Maturity Onset Diabetes of the Young

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Maturity-onset diabetes of the young (MODY) is a group of autosomal dominantly inherited diseases, characterized by impaired insulin secretion with minimal or no defects in insulin action. MODY is recognized clinically as type 2 diabetes occurring generally before the age of 25 in individuals with a BMI <25 kg/m2(144). MODY accounts for the majority of monogenic diabetes cases and 1-5% of all cases of diabetes (227). There are eight syndromes currently described as MODY; however, these eight genes do not appear to account for all cases of clinically diagnosed MODY.

Table 3 MODY Genes

MODY subtype

Gene symbol

Chromosome position

Gene name




Hepatocyte nuclear factor 4, alpha




Glucokinase (hexokinase 4)




Hepatocyte nuclear factor-1 homeobox A




Pancreatic and duodenal homeobox 1




Hepatocyte nuclear factor-1 homeobox B




Neurogenic differentiation factor 1




Kruppel-like factor 11

MODY3 and MODY2 are the two most prevalent forms of MODY. Estimated from a study on 90 MODY families, MODY3 accounts for 63% MODY, and MODY2 accounts for 20% MODY (228). Unlike DM2, patients with MODY are usually nonobese and do not have metabolic syndrome (227). Determining the subtype of MODY is helpful for clinical decision making (229). MODY3 and MODY1 patients are sensitive to sulfonylureas for years before insulin is needed. MODY2 tends to have mild symptoms and often requires only lifestyle interventions. The genetic basis of each subtype of MODY is discussed later (Table 3).

MODY1 is caused by loss-of-function mutations of the HNF4A gene. HNF4A encodes a nuclear transcription factor HNF4-a and regulates expression of many genes in human liver and pancreatic islets, including HNF1A (the MODY3 gene) (230). Acting as a dimer, HNF-4a plays a crucial role in glucose-stimulated insulin secretion, which has been validated in HNF-4a knockout mice, related to the dysfunction of K+-ATP channels (231). Mutated HNF-4a is dominant negative and can not form an active dimer, thus losing its transcriptional activity (232). HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, with the natural history of hyperinsulinemia at birth evolving to decreased insulin secretion and diabetes later in life (233).

MODY2 is caused by loss-of-function mutations of the GCK gene. GCK encodes glucokinase, which catalyzes the phosphorylation of glucose to produce glucose-6-phosphate, and is one of the key enzymes in the regulation of glucolysis and glycogen synthesis. As the rate-limiting enzyme catalyzing the first step and irreversible reaction of glucose metabolism, glucokinase plays a pivotal role as the glucose sensor for b cells (234). Mutations of GCK decrease the sensor function and cause a pancreatic b-cell secretory defect, despite normal insulin synthesis (235). MODY2 mutations are correlated with infant birth weight, and special consideration should be taken in the prenatal care and monitoring. MODY2 mutations in infants can decrease the birth weight by ~530 g because of a reduction of fetal insulin secretion, and MODY2 mutations of mothers can increase the infant birth weight by ~600 g because of fetal hyperinsulinemia in response to maternal hyperglycemia (236). These two effects are additive: an affected infant with an unaffected mother has decreased body weight; an affected infant with an affected mother has normal birth weight; an unaffected infant with an affected mother has increased body weight (236). In addition to described MODY2 mutations, some other mutations in GCK have been associated with severe hypoglycemia and abnormalities in fetal growth (237-240).

MODY3 is the most common type of MODY, caused by loss-of-function mutations of the HNF1A gene (228). The protein HNF1-a encoded by HNF1A is also known as transcription factor 1 (TCF1). HNF1-a regulates expression of many genes in pancreatic islets and liver tissue (230). Although HNF4-a is known to regulate the expression of HNF1-a, HNF1-a plays an essential role in the tissue-specific expression of HNF4-a in pancreatic islets (241). Binding of HNF1-a to a tissue-specific promoter upstream from the HNF4A promoter is required to maintain the HNF4A expression and pancreatic b-cell function (242). Mutant HNF1A causing defective insulin secretion has been validated in a mouse model (243). Like HNF4-a, HNF1-a also acts as a dimer, thus mutated HNF-1a has a dominant-negative effect because of impaired formation of active dimers.

