Maturity-Onset Diabetes Of The Young Essay
Maturity onset diabetes of the young or MODY is a family of mutations that are inherited autosomal dominant. There are already two well known types of Diabetes, Type 1 and Type 2. These two types involve, Type 1, the inability to produce insulin within the pancreas or, Type 2, the body rejects the insulin that the body makes. The inability to regulate the glucose leads to hyperglycemia which has many other adverse effects on the body, such as poor circulation and kidney damage (Froguel et al. 1992). In the 1970s these two types of diabetes were known and beginning to be better understood, although there was another disease that had similar symptoms and characteristics to diabetes had begun to arise (Tattersall 1998). To better understand the cause of this disease Fajans and Tattersall compiled a group of families with similar symptoms and began to test for genetic correlations between family members (Tattersall et al. 1975). Their findings allowed the discovery of the gene being heritable and lead to the next steps to identify this gene (Tattersall et al. 1975).Maturity-Onset Diabetes Of The Young Essay
The symptoms of MODY Type 2 are similar to that of a diabetic individual with frequent urination, elevated thirst, and possible weight loss. There are no physical abnormalities caused by this disease as it mostly affects the pancreas and the regulation of glucose. Excess high blood glucose over an extended period of time may lead to kidney damage that may result in an amputation (Froguel et al. 1992). Obesity may lead to an earlier onset of the disease. MODY Type 2 has a mutation in which the Glucokinase, GCK, enzyme is inactivated (Inoue et al. 2004) This mutation is linked to a single base pair mutation of GCK enzyme which is an enzyme that phosphorylates glucose
Maturity-onset diabetes of the young (MODY) was first reported in 1974 as mild familial diabetes with dominant inheritance.1 Classically, MODY was characterized by autosomal dominant inheritance, onset before 45 years of age, the absence of β-cell autoimmunity,2 absence of insulin resistance,3 and sustained β-cell function. However, the new diagnostic criteria set forth in the Practice Guideline for MODY in 20084 include onset before 25 years of age in one family member, presence of diabetes in two consecutive generations, absence of β-cell autoantibodies, and sustained endogenous insulin secretion. Preserved β-cell function is indicated by the lack of need for insulin treatment or a serum C-peptide level of >200 pmol/L even after 3 years of insulin treatment.4 Maturity-Onset Diabetes Of The Young Essay
Molecular methods for the diagnosis of MODY were first introduced after the 1990s. To date, mutations associated with MODY have been reported in least 14 different genes,5–14 including the following six genes encoding major factors: hepatocyte nuclear factor (HNF) 4α (HNF4α), glucokinase (GCK), HNF1α (HNF1α), pancreatic and duodenal homeobox 1 (PDX1), HNF1β (HNF1β), and neurogenic differentiation 1 (NEUROD1), which correspond to MODY subtypes 1–6, respectively. The following eight genes have been identified as possibly causative in MODY subtypes 7–14, respectively: Kruppel-like factor 11 (KLF11); carboxyl ester lipase; paired-box-containing gene 4 (PAX4); insulin (INS); B-lymphocyte kinase; adenosine triphosphate (ATP)-binding cassette, sub-family C (CFTR/MRP) member 8 (ABCC8); potassium channel, inwardly rectifying subfamily J, member 11 (KCNJ11); and adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1 (APPL1).11,12 The causative genes for MODY and their medical conditions are shown in Table 1.
Table 1 The causative genes for maturity-onset diabetes of the young (MODY) and medical conditions associated with each MODY subtype Maturity-Onset Diabetes Of The Young Essay
MODY is a rare condition, accounting for 1–5% of all cases of diabetes12,13 and 1–6% of pediatric cases of diabetes.14 Mutations in GCK, HNF1α, HNF4α, and HNF1β are the most frequently identified etiologies of MODY and, respectively, account for 32%, 52%, 10%, and 6% of all affected patients in the United Kingdom.11 However, the frequencies of these etiologies may differ among Asian and Caucasian populations. In Japan, 48.1% of pediatric cases of clinical MODY harbored already known MODY-related gene defects (GCK, 22.8%; HNF1A, 13.9%; HNF4A, 3.8%, and HNF1B, 7.6%), whereas in 51.9% cases, the causative mutations were not identified15 In Korea, only 10% of clinical MODY or childhood-onset type 2 diabetes cases harbored known MODY-related gene defects (GCK, 2.5%; HNF1A, 5%, and HNF1B, 2.5%)16 These data suggest that currently unidentified genes may cause MODY in Asian populations. The causative genes for MODY and their medical conditions are shown in Table 1.
