MODY2 in Asia: analysis of GCK mutations and clinical characteristics

in Endocrine Connections

Correspondence should be addressed to J Dong or L Liao: cwc_ll@sdu.edu.cn or liaolin@sdu.edu.cn

Aims

Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2.

Methods

We have collected 110 Asian patients with MODY2 from the PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: ‘maturity-onset diabetes of the young’ OR ‘MODY’ OR ‘maturity-onset diabetes of the young type 2’ OR ‘MODY2’ OR ‘GCK-DM’ OR ‘GCK-MODY’. Both mutations of GCK and clinical characteristics of MODY2 were analyzed.

Results

There were 96 different mutations that occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions and missense was the primary mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited mild elevation in FPG (5.4–8.3 mmol/L) and HbA1c (5.6–7.6%), respectively.

Conclusions

In most Asian patients, MODY2 occurred due to GCK mutation in coding regions, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.

Abstract

Aims

Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2.

Methods

We have collected 110 Asian patients with MODY2 from the PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: ‘maturity-onset diabetes of the young’ OR ‘MODY’ OR ‘maturity-onset diabetes of the young type 2’ OR ‘MODY2’ OR ‘GCK-DM’ OR ‘GCK-MODY’. Both mutations of GCK and clinical characteristics of MODY2 were analyzed.

Results

There were 96 different mutations that occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions and missense was the primary mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited mild elevation in FPG (5.4–8.3 mmol/L) and HbA1c (5.6–7.6%), respectively.

Conclusions

In most Asian patients, MODY2 occurred due to GCK mutation in coding regions, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.

Introduction

Currently, diabetes has become a public health problem that has garnered worldwide attention. In addition to the well-known type 1 diabetes (T1D) and type 2 diabetes (T2D), a growing number of special types of diabetes and their gene mutations have been discovered with continuous research.

MODY (maturity-onset diabetes of the young) refers to a heterogeneous group of monogenic forms of diabetes caused primarily by insulin secretion defects (1). It was first described as a single clinical entity in a large family in 1960, and generation familial history suggested that MODY was an early onset mild diabetes (usually before age 25), autosomal dominant inheritance and predominance of insulin deficiency (2). Since the breakthroughs of molecular genetic testing technology from 1990s, relevant studies have recognized that MODY comprises several different clinical syndromes of familial diabetes resulting from specific molecular defects (3). There are 14 genes that have been proven related to MODY, including HNF1A, GCK, HNF4A, HNF1B, ABCC8, and so on (4). In Europe, MODY accounted for 1–2% of the total diabetes population (5), but the exact prevalence of MODY all over the world was not known. Moreover, it was estimated to be responsible for 2 to 5% of cases of non-insulin-dependent diabetes mellitus (6).

Glucokinase (GCK, also named hexokinase IV) belongs to the hexokinase family and plays critical roles in glucose homeostasis (7, 8). The GCK enzyme constitutively expresses and catalyzes the initial rate limiting step in the glycolytic pathway by ATP-dependent phosphorylation of glucose to glucose-6-phosphate in presence of Mg ions (7). Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2 (9). Clinical features of MODY2 include a non-progressive slight increase in glycated hemoglobin (HbA1c), usually between 5.6% and 7.6%, and mildly raised fasting glucose (usually between 5.4–8.3 mmol/L) (10). The current strategy for identifying patients with a potential MODY2 mutation is to combine the clinical characteristics and molecular genetic testing (11, 12, 13).

The correct diagnosis is especially critical for patients with MODY2, because MODY2 patients do not require antihyperglycemic therapy except sometimes during pregnancy (14), and multiple studies have shown that no complications ensue in the absence of glucose-lowering therapy (15). Due to insufficient knowledge of MODY2, it was often misclassified as T1D or T2D and the patients were often treated improperly (16, 17). In this article, we analyzed the clinical characteristics and GCK mutations of Asian MODY2 patients, in order to facilitate the screening and diagnosis of MODY2 in Asia.

Subjects and methods

PubMed, Embase, Medline, Web of Science, the China National Knowledge Infrastructure (CNKI), and Wanfang were searched from the date of their inception to June 30, 2019 without language restrictions. The search strategy was composed of the following search terms: ‘maturity-onset diabetes of the young’ OR ‘MODY’ OR ‘maturity-onset diabetes of the young type 2’ OR ‘MODY2’ OR ‘GCK-DM’ OR ‘GCK-MODY’. All the enrolled studies confirmed with the following criteria: (1) articles aimed at Asian population; (2) the detailed clinical data of probands should have at least accurate FPG; and (3) described the GCK mutations and the patients were confirmed as MODY2 by DNA test. The flow chart showed identification of MODY2 in Asian countries and the reasons for their exclusions (Supplementary Fig. 1, see section on supplementary materials given at the end of this article). The definition of Asia is the continent that is to the east of Europe, the west of the Pacific Ocean, and the north of the Indian Ocean.

