinem/dgac322 -
Heliyon Sep 2023Diazoxide is a potential candidate for the treatment of transitional hypoglycaemia in infants. A clinical trial is currently underway to investigate whether low-dose...
Diazoxide is a potential candidate for the treatment of transitional hypoglycaemia in infants. A clinical trial is currently underway to investigate whether low-dose oral diazoxide is beneficial for severe or recurrent transitional neonatal hypoglycaemia (the NeoGluCO Study, registration ANZCTR12620000129987). The present study aimed to develop and validate the parameters for quantifying diazoxide from neonatal plasma samples, and to assess the stability of extemporaneously prepared diazoxide suspensions to support the NeoGluCO Study. To determine the plasma concentration of diazoxide, a protein precipitation mediated extraction protocol was developed, which demonstrated >94% diazoxide extraction recoveries from all samples. The method was linear over the range of 0.2-40 μg/mL (R > 0.9994) with a limit of quantification of 0.2 μg/mL. Accuracy of the method was within 97-106% with relative standard deviation < 6% for all samples. Diazoxide-plasma samples were stable for up to three months at -20 °C and up to 48 h when stored in the auto-sampler. Samples were stable for up to two freeze-thaw cycles, with further cycles compromising stability of diazoxide in plasma. The developed method was applied to determine chemical stability of the extemporaneously prepared diazoxide suspensions. These were stable at both 2-8 °C and 25 °C/60% RH, with 98% of diazoxide remaining after 35 days in both storage conditions. Diazoxide was successfully quantified from plasma collected from six neonates enrolled in the NeoGluCO Study, using the developed protocol. Overall, an efficient and reproducible extraction protocol was developed and validated for the estimation of diazoxide from human plasma.
PubMed: 37810084
DOI: 10.1016/j.heliyon.2023.e20101 -
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 -
Age and Ageing Mar 2022We present the case of an 83-year-old woman with recurrent episodes of delirium occurring overnight, associated with hypoglycaemia. Other causes for delirium were...
We present the case of an 83-year-old woman with recurrent episodes of delirium occurring overnight, associated with hypoglycaemia. Other causes for delirium were excluded. Laboratory findings were in keeping with endogenous insulin production. Computerised tomography imaging revealed a small mass in the pancreas supporting a presumed diagnosis of an insulinoma. Given the patient's frailty and cognitive impairment, a conservative management approach was taken. Diazoxide was commenced with resolution of episodes of delirium. This case highlights hypoglycaemia, and insulinoma, as a rare, but treatable cause of delirium. It demonstrates the importance of blood sugar screening in delirium. It emphasises the holistic modifications to management, which must be taken to ensure patient-centred care when caring for an older adult living with frailty, who may have cognitive impairment.
Topics: Aged; Aged, 80 and over; Delirium; Female; Frailty; Humans; Hypoglycemia; Insulinoma; Pancreatic Neoplasms
PubMed: 35305086
DOI: 10.1093/ageing/afac055 -
Frontiers in Endocrinology 2023Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study...
OBJECTIVE
Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations.
METHODS
We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (K) channel variants were assessed using patch clamp recording and Western blot.
RESULTS
Nine of 13 (69%) patients with ten different pathogenic variants (7 in , 2 in and 1 in ) were identified by the combined sequencing. The variant p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F K channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C K channels were defective in trafficking. One patient had a dominant mutation in the gene (p.I211F), and WES revealed mosaicism of this variant from another patient.
CONCLUSION
Pathogenic variants in K channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the gene is highly suggestive of a founder effect. The I211F mutation in the gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) K channels are also associated with the diazoxide-unresponsive phenotype.
Topics: Humans; Child; Diazoxide; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors; Congenital Hyperinsulinism; Genetic Association Studies; Adenosine Triphosphate
PubMed: 38033998
DOI: 10.3389/fendo.2023.1283907 -
Biotechnic & Histochemistry : Official... Apr 2023I investigated the effects of diazoxide, a mitochondrial potassium channel opener, on streptozotocin (STZ) induced pancreatic β cell damage via the...
