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Daohua Shi, Tiancheng Xie, Jie Deng, Peiguang Niu, Weizhen Wu
PURPOSE: We intend to investigate the association between tacrolimus-induced new-onset diabetes after transplantation (NODAT) and polymorphisms of CYP3A4, CYP3A5, ATP-binding cassette transporter sub-family C member 8 (ABCC8), and glucokinase (GCK) in renal transplant recipients. METHODS: Polymorphisms of CYP3A4 *18B, CYP3A5 *3, ABCC8 T-3C, and GCK G-30A were genotyped in 169 renal transplant recipients. Trough concentrations of tacrolimus were detected by an ELISA kit...
March 15, 2018: European Journal of Clinical Pharmacology
Naoyuki Kitao, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Kiyohiko Takahashi, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
OBJECTIVE: We investigated whether glucokinase and insulin receptor substrate-2 were required for beta cell proliferation induced by short-term high-fat (HF) diet feeding, as has been shown for long-term HF diet. METHODS: Eight-week-old C57BL/6 J mice were exposed to either a standard chow (SC) or HF diet. After 1 week on the diet, histopathological beta cell proliferation and gene expression in isolated islets were examined. Additionally, 8-week-old beta cell-specific glucokinase haploinsufficient (Gck+/- ) and Irs2 knockout (Irs2-/- ) mice were exposed to either an SC or HF diet...
March 12, 2018: Metabolism: Clinical and Experimental
Xiuzhen Li, Tzer Hwu Ting, Huiying Sheng, Cui Li Liang, Yongxian Shao, Minyan Jiang, Aijing Xu, Yunting Lin, Li Liu
BACKGROUND: There is scarcity of information on the clinical features and genetics of glucokinase-maturity-onset diabetes of the young (GCK-MODY) in China. The aim of the study was to investigate the clinical and molecular characteristics of Chinese children with GCK-MODY. METHODS: Eleven children with asymptomatic hyperglycemia and clinically suspected GCK-MODY were identified from the database of children with diabetes in the biggest children's hospital in South China...
March 6, 2018: BMC Pediatrics
Joanna Yuet-Ling Tung, Kara Boodhansingh, Charles A Stanley, Diva D De León
BACKGROUND: Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited. OBJECTIVE: To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes. DESIGN: Retrospective descriptive study. METHODS: Medical records were reviewed to extract clinical information...
March 1, 2018: Pediatric Diabetes
Emil V R Appel, Ida Moltke, Marit E Jørgensen, Peter Bjerregaard, Allan Linneberg, Oluf Pedersen, Anders Albrechtsen, Torben Hansen, Niels Grarup
We previously showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at discovering novel genetic determinants for glycated hemoglobin (HbA1C ) and at estimating the effect of known HbA1C -associated loci in the Greenlandic population. We analyzed genotype data from 4049 Greenlanders generated using the Illumina Cardio-Metabochip. We performed the discovery association analysis by an additive linear mixed model...
February 26, 2018: European Journal of Human Genetics: EJHG
Santosh L Saraf, Justin R Sysol, Alexandru Susma, Suman Setty, Xu Zhang, Krishnamurthy P Gudehithlu, Jose A L Arruda, Ashok K Singh, Roberto F Machado, Victor R Gordeuk
Homozygosity for the hemoglobin (Hb) S mutation (HbSS, sickle cell anemia) results in hemoglobin polymerization under hypoxic conditions leading to vaso-occlusion and hemolysis. Sickle cell anemia affects 1:500 African Americans and is a strong risk factor for kidney disease, although the mechanisms are not well understood. Heterozygous inheritance (HbAS; sickle cell trait) affects 1:10 African Americans and is associated with an increased risk for kidney disease in some reports. Using transgenic sickle mice, we investigated the histopathologic, ultrastructural, and gene expression differences with the HbS mutation...
February 2, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
Kuo-Ping Shen, Hui-Li Lin, Hsueh-Wei Yen, Su-Ling Hsieh, Li-Mei An, Bin-Nan Wu
This study examined the effects of eugenosedin-A (Eu-A) in a streptozotocin (STZ)/nicotinamide-induced rat model of type II diabetes mellitus (T2DM). Six-week-old Sprague-Dawley rats were randomly divided into three groups: (1) RD group, normal rats fed a regular diet (RD), (2) DM group, T2DM rats fed a high-fat diet, and (3) Eu-A group, T2DM rats fed a high fat diet plus oral Eu-A (5 mg/kg/day). After 30 days, the DM group had higher body weight, higher blood glucose and lower insulin levels than the RD group...