The following clinical and laboratory variables were studied: (1) country; (2) gender; (3) age at diagnosis; (4) familial history; (5) diabetes therapy (oral hypoglycemic agents (OHA), insulin, and diet); (6) BMI at recruitment; (7) laboratory test results at diagnosis, including fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2-h PG), fasting insulin (Fins), 2-h postprandial insulin (2-h Ins), hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c). Amino acid substitution and type and position of mutations in the respective gene were recorded. Methods used in the molecular diagnosis of published cases had to be described in detail (see references at Table 1).

Table 1

The detailed information of Asian MODY2 studies.

CountryEnrolled articlesPatientsReference
China1548(18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)
Japan238(33, 34)
Iran11(35)
Turkey219(36, 37)
Korea34(38, 39, 40)

Results

Gene mutations in MODY2

Twenty-three publications describing MODY2 mutations in Asian subjects were found using the aforementioned search terms. These publications dealt with 110 individuals from different families with a clinical profile consistent with MODY2. Of note, all the selected patients were the only proband in the families. They came from unrelated families from Asian countries and were born from non-consanguineous parents. The studies were collected from 5 countries in Asia, 15 of which were in China, accounting for the majority. The number of patients in Japan followed closely behind. The detailed information of enrolled countries and individuals were described in Table 1.

We recorded GCK mutations on each patient such as position of mutation and amino acid substitution. Methods used in the molecular diagnosis were described in detail in the original publications (Table 2). In total, 90 different GCK mutations were identified in coding regions, which included 76 (84.4%) missense, 4 (4.5%) nonsense, 6 (6.7%) deletions, 3 (3.3%) duplicates, and (1.1%) all exon deletion. All of these mutations were predicted to be deleterious, analyzed by online bioinformatics tools. Another six mutations were located outside the coding region involving c.1254-1G > C, c.208 + 3A > T, c.46-2A > G, c.483 + 2 T > A, c.679 + 1G > A, and IVS1B+12A > T. It is worth noting that c.46-2A > G was found in two unrelated families in Turkey, and four types of missense mutations (c.571C>T, c.572G>A, c.617C>G, and c.661 G>A) were found in five, three, three, and two unrelated families, respectively. Moreover, GCK mutations were distributed throughout the exon 1–10. Of note, the largest proportion (20.9%, 23/110) of the mutations was in exon 5, and 17 probands had the mutations in exon 7.

Table 2

GCK mutations of Asian MODY2 patients.

Country

No.

Exon

cDNA

Protein

China17c.749 G > Ap.R250H
22c.127 C > Tp.R43C
37c.781 G > Cp.G261R
47c.661 G > Ap.R221K
57c.771 G > Ap.W257STOP
65c.571 C > Tp.R191W
75c.507 G > Cp.K169N
85c.502 A > Gp.T168A
97c.704 T > Ap.M235T
105,9c.1136C > A + c.571C > Tp.A379E+p.R191W
116c.645 C > Ap.Y215STOP
121c.34 - 4 + 15del26NA
135c.544 G > Ap.V182M
14Intronic 4c.483 + 2 T > A
159c.1121_1132del12p.V374_A377del
164c.451_453delTCCp.S151del
17Intronic 6c.679 + 1G > A
182c.169_170delATinsGp. M57GfsX29
198c.883 G > Ap.G295S
205c.572 G > Ap.R191E
212c.122 T > CP.M41T
226c.661 G > Ap.E221K
237c.771 G > Ap.W257ter
241c.13 G > Cp.V5L
257c.1174 G > Tp.M391R
269c.1190 G > Tp.R397L
275c.485 G > Ap.G162D
282c.128 G > Ap.R43H
296c.676 G > Ap.V226M
3010c. 1348 G > Tp.A450T
313NAp.T82P
329NAp.R377L
332NAp.G44S
347NAp.A259S
352NAp.R43H
367NAp.R250C
372NAp.G44S
389NAp.T354M
394NAp.D135E
409NAp.T354M
414NAp.D135E
428NAp.G318R
435c.556 C > Tp.R186 stop
444c.367-374dupTTCGACTAp.Ile126fs
455c.571 C > Tp.R191W
466c.626 C > Tp.T209M
477c.824 G > Ap.R275H
481IVS1B+12 A > T
Iran498c.1010delAp.*352stop
Turkey502c.151 G > Tp.E51*
5110c.1396 T > Ap.*466R
529c.1148 C > Tp.S383L
53Intronicc.46-2 A > G
543c.214 G > Ap.G72R
555c.508 G > Ap.G170S
564c.368 T > Cp.F123S
577c.823 C > Tp.R275C
582c.173 T > Cp.L58P
595c.572 G > Ap.R191Q
60Intronicc.46-2 A > G
61Intronicc.208 + 3 A > T
629c.1178 T > Cp.M393T
637c.737 G > Cp.G246A
6410c.1256 T > Gp.F419C
65Intronicc.1254-1 G > C
663c.452 C > Gp.S151C
679c.1099 G > Ap.V367M
685c.506 A > Gp.K169R
Japan69All exon deletion
707c.706G > Ap.E236K
716c.617C > Tp.T206M
72All exon deletion
737c.781 G > Ap.G261R
742c.118 G > Ap.E40K
752c.175 C > Tp.P59S
764c.364 C > Tp.L122F
775c.572 G > Ap.R191Q
786c.617 C > Tp.T206M
795c.577 G > Tp.G193W
8010c.1278_1286dupp.S426_R428dup
815c.571 C > Tp.R191W
825c.538 A > Cp.N180H
839c.1232 C > Tp.S411F
846c.617 C > Gp.T206R
854c.437 T > Gp.L146R
862c.76 C > Tp.Q26*
878c.1019 G > Cp.S340T
888c.895 G > Cp.G299R
897c.751 A > Gp.M251V
909c.1055 T > Gp.L352R
918c.898 G > Tp.E300*
925c.571 C > Tp.R191W
937c.835_836 delp.E279Efs*49
945c.571C > Tp.R191W
959c.1144-1149 dupp.C382_S383dup
965c.556 C > Tp.R186*
973c.234 C > Gp.D78E
987c.764 C > Gp.T255S
999c.1142 T > Gp.M381R
1006c.1517 C > Tp.T206M
1012c.130 G > Ap.G44S
1025c.575 G > Ap.R191Q
1032c.182 A > Gp.Y61C
104All exon deletion
1055c.576 G > Tp.G193W
1065c.500 G > Ap.W167X
Korea1079c.1257-20_1315delNA
1082c.92 T > Cp.L30P
1099c.1151 C > Tp.S383P
1105c.191 C > Tp.R191W

