Intellectual disability in KATP channel neonatal diabetes

2020 ◽  
Author(s):  
Svalastoga P ◽  
Sulen A ◽  
Fehn JR ◽  
Aukland SM ◽  
Irgens H ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Katp Channel ◽  
Neonatal Diabetes

scholarly journals Intellectual Disability in KATP Channel Neonatal Diabetes

Diabetes Care ◽  
2020 ◽  
Vol 43 (3) ◽  
pp. 526-533 ◽  
Author(s):  
Pernille Svalastoga ◽  
Åsta Sulen ◽  
Jarle R. Fehn ◽  
Stein M. Aukland ◽  
Henrik Irgens ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Katp Channel ◽  
Neonatal Diabetes

scholarly journals Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel

2016 ◽  
Vol 149 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Maria S. Remedi ◽  
Jonathan B. Friedman ◽  
Colin G. Nichols
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Vascular System ◽  
Wild Type Mouse ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Gain Of Function ◽  
Insulin Promoter

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion.

scholarly journals Muscle Dysfunction Caused by a KATP Channel Mutation in Neonatal Diabetes Is Neuronal in Origin

Science ◽  
2010 ◽  
Vol 329 (5990) ◽  
pp. 458-461 ◽  
Author(s):  
R. H. Clark ◽  
J. S. McTaggart ◽  
R. Webster ◽  
R. Mannikko ◽  
M. Iberl ◽  
...  
Keyword(s):  
Katp Channel ◽  
Neonatal Diabetes ◽  
Muscle Dysfunction ◽  
Channel Mutation

The personalized approach to neonatal diabetes therapy depending on the genetic defect

2017 ◽  
Vol 1 (1) ◽  
pp. 36-39 ◽  
Author(s):  
Yulia V. Tikhonovich ◽  
Natalia A. Zubkova ◽  
Anatoly N. Tiulpakov
Keyword(s):  
Katp Channel ◽  
Genetic Disorders ◽  
Genetic Defect ◽  
Clinical Importance ◽  
Neonatal Diabetes ◽  
Diabetes Treatment ◽  
Diabetes Therapy ◽  
Common Causes ◽  
Genetic Examination ◽  
Personalized Approach

Neonatal diabetes mellitus (NDM) is defined as a heterogeneous group of genetic disorders with onset before 6 months of age. Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of NDM. Accurate molecular diagnosis of NDM has significant clinical importance as it may influence diabetes treatment, explain pleiotropic features and define the prognosis in the examined subject as well as in other family members . In this report we present the results of a genetic examination of 70 patients with NDM, generalized the experience of using sulfonylurea in patients with KCNJ11 and ABCC8 genes mutations for the period from 2009 to 2016. A correlation is shown between the type of mutation, the course of the disease, and the sensitivity of patients to glibenclamide.

scholarly journals Metabolism-Excitation Coupling in a Model of KATP Channel Neonatal Diabetes Mellitus

2010 ◽  
Vol 98 (3) ◽  
pp. 578a
Author(s):  
Richard K.P. Benninger ◽  
Maria S. Remedi ◽  
Alessandro Ustione ◽  
W Steven Head ◽  
Colin G. Nichols ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Katp Channel ◽  
Neonatal Diabetes ◽  
Neonatal Diabetes Mellitus

scholarly journals Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: A mechanistic study

2014 ◽  
Vol 144 (5) ◽  
pp. 469-486 ◽  
Author(s):  
Peter Proks ◽  
Heidi de Wet ◽  
Frances M. Ashcroft
Keyword(s):  
Katp Channel ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Nucleotide Binding ◽  
Mechanistic Study ◽  
Xenopus Laevis Oocytes ◽  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Stimulatory Action ◽  
Channel Inhibition

Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas.

scholarly journals Sulfonylurea for the treatment of neonatal diabetes owing to KATP-channel mutations: a systematic review and meta-analysis

Oncotarget ◽  
2017 ◽  
Vol 8 (64) ◽  
pp. 108274-108285 ◽  
Author(s):  
Hongliang Zhang ◽  
Xiaobin Zhong ◽  
Zhenguang Huang ◽  
Chun Huang ◽  
Taotao Liu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Katp Channel ◽  
Meta Analysis ◽  
Neonatal Diabetes

scholarly journals Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of KATP channel-induced neonatal diabetes mellitus

Diabetologia ◽  
2011 ◽  
Vol 54 (5) ◽  
pp. 1087-1097 ◽  
Author(s):  
R. K. P. Benninger ◽  
M. S. Remedi ◽  
W. S. Head ◽  
A. Ustione ◽  
D. W. Piston ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Beta Cell ◽  
Murine Model ◽  
Katp Channel ◽  
Neonatal Diabetes ◽  
Neonatal Diabetes Mellitus
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