March 2018: Kaohsiung Journal of Medical Sciences
Marc Diedisheim, Masaya Oshima, Olivier Albagli, Charlotte Wennberg Huldt, Ingela Ahlstedt, Maryam Clausen, Suraj Menon, Alexander Aivazidis, Anne-Christine Andreasson, William G Haynes, Piero Marchetti, Lorella Marselli, Mathieu Armanet, Fabrice Chimienti, Raphael Scharfmann
OBJECTIVE: Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D). METHODS: Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets. RESULTS: Fibroblast growth factor 2 (FGF2) treatment reduced expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8, and GCK) and activated ectopic expression of MYC, HES1, SOX9, and NEUROG3...
February 8, 2018: Molecular Metabolism
Laura T Dickens, Rochelle N Naylor
PURPOSE OF REVIEW: Monogenic diabetes accounts for 1-2% of all diabetes cases, but is frequently misdiagnosed as type 1, type 2, or gestational diabetes. Accurate genetic diagnosis directs management, such as no pharmacologic treatment for GCK-MODY, low-dose sulfonylureas for HNF1A-MODY and HNF4A-MODY, and high-dose sulfonylureas for KATP channel-related diabetes. While diabetes treatment is defined for the most common causes of monogenic diabetes, pregnancy poses a challenge to management...
February 15, 2018: Current Diabetes Reports
Hanho Shin, Ji Hye Han, Juhwan Yoon, Hyo Jung Sim, Tae Joo Park, Siyoung Yang, Eun Kyung Lee, Rohit N Kulkarni, Josephine M Egan, Wook Kim
Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse β-cell lines, human islets and CB1R-null (CB1R-/- ) mice, we have now investigated the role of CB1Rs in modulating β-cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP-1-mediated cAMP accumulation and insulin secretion as well as glucose-stimulated insulin secretion in mouse β-cell lines and human islets. In addition, silencing CB1R in mouse β cells resulted in an increased expression of pro-insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in β cells lacking insulin receptor...
February 12, 2018: Journal of Cellular and Molecular Medicine
Shawn Sternisha, Peilu Liu, Alan G Marshall, Brian G Miller
Human glucokinase (GCK) acts as the body's primary glucose sensor and plays a critical role in glucose homeostatic maintenance. Gain-of-function mutations in gck produce hyperactive enzyme variants that cause congenital hyperinsulinism. Prior biochemical and biophysical studies suggest that activated disease variants can be segregated into two mechanistically distinct classes, termed α-type and β-type. Steady-state viscosity variation studies indicate that the kcat values of wild-type GCK and an α-type variant are partially diffusion-limited, whereas the kcat value of a β-type variant is viscosity-independent...
February 9, 2018: Biochemistry
Felipe Pollak C, Marcela Lagos L, José L Santos M, Helena Poggi, Abraham Urzúa C, Hana Rumié C
Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose...
September 2017: Revista Médica de Chile
Davide Basco, Quan Zhang, Albert Salehi, Andrei Tarasov, Wanda Dolci, Pedro Herrera, Ioannis Spiliotis, Xavier Berney, David Tarussio, Patrik Rorsman, Bernard Thorens
Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATP channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels...
February 7, 2018: Nature Communications
Luciana F Franco, Renata Peixoto-Barbosa, Renata P Dotto, José Gilberto H Vieira, Magnus R Dias-da-Silva, Luiz Carlos F Reis, Fernando M A Giuffrida, Andre F Reis
Identification of the correct etiology of diabetes brings important implications for clinical management. In this report, we describe a case of a 4-year old asymptomatic girl with diabetes since age 2, along with several individuals in her family with different etiologies for hyperglycemia identified in youth. Genetic analyses were made by Sanger sequencing, laboratory measurements included HbA1c, lipid profile, fasting C-peptide, pancreatic auto-antibodies (glutamic acid decarboxylase [GAD], Islet Antigen 2 [IA-2], and anti-insulin)...