Clinical characteristics of MODY2

The gender information of all 110 patients are available in Fig. 1A, of which 67 (60.9%) are male. In 70 families, 57 (81.4%) had a family history of hyperglycaemia (Fig. 1B). BMI or BMI percentiles at diagnosis were available for 103 of the 110 probands. For patients with BMI percentile data, we classified them according to WHO and CDC standards (41). For patients with BMI data, we classified them according to WHO standard (42). The distribution of BMI in Asian MODY2 patients are shown in Fig. 1C. Seventy of them (68%) had normal body weight, which was different from the T1D (low body weight is dominant) or T2D (over body weight is dominant). The group of below normal weight, overweight, and obesity accounted for 19.4%, 7.8%, and 4.8%, respectively. The treatments of 69 probands were provided in the original articles (Fig. 1D) and we found that 59 (85.5%) patients underwent diet therapy before DNA diagnosis. Whereas, nine (13%) probands received insulin or oral hypoglycaemic agents (OHA) and one person (1.5%) was treated with insulin and OHA.

Figure 1
Figure 1

Clinical characteristics of Asian MODY2 patients. (A, B, C, and D) The proportion of several clinical characteristics in enrolled probands: (A) gender, (B) familial history of hyperglycaemia, (C) BMI, and (D) treatment before diagnosis.

Citation: Endocrine Connections 9, 5; 10.1530/EC-20-0074

The clinical data at diagnosis of MODY2 patients are shown in Fig. 2 and Table 3. The age information of all 110 patients is shown in Fig. 2A, and most of the probands (81.8%) were under 25 years of age. HbA1c data (Fig. 2B) were available for 100 of the 110 individuals. HbA1c ranged between 4.6 and 9.3%, and the average HbA1c levels were 6.54 ± 0.65%. The probands with HbA1c between 5.6 and 7.6% account for 93% (93/100). FPG, 2h-PG and 2h-glucose increment were available for 110, 62, and 62 probands, respectively (Fig. 2C). The FPG ranged between 4.55 and 13.66 mmol/L, the value was 6.98 ± 1.17 mmol/L (mean ± s.d.). Ninety percent (99/110) of the probands had the levels of FPG within the range of 5.40–8.30 mmol/L. The levels of 2h-glucose increment in 32 individuals (51.6%) were below <3.00 mmol/L, the levels of 2h-PG in 47 (75.8%) probands were below 11.10 mmol/L. TC and TG in 26 patients and LDL and HDL in 25 patients were also analyzed; however, no significant difference was found.

Figure 2
Figure 2

Whisker plot for continuous clinical data of Asian MODY2 patients. (A, B, and C) Continuous data for the variables of (A) age, (B) HbA1c, (C) FPG, 2h-PG, and 2h-glucose increment.

Citation: Endocrine Connections 9, 5; 10.1530/EC-20-0074

Table 3

Clinical data of Asian MODY2 patients (probands only).

SubjectsNo. of patientsMean ± s.d.
FPG (mmol/L)1106.98 ± 1.17
2h-PG (mmol/L)6210 ± 2.86
2h-glucose increment (mmol/L)622.82 ± 2.03
HbA1c (%)1006.54 ± 0.65
Fins (mIU/L)7810.17 ± 11.19
2-h Ins (mIU/L)1935.16 ± 23.82
TC (mmol/L)264.46 ± 0.88
TG (mmol/L)261.1 ± 0.84
LDL252.39 ± 0.62
HDL251.26 ± 0.37

Discussion

Most studies of MODY2 were conducted in European Caucasians (43). However, the studies of MODY2 in Asia were not much. The reasons for low MODY2 diagnosis might be the following two. First, most of the MODY2 patients do not have obvious symptoms nor signs. Second, some of MODY2 patients are misdiagnosed as having type 1 or type 2 diabetes or impaired fasting glucose (5). Previous reports have shown that MODY2 was the most common form of MODY both in China and Japan when asymptomatic patients were systematically screened (44, 45).

