GCK is a glycolytic enzyme that catalyzes the conversion of glucose to glucose-6-phosphate and is referred to as the β-cell glucose sensor because it controls glucose-mediated insulin release. Heterozygous inactivating mutations in GCK cause GCK-MODY, also known as MODY2, which was first recognized in 1992 [9]. A total of 620 mutations in 1,441 families have been identified so far to cause hypoglycemia and hyperglycemia [10]. GCK mutations have been reported throughout the world. In one study of Japanese patients with pediatric-onset MODY-type diabetes, GCK-MODY was reportedly the most common form (approximately 48%) [11]. This proportion was similar to a report in European population [12]. However, only a small proportion (<5%) of MODY cases were caused by GCK-MODY in Korea and China [68].

The clinical disease manifests as mild fasting hyperglycemia (5.5 to 8.0 mmol/L, glycosylated hemoglobin range 5.8% to 7.6%) from birth that demonstrates slight deterioration with age. Patients are usually asymptomatic, so many are first discovered during routine screening such as during pregnancy. Severe hyperglycemia and microvascular complications are rare in GCK diabetes [13]. Clinical features of the Japanese patients with GCK-MODY were similar to those that had been previously reported for Caucasians, although 25% of patients demonstrated signs of insulin resistance [14].

Patients with GCK-MODY do not require treatment outside pregnancy because glucose-lowering therapy is ineffective and there is a lack of long-term complications [15]. In pregnancy, insulin may be required to prevent fetal overgrowth. The fetal growth in pregnancy is dependent on whether the mutation is inherited [16]. Management of pregnant women with GCK-MODY is based on fetal growth scans which are surrogates for fetal genotype.

HNF1A is a homeodomain-containing transcription factor, which is expressed in the liver, kidney, intestine, and pancreatic β-cells. Hnf1a-knockout mice developed diabetes because of impaired glucose-induced insulin secretion [17]. Mutations in HNF1A are the most common cause of MODY in Europe, North America, and Asia [18]. In Asia, 5% to 20% of MODY cases are caused by HNF1A mutations. A total of 414 different HNF1A mutations in 1,247 families have been discovered [19]. Although mutations are located throughout the minimal promoter, exons and flanking intronic regions, they are more often detected in exons 2 and 4. A novel missense mutation (R263L) of HNF1A was found in a Korean MODY family and reportedly caused diabetes through defective glucose sensing and insulin secretion [20].

Heterozygous HNF1A mutations result in progressive β-cell dysfunction that leads to diabetes in early adult life. These mutations demonstrate high penetrance; 63% of carriers develop diabetes by 25 years of age, and almost all carriers develop diabetes by the age of 55 [21]. Carriers develop glycosuria even before diabetes because of decreased renal glucose reabsorption [22]. Because hyperglycemia may be severe and worsens over time, the risks of microvascular and macrovascular complications are similar to type 1 diabetes mellitus (T1DM) and T2DM [23]. Therefore, tight glycemic control and close monitoring for diabetic complications are required in these patients.

Patients with HNF1A-MODY are sensitive to sulfonylurea therapy, which is recommended as first line treatment. An observational study suggests that patients with HNF1A-MODY can be switched safely from insulin to a sulfonylurea [24]. In a series of 43 diabetic patients, 34 switched from insulin to a sulfonylurea after HNF1A-MODY diagnosis, and 24 remained on sulfonylurea for 39 months with excellent glycemic control [25]. Good control may be maintained for many years, although most patients eventually progress to insulin treatment.

This was the first MODY to be described. HNF4A is a transcription factor that is expressed in the liver, intestine, kidney, and pancreatic islets. It is involved in the regulation of genes that are required for glucose transport and metabolism [26]. HNF4A mutations represent less than 10% of MODY cases in Europe, and more than 103 mutations in 173 families have been identified so far [19]. The clinical profile of heterozygous HNF4A mutations is similar to HNF1A MODY. It is estimated that 10% to 29% of HNF1A-negative patients actually have HNF4A mutations [27]. Patients with HNF4A diabetes are seldom diagnosed before adolescence. Heterozygous HNF4A mutations result in significant fetal macrosomia by increasing insulin secretion in utero and subsequent neonatal hypoglycemia [28]. Glycosuria does not present in HNF4A MODY, and low apolipoproteins (apoA11, apoCIII, and apoB) can be a diagnostic clue [29]. A similar response to sulfonylureas has been observed in patients with HNF4A-MODY [27].

