scholarly journals Clinical and Functional Characteristics of a Novel KLF11 Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yujing Sun ◽  
Jingru Qu ◽  
Jing Wang ◽  
Ruxing Zhao ◽  
Chuan Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Luciferase Reporter ◽  
Maturity Onset Diabetes ◽  
Insulin Expression ◽  
Insulin Promoter ◽  
Impaired Insulin ◽  
Reporter Assays

Background. Mutations in human KLF11 may lead to the development of maturity-onset diabetes of the young 7 (MODY7). This occurs due to impaired insulin synthesis in the pancreas. To date, the clinical and functional characteristics of the novel KLF11 mutation c.1061G > T have not yet been reported. Methods. Whole-exon sequencing was used to screen the proband and family members with clinical suspicion of the KLF11 variant. Luciferase reporter assays were used to investigate whether the KLF11 variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) analysis were used to analyze the KLF11 variant that regulates insulin expression and insulin secretion activity in beta cell lines. The Freestyle Libre H (Abbott Diabetes Care Ltd) was used to dynamically monitor the proband daily blood glucose levels. Results. Mutation screening for the whole exon genes identified a heterozygous KLF11 (c.1061G > T) variant in the proband, her mother, and her maternal grandfather. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed that the KLF11 (c.1061G > T) variant had impaired insulin promoter regulation activity. Moreover, this variant was found to impair insulin expression and insulin secretion in pancreatic beta cells. The proband had better blood glucose control without staple food intake ( p < 0.05 ). Conclusions. Herein, for the first time, we report a novel KLF11 (c.1061G > T) monogenic mutation associated with MODY7. This variant has impaired insulin promoter regulation activity and impairs insulin expression and secretion in pancreatic beta cells. Therefore, administering oral antidiabetic drugs along with dietary intervention may benefit the proband.

scholarly journals Phenotype of a transient neonatal diabetes point mutation (SUR1-R1183W) in mice

2020 ◽  
Vol 5 ◽  
pp. 15
Author(s):  
Gregor Sachse ◽  
Elizabeth Haythorne ◽  
Peter Proks ◽  
Michelle Stewart ◽  
Heather Cater ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Pancreatic Beta Cells ◽  
Constitutive Expression ◽  
Neonatal Diabetes ◽  
Gain Of Function ◽  
Human Phenotype ◽  
Transient Neonatal Diabetes

Background: The KATP channel plays a key role in glucose homeostasis by coupling metabolically generated changes in ATP to insulin secretion from pancreatic beta-cells.  Gain-of-function mutations in either the pore-forming (Kir6.2) or regulatory (SUR1) subunit of this channel are a common cause of transient neonatal diabetes mellitus (TNDM), in which diabetes presents shortly after birth but remits within the first few years of life, only to return in later life. The reasons behind this time dependence are unclear. Methods: In an attempt to understand the mechanism behind diabetes remission and relapse, we generated mice expressing the common TNDM mutation SUR1-R1183W. We employed Cre/LoxP technology for both inducible and constitutive expression of SUR1-R1183W specifically in mouse beta-cells, followed by investigation of their phenotype using glucose tolerance tests and insulin secretion from isolated islets.  Results: We found that the R1183W mutation impaired inhibition of KATP channels by ATP when heterologously expressed in human embryonic kidney cells. However, neither induced nor constitutive expression of SUR1-R1183W in mice resulted in changes in blood glucose homeostasis, compared to littermate controls. When challenged with a high fat diet, female mice expressing SUR1-R1183W showed increased weight gain, elevated blood glucose and impaired glycaemic control, but glucose-stimulated insulin secretion from pancreatic islets appeared unchanged. Conclusions: The mouse model of TNDM did not recapitulate the human phenotype. We discuss multiple potential reasons why this might be the case. Based on our findings, we recommend future TNDM mouse models employing a gain-of-function SUR1 mutation should be created using the minimally invasive CRISPR/Cas technology, which avoids many potential pitfalls associated with the Cre/LoxP system.