Although one of the characteristics of MODY2 was insidious onset, 81.8% of the MODY2 probands enrolled in our study were under 25 years of age at first diagnosis. Laboratory tests are helpful for early identification of MODY2 patients. Most MODY2 patients exhibited mild elevation in FPG levels and about 90% of patients had FPG values between 5.40–8.30 mmol/L. However, the majority of MODY2 patients did not have postprandial hyperglycemia (75.8% of patients had a level of 2h-PG below 11.10 mmol/L), and the increments of blood glucose were 2.82 ± 2.03 mmol/L during oral glucose tolerance test. Study showed that most of GCK mutations altered the set-point of insulin secretion and that their pancreas could still could secret insulin (46). So, patients with MODY2 do not need hypoglycemic agents treatment (14).

There were 11 MODY2 probands that did not meet the diagnostic criteria of HbA1c (5.6–7.6%) nor FPG (5.40–8.30 mmol/L). The details are as follows: (1) The FPG of one proband (34) was 4.55 mmol/L, and HbA1c was not available. The proband was diagnosed as MODY2 in the original article because of a harmful mutation (c.1517 C > T); (2) The FPG of five probands were 4.60 (33), 8.50 (30), 8.71 (37), 8.90 (23), 8.99 (36) mmol/L, respectively, and it did not meet the criteria of FPG. However, their HbA1c were between 5.6 and 7.6%. All of them were identified mutations and diagnosed as MODY2 in original articles; (3) One proband (18) had FPG 5.20 mmol/L and HbA1c 5.0%; however, the original article mentioned that both the proband and his father had mild raise in glucose. Moreover, both of them had harmful mutations (c.749 G > A); (4) One proband (22) had FPG 12.48 mmol/L and the HbA1c was non-available. The proband and her father were both detected with c.13 G > C mutation. Unfortunately, the original article did not mention whether the proband coexisted with other type of diabetes; (5) One 45-year-old proband (31) with FPG 5.27 mmol/L and HbA1c 9.3%. The proband was injected insulin when he was diagnosed as MODY2; (6) There were two untreated probands (31) (59 and 48 years old) with FPGs 9.80 mmol/L and 13.66 mmol/L and HbA1c 7.8% and 9.2%, respectively. The original article mentioned that the probands in (5) and (6) did not follow the criteria because these probands had a co-existing diagnosis of type 2 diabetes.

Appropriate sequencing method should be cost-effective in order to early diagnose MODY2. The methods of gene screening in enrolled studies included Sanger sequencing, targeted next generation sequencing (NGS) panels, and multiplex ligation-dependent probe amplification (MLPA). Both Sanger sequencing and NGS could detect the potentially causative small nucleotide polymorphisms (SNPs), small insertions/deletions, frameshift mutations, and null mutations (47). They are the common methods in diagnosis of MODY2. MLPA is typically applied to detect large deletion in genes. It is often used where a diagnosis of MODY2 is strongly suspected but no mutation is found by DNA sequencing (48).

Our study has several limitations. First, in order to analyze the characteristics of the MODY2 patients in Asia, the studies without adequate information were excluded. All the probands involved in our article had at least FPG, and patients were diagnosed as MODY2 by DNA tests. We regret that not all Asian countries were shown in the results, such as India which was completely missed. Second, we found that the most common mutations were located at exons 5 and 7 in Asian MODY2 patients. We still need further studies for the purpose of explaining the more precise molecular mechanism of MODY2.

In summary, our study showed that 90% (99/110) and 93% (93/100) of Asian MODY2 probands exhibited mild elevation in FPG (5.4–8.3 mmol/L) and HbA1c (5.6–7.6%). Most probands (81.4%, 57/70) had a family history of hyperglycaemia. We found that 79.2% (76/96) of GCK mutations in Asian patients were missense. We also found that 93.8% (90/96) of GCK mutations were located in the coding region and unevenly distributed along the 10 exons of the gene and that exon 5 (20.9%, 23/110) and exon 7 (15.5%, 17/110) were the most common locations. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EC-20-0074.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was funded by National Natural Science Foundation of China (81670757, 81570742) and the Grant for the Development of Science and Technology of Ji-nan City (201602172).

Author contribution statement

J Dong and L Liao contributed equally to this work.

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    DiaoCSarenTXiaoXSunXMaoLZhangXLiWYuSYuanTLiM Study on hybrid mutation of glucose kinase gene in two countries of MODY2. Chinese Journal of Diabetes 2010 6 405408.

    • Search Google Scholar
    • Export Citation
  • 22

    ZhengTYangZWuSWangSLuHMaXTuYJiaWXiangK. Screen of glucokinase gene in Chinese early-onset and multiple-diabetes population and discovery of a new missense mutation V5L. Chinese Journal of Diabetes 2010 9 660664.

    • Search Google Scholar
    • Export Citation
  • 23

    LeHRenLGuoFQinG. Gene mutation analysis of a type 2 adult-type diabetes mellitus. Henan Medical Research 2015 8 1113.

  • 24

    ZhaoXSuZPanLWangLZhangQZhangLLiuX. A case report of glucocorticoid gene heterozygous mutation in neonates with diabetes and literature review. Chinese Journal of Diabetes 2016 7 652654.

