scholarly journals MON-110 Utilization of GluCEST, a Novel Neuroimaging Technique, to Characterize the Brain Phenotype in Hyperinsulinism/Hyperammonemia Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Elizabeth Rosenfeld ◽  
Ravi P R Nanga ◽  
Ravinder Reddy ◽  
Andy Revell ◽  
David R Roalf ◽  
...  
Keyword(s):  
Chemical Exchange ◽  
Chemical Exchange Saturation Transfer ◽  
Hyperinsulinemic Hypoglycemia ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Learning Impairments ◽  
Siemens Scanner ◽  
Atypical Absence ◽  
Serum Ammonia

Abstract BACKGROUND: Hyperinsulinism/Hyperammonemia (HI/HA) syndrome is the second most common form of congenital hyperinsulinism. It is caused by gain-of-function mutations in glutamate dehydrogenase (GDH), a mitochondrial enzyme expressed in pancreatic β-cells, liver, kidney, and brain, and is responsible for metabolizing glutamate into α-ketoglutarate and ammonia. In addition to hyperinsulinemic hypoglycemia due to abnormal GDH activity in pancreatic β-cells, ~80% of patients have developmental delays, learning, or behavioral disorders and >60% have atypical absence seizures (Bahi-Buisson, 2008). These neurologic symptoms are not fully explained by hypoglycemia and are hypothesized to result from central nervous system (CNS) glutamate imbalance due to CNS GDH overactivity. Newer magnetic resonance imaging (MRI) techniques have allowed for sensitive estimation of CNS glutamate using Glutamate Chemical Exchange Saturation Transfer (GluCEST). We aimed to comprehensively characterize the biochemical and clinical neurologic phenotype of HI/HA leveraging GluCEST MRI. Methods: Subjects with confirmed HI/HA diagnosis and without contraindication to MRI had electroencephalogram (EEG), serum ammonia, and the following validated neurodevelopmental assessments: ABAS-3, BRIEF, and ASEBA CBCL (if <18 years) or ASR (if >18 years) completed. GluCEST MRI axial hippocampal and midsagittal slices were acquired on a 7.0T Siemens scanner and reported as GluCEST % contrast. Healthy control GluCEST % contrast data were obtained from a separate study using the same neuroimaging protocol. Results: 8 HI/HA subjects (4 female; mean age 28 years [range 16-56] years) participated to date. Median serum ammonia was 58 umol/L (IQR 39-89). 50% self-reported learning impairments and 37.5% self-reported prior ADHD diagnosis. Marked unilateral increase in hippocampal GluCEST % contrast was observed in 3/6 subjects (2 L>R; 1 R>L). Overall, median peak GluCEST % contrast level was significantly higher in HI/HA subjects than controls (10.3% [IQR 8.9-11.3] v. 8.0% [IQR 7.8-8.4], p=0.0013, n=6). Conclusions: This is the first study to evaluate CNS glutamate via GluCEST in HI/HA. Hippocampal glutamate, measured by GluCEST % contrast, was significantly higher in HI/HA subjects than healthy controls. Laterality in hippocampal glutamate was observed in half of subjects. These findings are remarkable given the known role of abnormal glutamate signaling in the development of epilepsy and neurocognitive impairment. Next steps are to complete midsagittal GluCEST image processing, EEG and neurodevelopmental assessment interpretations to explore correlations between CNS phenotype and brain glutamate pattern. GluCEST holds promise for elucidating the pathophysiology of CNS manifestations in HI/HA syndrome.

Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

2020 ◽  
Vol 33 (5) ◽  
pp. 671-674
Author(s):  
Tashunka Taylor-Miller ◽  
Jayne Houghton ◽  
Paul Munyard ◽  
Yadlapalli Kumar ◽  
Clinda Puvirajasinghe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Newborn Period ◽  
Case Presentation ◽  
Male Baby ◽  
Common Causes ◽  
Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

scholarly journals MON-089 Discovery and Identification of Late Stage Selective Nonpeptide Somatostatin Subtype 5 (sst5) Agonists for the Treatment of Hyperinsulinemic Hypoglycemia

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Melissa A Fowler ◽  
Jian Zhao ◽  
Emmanuel Sturchler ◽  
Elizabeth Rico ◽  
Rosalia de Necochea-Campion ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Somatostatin Receptor ◽  
Liver Microsomes ◽  
Glucagon Secretion ◽  
Receptor Activation ◽  
Hyperinsulinemic Hypoglycemia ◽  
Repeat Dose ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
In Vivo Models