I investigated the effects of diazoxide, a mitochondrial potassium channel opener, on streptozotocin (STZ) induced pancreatic β cell damage via the HSP70/HSP90/TLR4/AMPK signaling pathways in vitro. I used the pancreatic β cell line, 1.1B4, to create four groups: control, STZ treated, diazoxide treated, STZ + diazoxide treated. The STZ treated cells were exposed to 20 µM STZ for 2 h with or without 100 µM diazoxide for 24 h. Total antioxidant status (TAS), total oxidant status (TOS), cell viability and mitochondrial membrane potential (MMP) were measured. Expression of ATP-sensitive potassium channel (K) subunits, heat shock protein-70 (HSP70), heat shock protein-90 (HSP90), toll-like receptor 4 (TLR4), AMP-activated protein kinase (AMPK) and some apoptotic proteins were detected using western blotting. Apoptosis was assessed using TUNEL staining. STZ increased TOS and OSI in the pancreatic β cells; however, diazoxide failed to improve oxidative stress. Also, STZ increased tunnel positive cells in the pancreatic β cells. Diazoxide decreased the tunnel positive cells in the STZ treated β cell. STZ decreased MMP; however, diazoxide did not normalize MMP in the STZ induced β cells. Diazoxide increased the HSP70:HSP90 protein expression ratio. STZ decreased expression of AMPK and subunits of K channel and increased the expression of caspase-3 and TLR4 protein; diazoxide normalized the expression of all proteins studied. K channel opening by diazoxide protects pancreatic β cells against STZ toxicity via HSP70/HSP90/TLR4/AMPK signaling.
Topics: Diazoxide; Insulin-Secreting Cells; Streptozocin; AMP-Activated Protein Kinases; Toll-Like Receptor 4; Signal Transduction; Adenosine Triphosphate; Heat-Shock Proteins
PubMed: 36740984
DOI: 10.1080/10520295.2023.2168757 -
European Journal of Pediatrics Jan 2022Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in neonates and infants. Medical treatment includes the use of high concentrations...
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in neonates and infants. Medical treatment includes the use of high concentrations of glucose and combinations of diazoxide, octreotide and glucagon. We report our experience of using sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in the treatment of CHI in seven newborns who are poorly responding to standard medical therapy. Majority (87%) of infants achieved euglycaemia using a combination of oral feeding and the addition of sirolimus to standard medical treatment. One infant who failed to achieve euglycaemia even after surgery managed successfully with sirolimus. Diagnosis was confirmed by genetics evaluation; in three infants, novel mutations were detected. Outcome and long-term follow-up of all cases are described.Conclusion: Sirolimus can be considered in treatment of CHI refractory to standard medical treatment or in cases unresponsive to surgical treatment. What is Known: • Congenital hyperinsulinism (CHI) or persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) associated with mutations such as the ABBC8 or KCNJ gene known to cause hypoglycaemia refractory to standard medical treatment such as diazoxide and octreotide and may need subtotal pancreatectomy (STP). • Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, was recently reported to be useful for refractory CHI cases with variable efficacy. What is New: • Our case series describes efficacy and safety of sirolimus in seven genetically proven refractory CHI cases with mainly neonatal presentation. All patients' follow-ups are described. • Out of seven infants, six infants responded well to sirolimus, and among these one infant who failed to respond to surgery (STP) also successfully managed with sirolimus. • It highlights the right patient selection and right dose to successfully manage these cases without much adverse effects.
Topics: Congenital Hyperinsulinism; Diazoxide; Glucose; Humans; Hyperinsulinism; Infant; Infant, Newborn; Mutation; Sirolimus
PubMed: 34304300
DOI: 10.1007/s00431-021-04209-6 -
European Journal of Endocrinology Oct 2021Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for...
OBJECTIVE
Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for the clinical management of the condition. We aimed to determine the clinical features that help to identify KATP-hyperinsulinism at diagnosis.
DESIGN
We studied 761 individuals with KATP-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age. All were referred as part of routine clinical care.
METHODS
We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and receiver operator characteristic (ROC) analysis to identify the features that predict KATP-hyperinsulinism.
RESULTS
Higher birth weight, diazoxide unresponsiveness and diagnosis in the first week of life were independently associated with KATP-hyperinsulinism (adjusted odds ratio: 4.5 (95% CI: 3.4-5.9), 0.09 (0.06-0.13) and 3.3 (2.0-5.0) respectively). Birth weight and diazoxide unresponsiveness were additive and highly discriminatory for identifying KATP-hyperinsulinism (ROC area under the curve for birth weight 0.80, diazoxide responsiveness 0.77, and together 0.88, 95% CI: 0.85-0.90). In this study, 86% born large for gestation and 78% born appropriate for gestation and who did not respond to diazoxide treatment had KATP-hyperinsulinism. In contrast, of those individuals born small for gestation, none who were diazoxide responsive and only 4% of those who were diazoxide unresponsive had KATP-hyperinsulinism.
CONCLUSIONS
Individuals with hyperinsulinism born appropriate or large for gestation and unresponsive to diazoxide treatment are most likely to have an ABCC8 or KCNJ11 mutation. These patients should be prioritised for genetic testing of KATP channel genes.
Topics: Birth Weight; Congenital Hyperinsulinism; Diazoxide; Female; Humans; Infant, Newborn; KATP Channels; Male; Mutation; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors
PubMed: 34633981
DOI: 10.1530/EJE-21-0476