    • Search Google Scholar
    • Export Citation
  • 25

    XiaoFShiLZhangMMaLWangZXieL. A glucocorticoid gene Gly162Asp missense mutation causes adolescent onset of adult type 2 diabetes family report. Chinese Journal of Diabetes 2017 8 680685.

    • Search Google Scholar
    • Export Citation
  • 26

    XiaoF. A family analysis of adult-onset diabetes mellitus (MODY) and literature review. Journal of Practical Gynecologic Endocrinology 2017 9 1617.

    • Search Google Scholar
    • Export Citation
  • 27

    WangLFanHXueJSuYZhangGFengMXueHYangYSongW. Clinical and molecular genetic analysis of a family with type 2 diabetes mellitus in adolescents. Chinese Remedies and Clinics 2017 11 16001603.

    • Search Google Scholar
    • Export Citation
  • 28

    LiYLiYChangY. Discovery of new mutation sites in adult-type diabetes-related genes in adolescents. Basic and Clinical Medicine 2018 4 470474.

    • Search Google Scholar
    • Export Citation
  • 29

    XiaoT. Adolescent Onset Type 2 Diabetes Mellitus (D). Zhejiang, China: Zhejiang University2016.

  • 30

    LiXTingTHShengHLiangCLShaoYJiangMXuALinYLiuL. Genetic and clinical characteristics of Chinese children with glucokinase-maturity-onset diabetes of the young (GCK-MODY). BMC Pediatrics 2018 18 101. (https://doi.org/10.1186/s12887-018-1060-8)

    • Search Google Scholar
    • Export Citation
  • 31

    MaYHanXZhouXLiYGongSZhangSCaiXZhouLLuoYLiM A new clinical screening strategy and prevalence estimation for glucokinase variant-induced diabetes in an adult Chinese population. Genetics in Medicine 2019 21 939947. (https://doi.org/10.1038/s41436-018-0282-3)

    • Search Google Scholar
    • Export Citation
  • 32

    Ping XiaoYHua XuXLan FangYJiangLChenCLiangLLin WangC. GCK mutations in Chinese MODY2 patients: a family pedigree report and review of Chinese literature. Journal of Pediatric Endocrinology and Metabolism 2016 29 959964. (https://doi.org/10.1515/jpem-2015-0354)

    • Search Google Scholar
    • Export Citation
  • 33

    KawakitaRHosokawaYFujimaruRTamagawaNUrakamiTTakasawaKMoriyaKMizunoHMaruoYTakuwaM Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese. Diabetic Medicine 2014 31 13571362. (https://doi.org/10.1111/dme.12487)

    • Search Google Scholar
    • Export Citation
  • 34

    YorifujiTFujimaruRHosokawaYTamagawaNShiozakiMAizuKJinnoKMaruoYNagasakaHTajimaT Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatric Diabetes 2012 13 2632. (https://doi.org/10.1111/j.1399-5448.2011.00827.x)

    • Search Google Scholar
    • Export Citation
  • 35

    NoorianSSayarifardFFarhadiEBarbettiFRezaeiN. GCK mutation in a child with maturity onset diabetes of the young, type 2. Iranian Journal of Pediatrics 2013 23 226228.

    • Search Google Scholar
    • Export Citation
  • 36

    OzdemirTRKirbiyikÖDundarBNAbaciAKayaÖÖCatliGOzyilmazBAcarSKocAGuvencMS Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY). Journal of Pediatric Endocrinology and Metabolism 2018 31 12951304. (https://doi.org/10.1515/jpem-2018-0184)

    • Search Google Scholar
    • Export Citation
  • 37

    HalilogluBHysenajGAtayZGuranTAbaliSTuranSBereketAEllardS. GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey. Clinical Endocrinology 2016 85 393399. (https://doi.org/10.1111/cen.13121)

    • Search Google Scholar
    • Export Citation
  • 38

    ChoYKChoEHChoiHSKimSW. Novel deletion mutation in the glucokinase gene from a Korean man with GCK-MODY phenotype and situs inversus. Diabetes Research and Clinical Practice 2018 143 263266. (https://doi.org/10.1016/j.diabres.2018.07.036)

    • Search Google Scholar
    • Export Citation
  • 39

    ChoEHMinJWChoiSSChoiHSKimSW. Identification of maturity-onset diabetes of the young caused by glucokinase mutations detected using whole-exome sequencing. Endocrinology and Metabolism 2017 32 296301. (https://doi.org/10.3803/EnM.2017.32.2.296)

    • Search Google Scholar
    • Export Citation
  • 40

    HwangJSShinCHYangSWJungSYHuhN. Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients. Diabetes Research and Clinical Practice 2006 74 7581. (https://doi.org/10.1016/j.diabres.2006.03.002)

    • Search Google Scholar
    • Export Citation
  • 41

    PhillipsSMShulmanRJ. Measurement of growth in children. Waltham, MA, USA: UpToDate Inc. (available at: https://www.uptodate.cn/contents/zh-Hans/measurement-of-growth-in-children)

