Glucokinase maturity-onset diabetes of the young (GCK-MODY) represents a distinct subgroup of MODY that does not require hyperglycemia-lowering treatment and has very few diabetes-related complications. Three patients from two families who presented with clinical signs of GCK-MODY were evaluated. Whole-exome sequencing was performed and the effects of the identified mutations were assessed using bioinformatics tools, such as PolyPhen-2, SIFT, and in silico modeling. We identified two mutations: p.Leu30Pro and p.Ser383Leu. In silico analyses predicted that these mutations result in structural conformational changes, protein destabilization, and thermal instability. Our findings may inform future GCK-MODY diagnosis; furthermore, the two mutations detected in two Korean families with GCK-MODY improve our understanding of the genetic basis of the disease.
Computational Biology ; Computer Simulation ; Diabetes Complications ; Diabetes Mellitus, Type 2* ; Diagnosis ; Glucokinase* ; Humans

Congenital hyperinsulinism (CHI), the most important cause of hyperglycemia in early infancy, is a heterogenous disease characterized by dysregulation of insulin secretion. Mutations in five proteins have been associated with CHI: sulfonyl urea receptor 1; Kir 6.2; glucokinase; glutamate dehydrogenase and mitochondrial enzyme short-chain 3-hydroxyacyl-coenzyme A dehydrogenase. Early recognition of hypoglycemia, diagnosis of CHI and appropriate management of the hypoglycemia are of the utmost importance to prevent neurologic damage. We report a case of persistent hyperinsulinemic hypoglycemia in 8-month-old male infant. This patient has no mutation in previously mentioned genes. Treatment with diazoxide was successful without any severe side effects in this patient.
Congenital Hyperinsulinism* ; Diagnosis ; Diazoxide* ; Glucokinase ; Glutamate Dehydrogenase ; Humans ; Hyperglycemia ; Hyperinsulinism ; Hypoglycemia ; Infant ; Insulin ; Male ; Oxidoreductases ; Urea

Diabetes mellitus is a chronic syndrome of abnormal metabolism, determined by interaction of multifactorial genetic and environmental factors. Some specific types of diabetes, such as MODY, Leprechaunism, lipoatrophic diabetes, and Rabson-Mendenhall syndrome, are monogenic forms of diabetes and are inherited as a Mendelian pattern. The article reviews the research development of these Mendelian inherited diabetes will be reviewed.
Diabetes Mellitus, Type 2 ; etiology ; genetics ; Genetic Predisposition to Disease ; Glucokinase ; genetics ; Humans ; Mutation ; genetics

Maturity onset diabetes of the young (MODY) is a monogenic autosomal dominant inherited disease. Its clinical manifestations are asymptomatic with slightly elevated fasting blood glucose and few complications. This paper reports a novel mutation W257R in glucokinase () gene from a Chinese patient with MODY. Heterozygous mutation c.769T>C (p.W257R) in exon 7 of gene (Chr744187343) was found in the proband, her father and brother. This W257R mutation was first reported in Chinese population.
China ; Diabetes Mellitus, Type 2 ; genetics ; Female ; Glucokinase ; genetics ; Humans ; Male ; Mutation ; Pedigree

Maturity-onset diabetes of the young (MODY) is a heterogenous form of diabetes characterized by the early onset of diabetes, autosomal dominant inheritance, and impaired insulin secretion. MODY is mostly caused by mutations of the hepatocyte nuclear factor 1-alpha (HNF1-alpha) and glucokinase genes in Caucasians. However most Korean, Japanese, and Chinese patients with MODY do not express known MODY genes. The cause of MODY in Asians has not yet been elucidated clearly. This review focuses on studies on Asian patients with MODY.
Asian Continental Ancestry Group ; Diabetes Mellitus, Type 2 ; Glucokinase ; Hepatocyte Nuclear Factor 1-alpha ; Humans ; Insulin ; Wills

We studied the anti-diabetic effects of medicinal herb water extracts on expression of hepatic glucokinase (GCK), pyruvate dehydrogenase (PDH), and acetyl-CoA carboxylase (ACC) mRNA. The medicinal herbs used for experiments were Cornus officinalis (CO), Paeonia suffruticosa Andrews (PSA), Discorea japonica Thunb. (DJ), Rehmannia glutinosa (RG), Lycium chinense (LC), and Pyrus pyrifolia (PP). For GCK mRNA expression, CO, RG, and LC water extracts exhibited a more effective activity than other extracts. Cells treated with RG and LC water extracts showed an increase in expression of PDH mRNA to 191% and 124%, respectively, compared to control. Expression of ACC mRNA was significantly higher in LC water extract. These data indicate that CO, RG, and LC water extracts stimulates expression of hepatic GCK, PDH, and ACC mRNA.
Acetyl Coenzyme A ; Acetyl-CoA Carboxylase ; Cornus ; Glucokinase ; Lycium ; Oxidoreductases ; Paeonia ; Plants, Medicinal ; Pyrus ; Pyruvic Acid ; Rehmannia ; RNA, Messenger ; Water

