Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes

Eom, Young Sil; Gwon, A-Ryeong; Kwak, Kyung Min; Youn, Jin-Young; Park, Heekyoung; Kim, Kwang-Won; Kim, Byung-Joon

doi:10.4093/dmj.2019.0160

Cited by 8 publications

(11 citation statements)

References 32 publications

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“…Transgenic overexpression of human GXYLT1 was previously shown to impair Notch signaling ( 39 ). Notch signaling pathway is known to play an important role in regulating development of pancreas and also shown to be expressed in adult pancreas ( 40 ). In a recent study, Eom et al ( 40 ) compared glucose levels, insulin secretion, and islet and β-cell masses in Notch1 antisense transgenic (NAS) and control mice after intraperitoneal glucose tolerance test.…”

Section: Discussionmentioning

confidence: 99%

“…Notch signaling pathway is known to play an important role in regulating development of pancreas and also shown to be expressed in adult pancreas ( 40 ). In a recent study, Eom et al ( 40 ) compared glucose levels, insulin secretion, and islet and β-cell masses in Notch1 antisense transgenic (NAS) and control mice after intraperitoneal glucose tolerance test. Higher glucose levels, lower insulin secretion, and decreased total islet and β-cell masses were shown in NAS in comparison with control mice.…”

Section: Discussionmentioning

confidence: 99%

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Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

et al. 2021

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of whom half of them are diagnosed with T2D and the remaining age and sex matched non-diabetic controls identified from general practice records in Tayside, Scotland 1 . Comprehensive electronic medical records history dating back to 1990 including anthropometric, clinical, prescription and biochemistry is available for each participant through a unique anonymised community health index number provided by the Health Informatics Centre (HIC) in partnership with the University of Dundee and the National Health Service (NHS). Previous analysis from the GoDARTS has delivered crucial PGx findings in diabetes and related traits [2][3][4][5][6][7][8][9][10] . The GODARTS study was approved by the Tayside Committee for Medical Research Ethics and written, informed consent was obtained from each participant. In this study, participants diagnosed with type 2 diabetes with sulfonylurea prescription as monotherapy or add on to metformin were included. Subjects with a history of insulin use, diagnosed before 35 years of age and baseline HbA1c <7% or >14 % were removed.PMET1: Pharmacogenomics of Metformin (PMET) cohort 1, was established to study the metformin response of patients with T2D. The participants from the PMET1 cohort were selected from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, a subsample of the Kaiser Permanente Research Program on Genes, Environment, and Health (RPEGH). The criteria for selecting the participants from GERA cohort have been described previously [11][12][13] . A detailed description of the cohort and study design can also be found in dbGAP (dbGaP Study Accession: phs000674.v1.p1). Genotyping of the European ancestry was performed using the methods described previously [14][15][16] . The cohort was imputed using IMPUTE2 and 1000 Genome Phase I. This cohort was used as replication cohort for two metformin pharmacogenomics studies 10,17 . In this genomewide meta-analysis of sulfonylurea response, prescriptions of sulfonylurea added to initial metformin therapy, along with HbA1c levels, dose and adherence were available for genetic association studies. PMET2: Pharmacogenomics of Metformin (PMET) cohort 2, was established to study the metformin response of patients with T2D. The participants from the PMET2 cohort were selected from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPEGH), using the criteria previously established for PMET1. It was established using the research funding from the US National Institute of Health (NIH) grant (R01-GM117163). In this genomewide meta-analysis of sulfonylurea response, prescriptions of sulfonylurea added to initial metformin therapy, along with HbA1c levels, dose and adherence were available for genetic association studies. Genotypes for PMET2 were imputed to HRC.r1-1 EUR reference genome (GRCh37 build) using the Michigan Imputation Server. DCS:The DCS is a population based observational study from the West-Friesland region in the Netherlands established with the aim to improve diabetes care through empow...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

et al. 2021

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“…NOTCH signaling is considered to maintain b-cell mass in the adult pancreas 37 . Eom et al 38 showed that higher glucose levels and lower insulin secretion were observed in NOTCH1 antisense transgenic mice. In addition, the NOTCH1 signaling pathway was suppressed in diabetic rats 36 .…”

Section: Discussionmentioning

confidence: 99%

Micro ribonucleic acid‐363 regulates the phosphatidylinositol 3‐kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus

Peng

Wang

et al. 2021

J of Diabetes Invest

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Aims/Introduction Glucose metabolic disorder is the main cause for type 2 diabetes progression. Exploring the molecular mechanisms of metabolic disorder are crucial for type 2 diabetes treatment. Materials and Methods Micro ribonucleic acid (miR)‐363, NOTCH1 and forkhead box C2 (FOXC2) expressions in high glucose (HG)‐treated HepG2 cells and the livers of type 2 diabetes mellitus rats were assessed using quantitative polymerase chain reaction. Protein levels of NOTCH1, FOXC2 and phosphatidylinositol 3‐kinase (PI3K)/serine/threonine protein kinase (Akt)‐related proteins were evaluated using western blot. Lipid accumulation was determined using Oil Red O staining. Then glucose consumption, blood glucose level and glycogen content were detected using kits. Finally, dual luciferase reporter assay was used to verify the binding relationship between miR‐363 and NOTCH1, and the binding relationship between miR‐363 and FOXC2. Results MiR‐363 was significantly upregulated in the livers of diabetic rats and HG‐induced HepG2 cells, whereas NOTCH1 and FOXC2 were downregulated. In HG‐induced HepG2 cells, miR‐363 inhibitor markedly increased glucose consumption and uptake, and reduced accumulation of lipid droplets. Then NOTCH1 and FOXC2 were identified as downstream targets of miR‐363. NOTCH1 overexpression or FOXC2 overexpression could ameliorate glucose and lipids metabolism disorder in type 2 diabetes model cells. In addition, we found that FOXC2 inhibition abolished the effect of NOTCH1 overexpression on HG‐induced HepG2 cells. Finally, we proved that the PI3K/Akt pathway was the downstream pathway of FOXC2. Conclusion MiR‐363 was considered as a key regulator of glucose and lipids metabolism in type 2 diabetes mellitus, which regulated PI3K/Akt axis by targeting NOTCH1 and FOXC2, thus leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes.

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“…Following these studies, we selected collagenase with neutral protease (called Collagenase AF‐1 GMP grade) and collagenase with thermolysin (called Liberase MTF C/T GMP grade). As control enzymes, Roche Collagenase P was used because of its historical use in porcine and rodent islet isolations 20‐23 …”

Section: Introductionmentioning

confidence: 99%

“…As control enzymes, Roche Collagenase P was used because of its historical use in porcine and rodent islet isolations. 20 , 21 , 22 , 23 …”

Section: Introductionmentioning

confidence: 99%

Comparison of islet isolation result and clinical applicability according to GMP‐grade collagenase enzyme blend in adult porcine islet isolation and culture

Kwak

Park

Shim

et al. 2021

Xenotransplantation

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Background Porcine islet xenotransplantation is a promising treatment for type 1 diabetes as an alternative to human pancreatic islet transplantation and long‐term insulin therapy. Several research groups have explored porcine islets as an alternative to the inconsistent and chronic shortage of pancreases from human organ donors. Studies have confirmed successful transplant of porcine islets into non‐human primate models of diabetes; however, in most cases, they require more than one adult porcine donor to achieve sufficient viable islet mass for sustained function. The importance of GMP‐grade reagents includes the following: specific enzymes utilized in the pancreatic isolation process were identified as a key factor in successful human clinical islet transplantation trials using cadaveric islets. As xenotransplantation clinical research progresses, isolation reagents and digestion enzymes play a key role in the consistency of the product and ultimately the outcome of the islet xenotransplant. In this study, we evaluated several commercially available enzyme blends that have been used for islet isolation. We evaluated their impact on islet isolation yield and subsequent islet function as part of our plan to bring xenotransplantation into clinical xenotransplantation trials. Methods Adult porcine islets were isolated from 16 to 17‐month‐old Yucatan miniature pigs following standard rapid procurement. Pigs weighed on average 48.71 ± 2.85 kg, and the produced pancreases were 39.51 ± 1.80 grams (mean ± SEM). After ductal cannulation, we evaluated both GMP‐grade enzymes (Collagenase AF‐1 GMP grade and Liberase MTF C/T GMP grade) and compared with standard non‐GMP enzyme blend (Collagenase P). Islet quality control assessments including islet yield, islet size (IEQ), membrane integrity (acridine orange/propidium iodide), and functional viability (GSIS) were evaluated in triplicate on day 1 post‐islet isolation culture. Results Islet yield was highest in the group of adult pigs where Collagenase AF‐1 GMP grade was utilized. The mean islet yield was 16 586 ± 1391 IEQ/g vs 8302 ± 986 IEQ/g from pancreases isolated using unpurified crude Collagenase P. The mean islet size was higher in Collagenase AF‐1 GMP grade with neutral protease than in Collagenase P and Liberase MTF C/T GMP grade. We observed no significant difference between the experimental groups, but in vitro islet function after overnight tissue culture was significantly higher in Collagenase AF‐1 GMP grade with neutral protease and Liberase MTF C/T GMP grade than the crude control enzyme group. As expected, the GMP‐grade enzyme has significantly lower endotoxin levels than the crude control enzyme group when measured. Conclusions This study validates the importance of using specifically blended GMP grade for adult pig islet isolation for xenotransplantation trials and the ability to isolate a sufficient number of viable islets from one adult pig to provide a sufficient number for islets for a clinical islet transplantation. GMP‐grade enzymes are highl...

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Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes

Cited by 8 publications

References 32 publications

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

Micro ribonucleic acid‐363 regulates the phosphatidylinositol 3‐kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus

Comparison of islet isolation result and clinical applicability according to GMP‐grade collagenase enzyme blend in adult porcine islet isolation and culture

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