    • Search Google Scholar
    • Export Citation
  • 42

    PerreaultL. Obesity in adults: prevalence, screening, and evaluation. Waltham, MA, USA: UpToDate Inc. (available at https://www.uptodate.cn/contents/zh-Hans/obesity-in-adults-prevalence-screening-and-evaluation)

    • Search Google Scholar
    • Export Citation
  • 43

    ChakeraAJSteeleAMGloynALShepherdMHShieldsBEllardSHattersleyAT. Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care 2015 38 13831392. (https://doi.org/10.2337/dc14-2769)

    • Search Google Scholar
    • Export Citation
  • 44

    ShimadaFMakinoHHashimotoNTairaMSeinoSBellGIKanatsukaAYoshidaS. Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family. Diabetologia 1993 36 433437. (https://doi.org/10.1007/BF00402280)

    • Search Google Scholar
    • Export Citation
  • 45

    XuJYDanQHChanVWatNMTamSTiuSCLeeKFSiuSCTsangMWFungLM Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. European Journal of Human Genetics 2005 13 422427. (https://doi.org/10.1038/sj.ejhg.5201347)

    • Search Google Scholar
    • Export Citation
  • 46

    LuMLiC. Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes. Annals of the New York Academy of Sciences 2018 1411 6582. (https://doi.org/10.1111/nyas.13448)

    • Search Google Scholar
    • Export Citation
  • 47

    ParkSSJangSSAhnCHKimJHJungHSChoYMLeeYAShinCHChaeJHKimJH Identifying pathogenic variants of monogenic diabetes using targeted panel sequencing in an East Asian population. Journal of Clinical Endocrinology and Metabolism 2019 [epub]. (https://doi.org/10.1210/jc.2018-02397)

    • Search Google Scholar
    • Export Citation
  • 48

    KomazecJZdravkovicVSajicSJesicMAndjelkovicMPavlovicSUgrinM. The importance of combined NGS and MLPA genetic tests for differential diagnosis of maturity onset diabetes of the young. Endokrynologia Polska 2019 70 2836. (https://doi.org/10.5603/EP.a2018.0064)

    • Search Google Scholar
    • Export Citation

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  • View in gallery

    Clinical characteristics of Asian MODY2 patients. (A, B, C, and D) The proportion of several clinical characteristics in enrolled probands: (A) gender, (B) familial history of hyperglycaemia, (C) BMI, and (D) treatment before diagnosis.

  • View in gallery

    Whisker plot for continuous clinical data of Asian MODY2 patients. (A, B, and C) Continuous data for the variables of (A) age, (B) HbA1c, (C) FPG, 2h-PG, and 2h-glucose increment.

  • 1

    GiuffridaFMReisAF. Genetic and clinical characteristics of maturity-onset diabetes of the young. Diabetes Obesity and Metabolism 2005 7 318326. (https://doi.org/10.1111/j.1463-1326.2004.00399.x)

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  • 2

    FajansSSConnJW. Tolbutamide-induced improvement in carbohydrate tolerance of young people with mild diabetes mellitus. Diabetes 1960 9 8388. (https://doi.org/10.2337/diab.9.2.83)

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  • 3

    FroguelPVaxillaireMSunFVelhoGZoualiHButelMOLesageSVionnetNClementKFougerousseF. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992 356 162164. (https://doi.org/10.1038/356162a0)

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    DottoRPGiuffridaFMFrancoLMathezALWeinertLSSilveiroSPSaJRReisAFDias-da-SilvaMR. Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations. Diabetes Research and Clinical Practice 2016 116 100104. (https://doi.org/10.1016/j.diabres.2016.04.035)

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  • 5

    FirdousPNissarKAliSGanaiBAShabirUHassanTMasoodiSR. Genetic testing of maturity-onset diabetes of the young current status and future perspectives. Frontiers in Endocrinology 2018 9 253. (https://doi.org/10.3389/fendo.2018.00253)

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    NyuntOWuJYMcGownINHarrisMHuynhTLeongGMCowleyDMCotterillAM. Investigating maturity onset diabetes of the young. Clinical Biochemist: Reviews 2009 30 6774.

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    MatschinskyFLiangYKesavanPWangLFroguelPVelhoGCohenDPermuttMATanizawaYJettonTL. Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. Journal of Clinical Investigation 1993 92 20922098. (https://doi.org/10.1172/JCI116809)

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    MatschinskyFM. Glucokinase, glucose homeostasis, and diabetes mellitus. Current Diabetes Reports 2005 5 171176. (https://doi.org/10.1007/s11892-005-0005-4)

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    BishayRHGreenfieldJR. A review of maturity onset diabetes of the young (MODY) and challenges in the management of glucokinase-MODY. Medical Journal of Australia 2017 207 223. (https://doi.org/10.5694/mja16.01467)

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  • 10

    SteeleAMShieldsBMWensleyKJColcloughKEllardSHattersleyAT. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 2014 311 279286. (https://doi.org/10.1001/jama.2013.283980)

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    SagenJVBjorkhaugLMolnesJRaederHGrevleLSovikOMolvenANjolstadPR. Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry. Pediatric Diabetes 2008 9 442449. (https://doi.org/10.1111/j.1399-5448.2008.00399.x)