Rhemannie Radix Preparata (RRP) has been previously employed in traditional oriental medicine as a treatment for diabetic thirst and improving blood flow. The aim of this study was to evaluate its hypoglycemic control by assaying the activities of key enzymes of carbohydrate metabolism in streptozotocin-(STZ)-induced diabetic rats. Further, RRP extracts were prepared in water (RRPW), in 50% ethanol (RRP50), and in 100% ethanol (RRP100), respectively, and compared for their actions in diabetic rats. The oral treatment of RRP (5 mg/kg b.w./d) to diabetic rats for 21 days resulted in a significant decline in blood glucose by 67% compared to diabetic control rats (P < 0.05). The altered activities of glucokinase, glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), and acetyl CoA carboxylase (ACC) in the livers of diabetic rats were reversed significantly to near-normal levels by the administration of RRP (P < 0.05). Among the three RRP extracts, RRP100 was the most effective in terms of hypoglycemic action. However, the administration of RRP to diabetic rats did not improve insulin production. The modulatory effects of RRP100 on the attenuation of carbohydrate enzyme activities appear to hold promise for widespread use for the treatment of diabetes in the future.
Acetyl-CoA Carboxylase ; Animals ; Blood Glucose ; Carbohydrate Metabolism ; Ethanol ; Glucokinase ; Gluconates ; Glucosephosphate Dehydrogenase ; Hypoglycemic Agents ; Insulin ; Liver ; Medicine, East Asian Traditional ; Phosphogluconate Dehydrogenase ; Rats ; Thirst ; Water

OBJECTIVES: Mutations in the glucokinase (GCK) gene are considered a possible cause of maturity-onset diabetes of the young. The purpose of this study was to evaluate the contribution of this gene to the development of non insulin dependent diabetes mellitus (NIDDM), gestational diabetes mellitus (GDM) and post-renal transplantation diabetes mellitus (PTDM). METHOD: Identification of GCK mutation was attempted on 39 NIDDM patients, 2 GDM patients and 58 selected renal allograft recipients with PTDM and 45 normal controls. The exons in the GCK gene were examined by polymerase chain reaction (PCR), followed by analysis of single-stranded DNA conformational polymorphism (SSCP). The abnormal bands were also confirmed by DNA sequenc- ing analysis. The exons of affected family members were also investigated for mutations of the GCK gene. RESULTS: Two of the 58 PTDM patients (3.4%) were found to have GCK mutations. One had the mutation on exon 5 and the other on intron 7. One control subject had the mutation on intron 9. The mutation of exon 5 was identified as a substitution of CCT(proline) for CTT (leucine) at codon 164, which has not ever reported before. The family members of the PTDM patient with mutation of exon 5 were analyzed by PCR followed by SSCP, and two of them revealed the same mutation. The abnormal band on the SSCP analysis of exon 7 was identified as the insertion of base C/T at the 39th nucleotide in intron 7. Two family members of this patients also had same band on SSCP. The one mutation of 45 normal controls was CT located at the 8th nucleotide in intron 9, which was a common polymorphism. CONCLUSON: We found GCK mutations in subjects with PTDM and we speculate that these mutations may be one of the contributing cause of PTDM.
Allografts ; Codon ; Diabetes Mellitus ; Diabetes Mellitus, Type 2* ; Diabetes, Gestational ; DNA ; DNA, Single-Stranded ; Exons ; Female ; Glucokinase* ; Humans ; Insulin ; Introns ; Polymerase Chain Reaction ; Polymorphism, Single-Stranded Conformational ; Pregnancy

OBJECTIVETo establish a reliable platform for screening glucokinase activators (GKAs) in vitro.

METHODSPancreatic glucokinase (PGK) protein expressed in a prokaryotic expression system as a histidine-tagged fusion protein from Homo sapiens was produced. Then, response surface methodology (RSM) was used to optimize the microplate-based GKA screening platform. In the first step of optimization with Plackett-Burman design (PBD), initial pH, reaction time and MgCl2 were found to be important factors affecting the activity ratio of GKA (RO-28-1675) significantly. In the second step, a 2(3) full factorial central composite design (CCD) and RSM were applied to the optimal condition determination of each significant variable. A second-order polynomial was determined by a multiple regression analysis of the experimental data.

RESULTSThe following optimal values for the critical factors were obtained: initial pH 0 (7.0), reaction time-0.63 (13.7 min) and MgCl2 0.11 (2.11 mmol/L) with a predicted value of the maximum activity ratio of 34.1%.

CONCLUSIONUnder the optimal conditions, the practical activity ratio is 34.8%. The determination coefficient (R2) is 0.9442, ensuring adequate credibility of the model. LLAE3, extracted from Folium nelumbinis in our laboratory, has prominently activated effects on PGK.

Analysis of Variance ; Drug Discovery ; methods ; Enzyme Activators ; analysis ; Escherichia coli ; genetics ; Genetic Vectors ; Glucokinase ; metabolism ; Humans ; Hydrogen-Ion Concentration ; Hypoglycemic Agents ; analysis ; Kinetics ; Time Factors

Abatacept ; Case-Control Studies ; Chromosomes, Human, Pair 2 ; Diabetes, Gestational ; genetics ; Exons ; Female ; Genetic Predisposition to Disease ; Glucokinase ; genetics ; Humans ; Immunoconjugates ; genetics ; Mutation ; Pregnancy ; Promoter Regions, Genetic