To improve the prognosis of MODY, it is important to identify the affected subjects as early as possible. To this end, specific molecular analyses are available to predict the clinical disease course and offer the most appropriate treatment.14 However, approximately 80% of patients with MODY may be misdiagnosed with type 1 or type 2 diabetes mellitus at diagnosis,17 and current calculations indicate a delay of approximately 15 years from the diagnosis of diabetes to the genetic diagnosis of MODY.17
This review discusses the current perspectives on the diagnosis and treatment of MODY, in particular, the six major subtypes (MODY 1–6).
Diagnosis of MODY
At diagnosis, MODY cannot be distinguished easily from type 1 and type 2 diabetes mellitus based on clinical characteristics.13,14 Rather, type 1 diabetes mostly differs from MODY in terms of disease etiology, as the pathogenesis of the latter does not involve pancreatic β-cell autoimmunity. Patients with MODY usually maintain β-cell function, exhibit a stimulated serum C-peptide level exceeding 200 pmol/L, and their diabetes is well-controlled with no or low-dose insulin for at least 5 years after diagnosis.14 Although the clinical manifestations of youth-onset type 2 diabetes substantially resemble those of MODY, patients with the former condition are generally obese, whereas the latter condition is not associated with overweight.Maturity-Onset Diabetes Of The Young Essay Still, approximately 10–15% of Japanese school children with type 2 diabetes are non-obese.18,19 Additionally, some patients with MODY, particularly those belonging to ethnic groups with a higher prevalence of obesity (eg, Hispanic), may become overweight or obese due to poor dietary habits and sedentary lifestyles. Furthermore, both MODY and type 2 diabetes are associated with a strong family history of diabetes. For example, studies revealed that approximately 70% of Japanese school children with type 2 diabetes had a family history of type 2 diabetes among first- and second-degree relatives. Those with nonobese type 2 diabetes had a particularly strong family background of the disease.18,19 Therefore, the correct diagnosis of MODY and determination of subtype should be based on genetic testing. Candidates for genetic testing include nonobese subjects with hyperglycemia, no evidence of β-cell autoimmunity, preserved β-cell function, and a strong family history of a similar type of diabetes among the first-degree relatives.Maturity-Onset Diabetes Of The Young Essay
Currently, genetic testing is performed worldwide to facilitate predictions of the clinical course and prognosis of MODY. Known MODY-related genes can be identified by direct sequencing with sensitivity rates as high as 100%,14 and next-generation sequencing methods (eg, gene-targeted and whole-exome sequencing) have been successfully used to identify mutations in MODY genes.16 However, genetic testing remains expensive and is necessarily limited to cases of strongly suspected MODY. These patients should be offered the most suitable treatment from among various pharmacological therapies, including oral antidiabetic drugs (OADs) and insulin.Maturity-Onset Diabetes Of The Young Essay
Diagnosis of the subtypes of MODY
sAs shown in Table 1, at least 14 MODY subtypes have been reported, of which 1–6 are the major subtypes. As noted above, eight other subtypes have been identified, including MODY 14, which was recently associated with the causative gene APPL1 in large families.20 Most MODY-causative genes, except GCK, encode transcription factors expressed in pancreatic β-cells (Figure 1). MODY subtype determination is important, as the subtypes differ in terms of the age of onset, clinical course and progression, type of hyperglycemia, and response to treatment.14 Most patients with MODY exhibit the clinical characteristics of isolated diabetes or mild fasting hyperglycemia. However, some MODY subtypes are associated with additional manifestations, such as renal abnormalities (MODY5) or pancreatic exocrine dysfunction (MODY8). This review mainly describes the clinical characteristics of the six major subtypes of MODY.Maturity-Onset Diabetes Of The Young Essay
Figure 1 Expression of maturity-onset diabetes of the young (MODY)-causative genes in pancreatic β-cells and mechanism of insulin secretion. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine 3ʹ,5ʹ-monophosphate; PKA, protein kinase A; Epac, exchange protein directly activated by cAMP; KATP channel, ATP-sensitive potassium channel; VDCC, voltage-dependent calcium channel; GCK, glucokinase; HNF4α, hepatocyte nuclear factor 4α; HNF1α, hepatocyte nuclear factor 1α; PDX1, pancreatic and duodenal homeobox 1; HNF1β, hepatocyte nuclear factor 1β; NEUROD1, neurogenic differentiation 1.