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    MurphyREllardSHattersleyAT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nature Clinical Practice: Endocrinology and Metabolism 2008 4 200213. (https://doi.org/10.1038/ncpendmet0778)

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    TimsitJSaint-MartinCDubois-LaforgueDBellanne-ChantelotC. Searching for Maturity-Onset Diabetes of the Young (MODY): when and what for? Canadian Journal of Diabetes 2016 40 455461. (https://doi.org/10.1016/j.jcjd.2015.12.005)

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  • 14

    American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in Diabetes-2020. Diabetes Care 2020 43 (Supplement 1) S14S31. (https://doi.org/10.2337/dc20-S002)

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  • 15

    Rubio-CabezasOHattersleyATNjølstadPRMlynarskiWEllardSWhiteNChiDVCraigME & International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatric Diabetes 2014 15 (Supplement 20) 4764. (https://doi.org/10.1111/pedi.12192)

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  • 16

    ShieldsBMHicksSShepherdMHColcloughKHattersleyATEllardS. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010 53 25042508. (https://doi.org/10.1007/s00125-010-1799-4)

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  • 17

    ShammasCNeocleousVPhelanMMLianLYSkordisNPhylactouLA. A report of 2 new cases of MODY2 and review of the literature: implications in the search for type 2 diabetes drugs. Metabolism: Clinical and Experimental 2013 62 15351542. (https://doi.org/10.1016/j.metabol.2013.06.007)

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  • 18

    LiuY. Application of Next-Generation Sequencing in the Detection of Disease-Causing Genes in Adult-Type Diabetes Mellitus in Chinese Adolescents (D). Beijing, China: Peking Union Medical College2016.

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    • Export Citation
  • 19

    LiXLiuLLiangCShengHZhaoX. Maturity-onset diabetes of the young 2 with a novel mutation of glucokinase gene in a Chinese boy and the clinical follow-up. Zhonghua Er Ke za Zhi: Chinese Journal of Pediatrics 2014 52 867871.

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  • 20

    ZhengTSWuSHYangZLuHJXiangKS. Mutation screening of GCK gene in Chinese early-onset diabetes population. Zhonghua Yixue Yichuanxue Zazhi: Chinese Journal of Medical Genetics 2005 22 671674.

    • Search Google Scholar
    • Export Citation
  • 21

    DiaoCSarenTXiaoXSunXMaoLZhangXLiWYuSYuanTLiM Study on hybrid mutation of glucose kinase gene in two countries of MODY2. Chinese Journal of Diabetes 2010 6 405408.

    • Search Google Scholar
    • Export Citation
  • 22

    ZhengTYangZWuSWangSLuHMaXTuYJiaWXiangK. Screen of glucokinase gene in Chinese early-onset and multiple-diabetes population and discovery of a new missense mutation V5L. Chinese Journal of Diabetes 2010 9 660664.

    • Search Google Scholar
    • Export Citation
  • 23

    LeHRenLGuoFQinG. Gene mutation analysis of a type 2 adult-type diabetes mellitus. Henan Medical Research 2015 8 1113.

  • 24

    ZhaoXSuZPanLWangLZhangQZhangLLiuX. A case report of glucocorticoid gene heterozygous mutation in neonates with diabetes and literature review. Chinese Journal of Diabetes 2016 7 652654.

    • Search Google Scholar
    • Export Citation
  • 25

    XiaoFShiLZhangMMaLWangZXieL. A glucocorticoid gene Gly162Asp missense mutation causes adolescent onset of adult type 2 diabetes family report. Chinese Journal of Diabetes 2017 8 680685.

    • Search Google Scholar
    • Export Citation
  • 26

    XiaoF. A family analysis of adult-onset diabetes mellitus (MODY) and literature review. Journal of Practical Gynecologic Endocrinology 2017 9 1617.

    • Search Google Scholar
    • Export Citation
  • 27

    WangLFanHXueJSuYZhangGFengMXueHYangYSongW. Clinical and molecular genetic analysis of a family with type 2 diabetes mellitus in adolescents. Chinese Remedies and Clinics 2017 11 16001603.

    • Search Google Scholar
    • Export Citation
  • 28

    LiYLiYChangY. Discovery of new mutation sites in adult-type diabetes-related genes in adolescents. Basic and Clinical Medicine 2018 4 470474.

    • Search Google Scholar
    • Export Citation
  • 29

    XiaoT. Adolescent Onset Type 2 Diabetes Mellitus (D). Zhejiang, China: Zhejiang University2016.