MODY4, caused by a loss-of-function mutation (Glu224Lys) of PDX1, has been described in one family. PDX1 encodes insulin promoter factor 1 (IPF-1), which is needed for islet cell development (244). Homozygosity for the PDX1 mutation caused pancreatic agenesis (245) while the obligatory carrier members of the family had MODY4. In addition, IPF-1 is critical for the maintenance of b-cell function by regulating b-cell-specific gene expression, including insulin (246). The regulation of the tissue-specific expression of HNF4A in the pancreatic islets is an important mechanism whereby PDX1 causes MODY (241).

MODY5 is caused by mutations of HNF1B. Different from other MODYs, MODY5 patients have significant cystic renal disease in addition to diabetes (247, 248). Some MODY5 patients have pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities as well (249). HNF1B encodes a transcription factor HNF1-b, also known as transcription factor 2 (TCF2). It activates transcription of target genes as a homodimer or as a heterodimer with HNF-1-a (250). Besides, HNF1-b can also regulate the expression of HNF1-a (241). Selective knockout of HNF1B in pancreatic islets can cause defective insulin release in a mouse model, indicating that HNF1-b is involved in regulating the b-cell transcription factor network and is necessary for glucose sensing or glycolytic signaling (226). HNF1B mutations were also associated with low birth weight (251, 252) and renal developmental disorders (249).

MODY6 is caused by mutations of NEUROD1. NEUROD1 encodes neurogenic differentiation 1 (NEUROD1), which belongs to the basic helix-loop-helix (bHLH) family of transcription factors, and is a key regulator of pancreatic islet development and insulin gene transcription. The protein forms heterodimers with other bHLH proteins and regulates insulin gene transcription by binding to the E-box motif on the insulin promoter (253). Mutations of NEUROD1 disrupt the DNA-binding domain and abolish the E-box binding activity of the NEUROD1 protein, thus causing MODY6, which is characterized by low serum insulin levels (254).

MODY7 is caused by mutations of the Kruppel-like factor 11 gene (KLF11), a zinc finger transcription factor. KLF11 plays a role in the regulation of pancreatic b-cell physiology. KLF11 binds to the insulin promoter and regulates glucose-induced expression of the insulin gene. Mutations impairing its transcriptional activity cause MODY7 (255).

In summary, all of the seven known MODY genes are involved in defects in insulin secretion from the pancreatic b cell. Besides the monogenic inheritance, the most striking feature of MODY is normal insulin action, which distinguishes it from DM2. Among the seven MODY genes, six genes (HNF4A, HNF1A, PDX1, HNF1B, NEUROD1, and KLF11) are members of the transcription factor network that maintains the pancreatic islet b-cell function; the other gene GCK is a critical enzyme for glucose metabolism and is necessary for glucose sensing or glycolytic signaling. Besides MODY3 and MODY2 (which accounts for ~83% of MODY), the other types of MODY are rare (228). Some cases with clinical manifestations of MODY have not been linked to the known MODY loci. Novel MODY genes remain to be found. A recent study reported that mutations of the carboxyl ester lipase (bile salt-stimulated lipase) gene (CEL) at Chr9q34.3 may be a new type of MODY (MODY8). CEL is excreted by the pancreas and is responsible for the hydrolysis and absorption of cholesterol esters and other dietary esters. Frameshift mutations caused by single-nucleotide deletion can cause defects in the enzyme activity. These patients have both diabetes and exocrine pancreatic dysfunction (256). The pathogenesis of diabetes in MODY8 needs to be clarified by further study. Beside these genes, two missense mutations R46Q and R55C in the INS gene were recently reported to cause MODY by impairing the insulin activity or insulin biosynthesis (257).

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