Limei Liu1, Yanjun Liu2, Xiaoxu Ge3, Xipeng Liu4, Chen Chen5, Yanzhong Wang6, Ming Li3, Jun Yin3, Juan Zhang3, Yating Chen3, Rong Zhang3, Yanyan Jiang3, Weijing Zhao3, Di Yang7, Taishan Zheng3, Ming Lu8, Langen Zhuang9, Meisheng Jiang10. 1. Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China. Electronic address: lmliu@sjtu.edu.cn. 2. Department of Internal Medicine, Charles R. Drew University, USA; David Geffen School of Medicine at University of California, USA. 3. Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China. 4. State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong-Chuan Road, Shanghai 200240, China. 5. Department of Molecular Cell and Biology, University of California at Berkeley, USA. 6. School of Population Health and Environmental Science, King's College London, UK. 7. Department of Nutritional Sciences and Toxicology, University of California at Berkeley, USA. 8. Department of Endocrinology & Metabolism, Putuo Hospital Attached to Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai 200000, China. 9. Department of Endocrinology, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China. 10. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Abstract
OBJECTIVE: Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secretion and/or hepatic glycogen synthesis leading to mild chronic hyperglycaemia of maturity onset diabetes of young type 2 (MODY2). However, the effect of naturally occurring GCK mutations on the pathogenesis for MODY2 hyperglycaemia remains largely unclear, especially in the Asian population. The aim of this study is to explore the potential pathogenicity of novel GCK mutations related to MODY2. METHODS: Genetic screening for GCK mutations from 96 classical MODY families was performed, and structure-function characterization and clinical profile of identified GCK mutations were conducted. RESULTS: Five novel (F195S, I211T, V222D, E236G and K458R) and five known (T49N, I159V, R186X, A188T and M381T) mutations were identified and co-segregated with hyperglycaemia in their pedigrees. R186X generates non-functional truncated form and V222D and E236G fully inactivate glucokinase due to severe structure disruptions. The other seven GCK mutations exhibited marked reductions in catalytic efficiency and thermo-stability; notably, the interaction with GKRP was significantly enhanced in I211T, I159V, T49N and K458R, reduced in F195S and M381T, and completely lost with A188T. 31% (17/55) of MODY2 patients showed signs of insulin resistance. Conventional hypoglycaemia treatment did not improve the HbA1C in MODY2 patients when insulin resistance is not present. CONCLUSIONS: Five novel GCK mutations have been identified in Chinese MODY. The defects in enzymatic activity and protein stability, together with alteration of GKRP binding on GCK mutants may synergistically contribute to the development of MODY2 hyperglycaemia. No treatment should be prescribed to MODY2 patients when insulin resistance is not present.
OBJECTIVE: Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secretion and/or hepatic glycogen synthesis leading to mild chronic hyperglycaemia of maturity onset diabetes of young type 2 (MODY2). However, the effect of naturally occurring GCK mutations on the pathogenesis for MODY2 hyperglycaemia remains largely unclear, especially in the Asian population. The aim of this study is to explore the potential pathogenicity of novel GCK mutations related to MODY2. METHODS: Genetic screening for GCK mutations from 96 classical MODY families was performed, and structure-function characterization and clinical profile of identified GCK mutations were conducted. RESULTS: Five novel (F195S, I211T, V222D, E236G and K458R) and five known (T49N, I159V, R186X, A188T and M381T) mutations were identified and co-segregated with hyperglycaemia in their pedigrees. R186X generates non-functional truncated form and V222D and E236G fully inactivate glucokinase due to severe structure disruptions. The other seven GCK mutations exhibited marked reductions in catalytic efficiency and thermo-stability; notably, the interaction with GKRP was significantly enhanced in I211T, I159V, T49N and K458R, reduced in F195S and M381T, and completely lost with A188T. 31% (17/55) of MODY2patients showed signs of insulin resistance. Conventional hypoglycaemia treatment did not improve the HbA1C in MODY2patients when insulin resistance is not present. CONCLUSIONS: Five novel GCK mutations have been identified in Chinese MODY. The defects in enzymatic activity and protein stability, together with alteration of GKRP binding on GCK mutants may synergistically contribute to the development of MODY2 hyperglycaemia. No treatment should be prescribed to MODY2patients when insulin resistance is not present.