  • 30

    LiXTingTHShengHLiangCLShaoYJiangMXuALinYLiuL. Genetic and clinical characteristics of Chinese children with glucokinase-maturity-onset diabetes of the young (GCK-MODY). BMC Pediatrics 2018 18 101. (https://doi.org/10.1186/s12887-018-1060-8)

    • Search Google Scholar
    • Export Citation
  • 31

    MaYHanXZhouXLiYGongSZhangSCaiXZhouLLuoYLiM A new clinical screening strategy and prevalence estimation for glucokinase variant-induced diabetes in an adult Chinese population. Genetics in Medicine 2019 21 939947. (https://doi.org/10.1038/s41436-018-0282-3)

    • Search Google Scholar
    • Export Citation
  • 32

    Ping XiaoYHua XuXLan FangYJiangLChenCLiangLLin WangC. GCK mutations in Chinese MODY2 patients: a family pedigree report and review of Chinese literature. Journal of Pediatric Endocrinology and Metabolism 2016 29 959964. (https://doi.org/10.1515/jpem-2015-0354)

    • Search Google Scholar
    • Export Citation
  • 33

    KawakitaRHosokawaYFujimaruRTamagawaNUrakamiTTakasawaKMoriyaKMizunoHMaruoYTakuwaM Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese. Diabetic Medicine 2014 31 13571362. (https://doi.org/10.1111/dme.12487)

    • Search Google Scholar
    • Export Citation
  • 34

    YorifujiTFujimaruRHosokawaYTamagawaNShiozakiMAizuKJinnoKMaruoYNagasakaHTajimaT Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatric Diabetes 2012 13 2632. (https://doi.org/10.1111/j.1399-5448.2011.00827.x)

    • Search Google Scholar
    • Export Citation
  • 35

    NoorianSSayarifardFFarhadiEBarbettiFRezaeiN. GCK mutation in a child with maturity onset diabetes of the young, type 2. Iranian Journal of Pediatrics 2013 23 226228.

    • Search Google Scholar
    • Export Citation
  • 36

    OzdemirTRKirbiyikÖDundarBNAbaciAKayaÖÖCatliGOzyilmazBAcarSKocAGuvencMS Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY). Journal of Pediatric Endocrinology and Metabolism 2018 31 12951304. (https://doi.org/10.1515/jpem-2018-0184)

    • Search Google Scholar
    • Export Citation
  • 37

    HalilogluBHysenajGAtayZGuranTAbaliSTuranSBereketAEllardS. GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey. Clinical Endocrinology 2016 85 393399. (https://doi.org/10.1111/cen.13121)

    • Search Google Scholar
    • Export Citation
  • 38

    ChoYKChoEHChoiHSKimSW. Novel deletion mutation in the glucokinase gene from a Korean man with GCK-MODY phenotype and situs inversus. Diabetes Research and Clinical Practice 2018 143 263266. (https://doi.org/10.1016/j.diabres.2018.07.036)

    • Search Google Scholar
    • Export Citation
  • 39

    ChoEHMinJWChoiSSChoiHSKimSW. Identification of maturity-onset diabetes of the young caused by glucokinase mutations detected using whole-exome sequencing. Endocrinology and Metabolism 2017 32 296301. (https://doi.org/10.3803/EnM.2017.32.2.296)

    • Search Google Scholar
    • Export Citation
  • 40

    HwangJSShinCHYangSWJungSYHuhN. Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients. Diabetes Research and Clinical Practice 2006 74 7581. (https://doi.org/10.1016/j.diabres.2006.03.002)

    • Search Google Scholar
    • Export Citation
  • 41

    PhillipsSMShulmanRJ. Measurement of growth in children. Waltham, MA, USA: UpToDate Inc. (available at: https://www.uptodate.cn/contents/zh-Hans/measurement-of-growth-in-children)

    • Search Google Scholar
    • Export Citation
  • 42

    PerreaultL. Obesity in adults: prevalence, screening, and evaluation. Waltham, MA, USA: UpToDate Inc. (available at https://www.uptodate.cn/contents/zh-Hans/obesity-in-adults-prevalence-screening-and-evaluation)

    • Search Google Scholar
    • Export Citation
  • 43

    ChakeraAJSteeleAMGloynALShepherdMHShieldsBEllardSHattersleyAT. Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care 2015 38 13831392. (https://doi.org/10.2337/dc14-2769)

    • Search Google Scholar
    • Export Citation
  • 44

    ShimadaFMakinoHHashimotoNTairaMSeinoSBellGIKanatsukaAYoshidaS. Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family. Diabetologia 1993 36 433437. (https://doi.org/10.1007/BF00402280)

    • Search Google Scholar
    • Export Citation
  • 45

    XuJYDanQHChanVWatNMTamSTiuSCLeeKFSiuSCTsangMWFungLM Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. European Journal of Human Genetics 2005 13 422427. (https://doi.org/10.1038/sj.ejhg.5201347)

    • Search Google Scholar
    • Export Citation
  • 46

    LuMLiC. Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes. Annals of the New York Academy of Sciences 2018 1411 6582. (https://doi.org/10.1111/nyas.13448)

    • Search Google Scholar
    • Export Citation
  • 47

    ParkSSJangSSAhnCHKimJHJungHSChoYMLeeYAShinCHChaeJHKimJH Identifying pathogenic variants of monogenic diabetes using targeted panel sequencing in an East Asian population. Journal of Clinical Endocrinology and Metabolism 2019 [epub]. (https://doi.org/10.1210/jc.2018-02397)

    • Search Google Scholar
    • Export Citation
  • 48

    KomazecJZdravkovicVSajicSJesicMAndjelkovicMPavlovicSUgrinM. The importance of combined NGS and MLPA genetic tests for differential diagnosis of maturity onset diabetes of the young. Endokrynologia Polska 2019 70 2836. (https://doi.org/10.5603/EP.a2018.0064)

    • Search Google Scholar
    • Export Citation