scholarly journals Molecular mechanisms of congenital hyperinsulinism

2015 ◽  
Vol 54 (2) ◽  
pp. R119-R129 ◽  
Author(s):  
Sofia A Rahman ◽  
Azizun Nessa ◽  
Khalid Hussain
Keyword(s):  
Insulin Secretion ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
State Of The Art ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Genetic Abnormalities ◽  
Hydroxyacyl Coa Dehydrogenase

Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.

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 Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

2018 ◽  
Vol 51 (1) ◽  
pp. 201-216 ◽  
Author(s):  
Arwa M.T. Al-Nahdi ◽  
Annie John ◽  
Haider  Raza
Keyword(s):  
Oxidative Stress ◽  
Insulin Secretion ◽  
Molecular Mechanisms ◽  
Protective Action ◽  
Mitochondrial Enzymes ◽  
Partial Recovery ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Mitochondrial Energy Metabolism ◽  
Mitochondrial Functions

Background/Aims: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells. Methods: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. Results: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. Conclusion: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic β-cells against STZ-induced cytotoxicity.

Protein-induced hyperinsulinaemic hypoglycaemia due to a homozygous HADH mutation in three siblings of a Saudi family

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Omer Babiker ◽  
Sarah E. Flanagan ◽  
Sian Ellard ◽  
Hesham Al Girim ◽  
Khalid Hussain ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Saudi Family ◽  
Key Genes

AbstractHyperinsulinaemic hypoglycaemia (HH) is caused by mutations in the key genes involved in regulation of insulin secretion from the pancreatic β-cells and mutations in

scholarly journals ILDR2 stabilization is regulated by its interaction with GRP78

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazuhisa Watanabe ◽  
Kazuhiro Nakayama ◽  
Satoshi Ohta ◽  
Ayumi Matsumoto ◽  
Hidetoshi Tsuda ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Novel Proteins ◽  
Novel Association ◽  
Ubiquitin Proteasome ◽  
Novel Target

AbstractIldr2 was initially identified as a genetic modifier of diabetes susceptibility in B6.DBA Lepob congenic mice, and was associated with decreased β-cell replication rates, reduced β-cell mass, and persistent mild hypoinsulinemic hyperglycemia. However, the molecular mechanisms of how the ILDR2 protein is involved in these effects are largely unknown. We sought to identify ILDR2-interacting proteins to further elucidate the molecular mechanisms underpinning ILDR2 function in pancreatic β-cells. Using TAP tag technology, we purified proteins interacting with ILDR2 in the pancreatic β-cell line MIN6, and identified the endoplasmic reticulum resident chaperones, GRP78 and PDIA1, as novel proteins interacting with ILDR2. We demonstrated that GRP78 interacted with ILDR2 and was possibly involved in ILDR2 stabilization by inhibiting ubiquitin–proteasome degradation. Additionally, adenoviral ILDR2 knockdown led to reduced glucose-responsive insulin secretion in MIN6 β-cells, suggesting ILDR2 may be implicated in a new pathway in hypoinsulinemic hyperglycemia. These data provide evidence for a novel association between GRP78 and ILDR2, and suggest GPR78-ILDR2 may a novel target for diabetic therapeutic modulation in decreased insulin secretion.

scholarly journals Neuromedin U uses Gαi2 and Gαo to suppress glucose-stimulated Ca2+ signaling and insulin secretion in pancreatic β cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250232
Author(s):  
Weidong Zhang ◽  
Hideyuki Sakoda ◽  
Yuki Nakazato ◽  
Md Nurul Islam ◽  
François Pattou ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Er Stress ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Mitochondrial Dynamics ◽  
Intracellular Camp ◽  
Β Cells ◽  
Β Cell ◽  
Signaling Mechanism

Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes, including impairment of pancreatic β-cell function via induction of mitochondrial dysfunction and endoplasmic reticulum (ER) stress, ultimately suppressing insulin secretion. NMU has two receptors, NMU receptor 1 (NMUR1) and NMUR2, both of which are G-protein–coupled receptors (GPCRs). Only NMUR1 is expressed in mouse islets and β cell–derived MIN6-K8 cells. The molecular mechanisms underlying the insulinostatic action mediated by NMUR1 in β cells have yet to be elucidated. In this study, we explored the molecular mechanism driving impairment of insulin secretion in β cells by the NMU–NMUR1 axis. Pretreatment with the Gαi/o inhibitor Bordetella pertussis toxin (PTX), but not the Gαq inhibitor YM254890, abolished NMU-induced suppression of glucose-stimulated insulin secretion and calcium response in β cells. Knockdown of Gαi2 and Gαo in β cells counteracted NMU-induced suppression of insulin secretion and gene alterations related to mitochondrial fusion (Mfn1, Mfn2), fission (Fis1, Drp1), mitophagy (Pink1, Park2), mitochondrial dynamics (Pgc-1α, Nrf1, and Tfam), ER stress (Chop, Atp2a3, Ryr2, and Itpr2), intracellular ATP level, and mitochondrial membrane potential. NMU decreased forskolin-stimulated intracellular cAMP in both mouse and human islets. We concluded that NMUR1 coupled to PTX-sensitive Gαi2 and Gαo proteins in β cells reduced intracellular Ca2+ influx and cAMP level, thereby causing β-cell dysfunction and impairment. These results highlight a novel signaling mechanism of NMU and provide valuable insights into the further investigation of NMU functions in β-cell biology.

Regulatory effects of N-3 PUFAs on pancreatic β-cells and insulin-sensitive tissues

2021 ◽  
Vol 22 ◽  
Author(s):  
Wen Liu ◽  
Qing Zheng ◽  
Min Zhu ◽  
Xiaohong Liu ◽  
Jingping Liu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Secretion ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Nonalcoholic Fatty Liver ◽  
Wide Range ◽  
Regulatory Effects

: The N-3 polyunsaturated fatty acids (PUFAs) have a wide range of health benefits, including anti-inflammatory effects, improvements in lipids metabolism and promoting insulin secretion, as well as reduction of cancer risk. Numerous studies support that N-3 PUFAs have the potentials to improve many metabolic diseases, such as diabetes, nonalcoholic fatty liver disease and obesity, which are attributable to N-3 PUFAs mediated enhancement of insulin secretion by pancreatic β-cells and improvements in insulin sensitivity and metabolic disorders in peripheral insulin-sensitive tissues such as liver, muscles, and adipose tissue. In this review, we summarized the up-to-date clinical and basic studies on the regulatory effects and molecular mechanisms of N-3 PUFAs mediated benefits on pancreatic β-cells, adipose tissue, liver, and muscles in the context of glucose and/or lipid metabolic disorders. We also discussed the potential factors involved in the inconsistent results from different clinical researches of N-3 PUFAs.

Signal integration at the level of ion channel and exocytotic function in pancreatic β-cells

2011 ◽  
Vol 301 (6) ◽  
pp. E1065-E1069 ◽  
Author(s):  
Patrick E. MacDonald
Keyword(s):  
Insulin Secretion ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Signal Integration ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Precise Control ◽  
The Past ◽  
Associated Proteins ◽  
Body Energy

Whole body energy balance is ensured by the exquisite control of insulin secretion, the dysregulation of which has serious consequences. Although a great deal has been learned about the control of insulin secretion from pancreatic β-cells in the past 30 years, there remains much to be understood about the molecular mechanisms and interactions that underlie the precise control of this process. Numerous molecular interactions at the plasma membrane mediate the excitatory and amplifying events involved in insulin secretion; this includes interactions between ion channels, signal transduction machinery, and exocytotic proteins. The present Perspectives article considers evidence that key membrane and membrane-associated proteins essential to insulin secretion are regulated in concert as a functional unit, ensuring an integrated excitatory and exocytotic response to the signals that control insulin secretion.

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.

scholarly journals Short-chain 3-hydroxyacyl-CoA dehydrogenase is a negative regulator of insulin secretion in response to fuel and non-fuel stimuli in INS832/13 β-cells

2010 ◽  
Vol 2 (3) ◽  
pp. 157-167 ◽  
Author(s):  
Émilie PEPIN ◽  
Claudiane GUAY ◽  
Viviane DELGHINGARO-AUGUSTO ◽  
Erik JOLY ◽  
S.R. Murthy MADIRAJU ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Negative Regulator ◽  
Short Chain ◽  
Β Cells ◽  
Hydroxyacyl Coa Dehydrogenase
Sign in / Sign up

Export Citation Format

Share Document