PDX1 (also known as insulin promoter factor 1 [IPF1]) is a homeodomain-containing transcription factor that acts in pancreas development and insulin gene expression [30]. Homozygous mutations can cause permanent neonatal diabetes due to pancreas agenesis [31]. Heterozygous PDX1 mutations lead to β-cell dysfunction and MODY. PDX1-MODY is a very rare cause of MODY and was first described in 1997 [32].

HNF1B is encoded by the TCF2 gene, which is expressed in the liver, kidney, intestine, stomach, lung, ovary, and pancreatic islets and influences their embryonic development [33]. This form of diabetes is caused by heterozygous mutations in HNFIB, and is characterized by progressive nondiabetic renal dysfunction of variable severity, pancreatic atrophy and genital abnormalities [343536]. It is also called RCAD (renal cysts and diabetes syndrome). More than 65 mutations have been detected to date. Exon or complete gene deletions account for approximately half of cases [37]. A heterozygous P159L HNF1B mutation in a Korean family reportedly has functional consequences on glucose metabolism [38].

Birth weight can be significantly reduced by 900 g due to reduced insulin secretion in utero [35]. Half of carriers develop diabetes. Spontaneous de novo mutations occur relatively frequently; thus, a positive family history should not be required for diagnosis [39]. HNF1B-MODY phenotypes are different from HNF1A-MODY because diabetes develops due to both insulin resistance and defective insulin secretion. Patients with HNF1B-MODY do not respond well to sulfonylureas and usually require early insulin therapy [40].

NEUROD1 is a basic-loop-helix transcription factor that is involved in pancreatic and neuronal development. Heterozygous NEUROD1 mutations lead to diabetes as children or adults while mutations in both alleles result in neonatal diabetes with neurological abnormalities and learning disabilities [414243].

KLF11 is a zinc-finger transcription factor that is expressed in pancreatic islet cells. KLF11 binds to and activates the insulin promoter in mouse insulinoma cell lines in a high-glucose condition, which indicates that KLF11 is a glucose-inducible regulator of the insulin gene [44]. Two rare variants of KLF11 gene were identified in three families with early onset T2DM [45].

CEL is expressed in mammary glands and pancreatic acinar cells. CEL, also called bile salt-stimulated lipase, is a major component of pancreatic juice and is responsible for the hydrolysis of cholesterol esters as well as a variety of other dietary esters. CEL-MODY was first identified by Raeder et al. [46] in 2 Norwegian kindreds with autosomal dominant diabetes. Heterozygous mutations in the CEL gene result in pancreatic atrophy, fibrosis, and lipomatosis together with exocrine insufficiency and later endocrine dysfunction and diabetes [47].

PAX4 is a transcription factor that is essential for differentiation of insulin-producing β-cells in the mammalian pancreas. PAX4 gene mutations have been identified in Thai probands with MODY who did not have mutations in known MODY genes [48]. It has also been associated with ketosis-prone diabetes [49].

While INS gene mutations are a common cause of neonatal diabetes, they are also rare causes of diabetes in childhood or adulthood [50]. Heterozygous INS gene mutations decrease proinuslin molecule folding or cause β-cell apoptosis in the endoplasmic reticulum [51]. The treatment is generally insulin, although some patients manage with oral antidiabetic drugs.

BLK is a non-receptor tyrosine-kinase of the src family of proto-oncogenes, which acts as a stimulator of insulin synthesis and secretion in pancreatic β-cells via the transcription factors Pdx1 and Nkx6.1 [52]. Kim et al. [53] initially mapped this locus on chromosome 8p23 by a genomewide scan of 21 extended United States families segregating autosomal dominant MODY not caused by known MODY genes. They noted that there was a higher prevalence of obesity in individuals with diabetes that was linked to 8p23 than in diabetic individuals with MODY linked to other loci. Borowiec et al. [52] reported that mutations in BLK caused diabetes in three families.

The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic β-cell ATP-sensitive potassium (K-ATP) channel. Its activating homo- and heterozygous mutations cause neonatal diabetes, but heterozygous mutations can also cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY [54]. The correct molecular diagnosis is important, as these patients can be treated with sulfonylureas.

The KCNJ11 gene encodes Kir6.2, a part of the K-ATP channel. Its activating homozygous mutations cause neonatal diabetes, but heterozygous mutations have been associated with a large spectrum of diabetes phenotypes in a French family [55]. The age at diagnosis varied from childhood to adulthood (13 to 59 years), and the treatment varied from diet to OAD or insulin. Of the 4 affected individuals, 2 maintained diabetes control with sulfonylurea therapy alone. Heterozygous KCNJ11 mutations were identified in Chinese family with early onset T2DM [56].