scholarly journals SEL BETA PANKREAS SINTESIS DAN SEKRESI INSULIN

2013 ◽  
Vol 4 (3) ◽  
Author(s):  
Eka Banjarnahor ◽  
Sunny Wangko
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Plasma Membranes ◽  
Secretory Granules ◽  
Chromosome 11 ◽  
Insulin Synthesis ◽  
Glucose Levels ◽  
Blood Glucose Levels

Abstract: Insulin synthesis and secretion are done by pancreatic beta cells. Preceding the insulin synthesis, there is a gen translation in chromosome 11 that produces insulin, packed in secretory granules. Insulin secretion is induced by the alteration of blood glucose levels, resulting in the occurence of intracellular reactions preceded by changes of ATP/ADP ratios that trigger the depolarisation of plasma membranes. Furthermore, extracellular Ca2+ ions move inward to beta cells to activate exocytosis. There are still many unknown problems so far in either the synthesis or secretion of insulin that cause unfulfilled insulin needs in the body.Keywords: beta cells, insulin, synthesis, secretionAbstrak: Sintesis dan sekresi insulin dilakukan oleh sel beta pankreas. Sintesis insulin diawali oleh salinan gen pada kromosom 11, yang akan menghasilkan insulin, di kemas di dalam granul-granul sekretorik. Sekresi insulin diinduksi oleh perubahan kadar glukosa, yang berakibat terjadinya reaksi intrasel yang diikuti adanya perbedaan rasio ATP/ADP yang memicu reaksi depolarisasi membran plasma. Sebagai akibat lanjut Ca2+ ekstrasel akan masuk ke dalam sel beta yang berfungsi mengaktifkan eksositosis. Sampai saat ini masih banyak ditemui masalah baik dalam hal sintesis maupun sekresi insulin yang mengakibatkan kebutuhan insulin tubuh tidak terpenuhi.Kata kunci: sel beta, insulin, sintesis, sekresi

scholarly journals Phenotype of a transient neonatal diabetes point mutation (SUR1-R1183W) in mice

2021 ◽  
Vol 5 ◽  
pp. 15
Author(s):  
Gregor Sachse ◽  
Elizabeth Haythorne ◽  
Peter Proks ◽  
Michelle Stewart ◽  
Heather Cater ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Beta Cells ◽  
Glucose Homeostasis ◽  
Pancreatic Beta Cells ◽  
Constitutive Expression ◽  
Neonatal Diabetes ◽  
Gain Of Function ◽  
Human Phenotype ◽  
Transient Neonatal Diabetes

Background: The KATP channel plays a key role in glucose homeostasis by coupling metabolically generated changes in ATP to insulin secretion from pancreatic beta-cells.  Gain-of-function mutations in either the pore-forming (Kir6.2) or regulatory (SUR1) subunit of this channel are a common cause of transient neonatal diabetes mellitus (TNDM), in which diabetes presents shortly after birth but remits within the first few years of life, only to return in later life. The reasons behind this time dependence are unclear. Methods: In an attempt to understand the mechanism behind diabetes remission and relapse, we generated mice expressing the common TNDM mutation SUR1-R1183W. We employed Cre/LoxP technology for both inducible and constitutive expression of SUR1-R1183W specifically in mouse beta-cells, followed by investigation of their phenotype using glucose tolerance tests and insulin secretion from isolated islets.  Results: We found that the R1183W mutation impaired inhibition of KATP channels by ATP when heterologously expressed in human embryonic kidney cells. However, neither induced nor constitutive expression of SUR1-R1183W in mice resulted in changes in blood glucose homeostasis, compared to littermate controls. When challenged with a high fat diet, female mice expressing SUR1-R1183W showed increased weight gain, elevated blood glucose and impaired glycaemic control, but glucose-stimulated insulin secretion from pancreatic islets appeared unchanged. Conclusions: The mouse model of TNDM did not recapitulate the human phenotype. We discuss multiple potential reasons why this might be the case. Based on our findings, we recommend future TNDM mouse models employing a gain-of-function SUR1 mutation should be created using the minimally invasive CRISPR/Cas technology, which avoids many potential pitfalls associated with the Cre/LoxP system.

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