Abstract Congenital hyperinsulinism (CHI) results from mutations within the insulin secretion pathway and is characterized by excessive and/or inappropriate insulin secretion by pancreatic islet β-cells. CHI is the most common cause of persistent hypoglycemia in newborns and infants and is estimated to affect 1:2500 to 1:50,000 live births. Prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. If medical control of CHI is unsuccessful, a near-total pancreatectomy may be required, but hypoglycemia often persists. The neuropeptide somatostatin is an important modulator of pancreatic hormonal signaling and activity at different somatostatin receptor (sst) subtypes dictates the suppression of insulin and/or glucagon. The injectable peptide drugs octreotide and lanreotide are potent sst2 agonists used to treat CHI, but in addition to suppressing insulin, the sst2 activity of these peptides may also inhibit glucagon secretion, potentially reducing effectiveness and compromising a key defense against hypoglycemia. Glucagon secretion from α-cells is inhibited through activation of sst2 receptors, while insulin secretion from β-cells is inhibited through activation of sst2 and sst5. We therefore hypothesize that agonists selectively targeting sst5 and lacking sst2 activity will offer an improved efficacy/safety profile for patients with hyperinsulinemic hypoglycemia. Using iterative medicinal chemistry and pharmacology, Crinetics has discovered several classes of highly potent, orally bioavailable, small molecule sst-subtype selective agonists with drug-like pharmaceutical properties. Our discovery efforts aimed at finding a compound to treat CHI have yielded potent and selective nonpeptide sst5 agonists with sub-nanomolar EC50s in cell-based assays of receptor activation. Insulin secretion from isolated human and rat islets was suppressed upon exposure to sst5 agonists. Potent and selective sst5 agonists were then evaluated in a number acute and repeat dose in vivo models (e.g., oGTT, fed/fasted conditions, sulfonylurea-induced hypoglycemia) to assess physiological effects and to gain mechanistic insights. As predicted by the in vitro pharmacology, selective nonpeptide sst5 agonists suppressed insulin secretion and raised blood glucose levels in each model, while having minimal effects on glucagon secretion. Leading sst5 agonists were also evaluated for drug like characteristics, including stability in liver microsomes, lack of inhibition of cytochromes P450 and the hERG ion channel, and were shown to exhibit good exposure upon oral dosing in both rats and dogs. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in genotoxicity, safety pharmacology, and general toxicity studies to determine the molecule most suitable for evaluation in human clinical trials.

ATP-sensitive K+ channels and disease: from molecule to malady

2007 ◽  
Vol 293 (4) ◽  
pp. E880-E889 ◽  
Author(s):  
Frances M. Ashcroft
Keyword(s):  
Neonatal Diabetes ◽  
Channel Structure ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
American Physiological Society ◽  
And Function ◽  
The Relationship

This essay is based on a lecture given to the American Physiological Society in honor of Walter B. Cannon, an advocate of homeostasis. It focuses on the role of the ATP-sensitive potassium K+ (KATP) channel in glucose homeostasis and, in particular, on its role in insulin secretion from pancreatic β-cells. The β-cell KATP channel comprises pore-forming Kir6.2 and regulatory SUR1 subunits, and mutations in either type of subunit can result in too little or too much insulin release. Here, I review the latest information on the relationship between KATP channel structure and function, and consider how mutations in the KATP channel genes lead to neonatal diabetes or congenital hyperinsulinism.

scholarly journals Congenital hyperinsulinism

2010 ◽  
Vol 56 (6) ◽  
pp. 41-47
Author(s):  
M A Melikian
Keyword(s):  
Insulin Secretion ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Morphological Features ◽  
Genetic Defects ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Clinical Characteristic

Congenital hyperinsulinism (CHI) is one of the main causes underlying the development of persistent hypoglycemic conditions in children. Biochemically, CHI is characterized by inadequate insulin secretion from pancreatic β-cells. CHI is a heterogeneous pathology in terms of clinical manifestations, morphological features, and molecular-genetic defects contributing to its development. The present paper is focused on the current views of CHI pathogenesis; the clinical characteristic of the disease is given and the internationally accepted protocols for the examination and treatment of children with congenital hyperinsulinism are described.

Loss of functional KATP channels in pancreatic β–cells causes persistent hyperinsulinemic hypoglycemia of infancy

1996 ◽  
Vol 2 (12) ◽  
pp. 1344-1347 ◽  
Author(s):  
Charlotte Kane ◽  
Ruth M. Shepherd ◽  
Paul E. Squires ◽  
Paul R.V. Johnson ◽  
Roger F.L. James ◽  
...  
Keyword(s):  
Katp Channels ◽  
Hyperinsulinemic Hypoglycemia ◽  
Β Cells ◽  
Pancreatic Β Cells

MICROCHEMICAL ASSAYS OF GLUCOSE AND GLUCOSE-6-PHOSPHATE IN MAMMALIAN PANCREATIC β-CELLS

1968 ◽  
Vol 59 (3) ◽  
pp. 479-486 ◽  
Author(s):  
Lars-Ake Idahl ◽  
Bo Hellman
Keyword(s):  
Glucose Level ◽  
Exocrine Pancreas ◽  
The Other ◽  
Wide Concentration Range ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Enzymatic Cycling ◽  
Glucose Diffusion ◽  
Significant Barrier ◽  
The Brain

ABSTRACT The combination of enzymatic cycling and fluorometry was used for measuring glucose and glucose-6-phosphate in pancreatic β-cells from obese-hyperglycaemic mice. The glucose level of the β-cells corresponded to that of serum over a wide concentration range. In the exocrine pancreas, on the other hand, a significant barrier to glucose diffusion across the cell membranes was demonstrated. During 5 min of ischaemia, the glucose level remained practically unchanged in the β-cells while it increased in the liver and decreased in the brain. The observation that the pancreatic β-cells are characterized by a relatively low ratio of glucose-6-phosphate to glucose may be attributed to the presence of a specific glucose-6-phosphatase.

Sign in / Sign up

Export Citation Format

Share Document