December 2017: Archives of Endocrinology and Metabolism
Y Wang, X Ding, Z Tan, K Xing, T Yang, Y Wang, D Sun, C Wang
Using the PorcineSNP80 BeadChip, we performed a genome-wide association study for seven reproductive traits, including total number born, number born alive, litter birth weight, average birth weight, gestation length, age at first service and age at first farrowing, in a population of 1207 Large White pigs. In total, we detected 12 genome-wide significant and 41 suggestive significant SNPs associated with six reproductive traits. The proportion of phenotypic variance explained by all significant SNPs for each trait ranged from 4...
February 7, 2018: Animal Genetics
S Ben Khelifa, R Martinez, A Dandana, I Khochtali, S Ferchichi, L Castaño
Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in β-cell function. Mutations in the GCK and HNF1A genes are the most common cause of MODY among Caucasians. The etiology of MODY in Tunisia stills a challenge for researchers. The aim of this study was to screen for mutations in GCK, HNF1A, HNF4A and INS genes in North African Tunisians subjects, in whom the clinical profile was very suggestive of MODY...
February 2, 2018: Gene
Dannielle DeWaal, Veronique Nogueira, Alexander R Terry, Krushna C Patra, Sang-Min Jeon, Grace Guzman, Jennifer Au, Christopher P Long, Maciek R Antoniewicz, Nissim Hay
Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained...
January 31, 2018: Nature Communications
Muniesh Muthaiyan Shanmugam, Prerana Bhan, Hsin-Yi Huang, Jung Hsieh, Tzu-En Hua, Gong-Her Wu, Helly Punjabi, Víctor Daniel Lee Aplícano, Chih-Wei Chen, Oliver Ingvar Wagner
To understand how ciliopathies such as polycystic kidney disease or Bardet-Biedl syndrome develop, we need to understand the basic molecular mechanisms underlying cilia development. Cilia growth depends on a functional intraflagellar transport (IFT) machinery, and we hypothesized that various kinases and phosphatases might be involved in this regulatory process. A candidate screen revealed two kinases PKG-1 (a cGMP-dependent protein kinase) and GCK-2 (a MAP4K3 kinase involved in mTOR signaling) significantly affecting dye filling, chemotaxis, cilia morphology, and IFT component distribution...
January 29, 2018: Molecular and Cellular Biology
Polina V Popova, Alexandra A Klyushina, Lyudmila B Vasilyeva, Alexandra S Tkachuk, Yana A Bolotko, Andrey S Gerasimov, Evgenii A Pustozerov, Ekaterina N Kravchuk, Alexander Predeus, Anna A Kostareva, Elena N Grineva
We hypothesized that the association of certain lifestyle parameters with gestational diabetes mellitus (GDM) risk would depend on susceptibility loci. In total, 278 Russian women with GDM and 179 controls completed questionnaires about lifestyle habits (food consumption, physical activity and smoking). GDM was diagnosed according to the criteria of the International Association of Diabetes and Pregnancy Study Groups. Maternal blood was sampled for genotyping single-nucleotide polymorphisms (SNPs) in MTNR1B (rs10830963 and rs1387153), GCK (rs1799884), KCNJ11 (rs5219), IGF2BP2 (rs4402960), TCF7L2 (rs7903146 and rs12255372), CDKAL1 (rs7754840), IRS1 (rs1801278) and FTO (rs9939609)...
December 19, 2017: Oncotarget
Aisha Al Senani, Nishath Hamza, Hanan Al Azkawi, Manal Al Kharusi, Nashat Al Sukaiti, Maryam Al Badi, Moza Al Yahyai, Matthew Johnson, Elisa De Franco, Sarah Flanagan, Andrew Hattersley, Sian Ellard, Waad-Allah Mula-Abed
BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare disorder worldwide where diabetes is diagnosed in the first 6 months of life. However, Oman has a relatively high incidence of NDM. METHODS: In this study, we investigated the genetic etiologies underlying NDM and their prevalence in Oman. We collected a cohort of 24 NDM patients, with and without genetic diagnosis, referred to our center from 2007 to 2015. All patients without a genetic diagnosis were tested for mutations in 23 NDM-associated genes using a custom-targeted next-generation sequencing (NGS) panel and methylation analysis of the 6q24 locus...
January 26, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
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