GCK, a glucose sensor expressed in pancreatic β-cells, is a key enzyme in glucose metabolism that catalyzes the conversion of glucose to glucose-6-phosphate and thus controls glucose-mediated insulin secretion. More than 600 mutations in GCK have been identified in >1,000 families, and these alterations lead to both hyperglycemia and hypoglycemia.21 Heterozygous inactive mutations are associated with mild and often subclinical hyperglycemia from birth, and this condition gradually deteriorates with age11 Essentially, these mutations elevate the glucose threshold for insulin secretion, resulting in an elevated fasting plasma glucose level (5.5–8 mmol/L). Such patients exhibit a slight increase in the 2-hr plasma glucose level during oral glucose tolerance testing (OGTT; increase in 4.5 mmol/L = 90th percentile).4,22 These patients usually have a HbA1c level of <64 mmol/mol.23 Maturity-Onset Diabetes Of The Young Essay
Patients with MODY2 are usually asymptomatic. The majority are discovered through routine examinations during pregnancy or school-based urine glucose screening tests. MODY2 presents in approximately 2–6% of patients with gestational diabetes and can be distinguished based on clinical manifestations and the fasting glucose level.24,25 The birth weights of babies in MODY2 families depend on the mutation statuses of both the fetus and mother. If both harbor a GCK mutation, a maternal increase in plasma glucose will induce an appropriate insulin release in the fetus and a normal birth weight. However, if only the mother harbors the GCK mutation, maternal hyperglycemia will elicit increased fetal insulin secretion and a birth weight approximately 500 g higher than that of a baby who harbors the mutation.26 In Japan, Yorifuji et al reported that 22.8% of patients in whom MODY was detected through school urine glucose screening programs were finally diagnosed with MODY2 through genetic testing. Accordingly, MODY2 is most frequent subtype in Japanese children.15 The clinical course of this subtype may be mild and nonprogressive, and microvascular and macrovascular complications rarely occur despite long-term exposure to mild hyperglycemia.26,27
MODY 3 (HNF1α-MODY)
The transcription factor HNF1α is expressed in the liver, kidney, intestine and pancreatic β-cells. HNF1a knockout mice develop diabetes consequent to defective glucose-induced insulin secretion.28,29 Mutations in HNF1a are the most frequent causes of MODY in Europe, North America, and some Asian countries.11,14,16 In Japan, mutations in HNF1 a were detected in 13.9% of patients with clinical MODY.15 Studies of approximately 1200 families have identified >400 different HNF1a mutations,30 of which a mutation (P291fsinsC) in exon 4 is most common.31 Heterozygous mutations of HNF1a cause a progressive insulin deficiency that manifests as mild hyperglycemia in childhood and as diabetes during early adulthood.15,32 MODY3 is rarely discovered in children younger than 8 years of age.15 Maturity-Onset Diabetes Of The Young Essay
Hyperglycemia associated with MODY3 may be progressive and deteriorating. In these patients, the risks of microvascular and macrovascular complications are similar to those observed in patients with type 1 and type 2 diabetes.33 Interestingly, HNF1a mutation carriers develop postprandial glycosuria before the onset of diabetes due to renal tubular dysfunction and a consequently low renal threshold for glucose absorption.34 In the fetus, HNF1a mutational heterozygosity does not influence the birth weight because insulin secretion in utero remains normal.35
The transcription factor HNF4α is expressed primarily in the liver but also in the pancreas and kidney,36 where it regulates the expression of genes required for glucose transport and metabolism. Mutations in HNF4α are relatively uncommon, accounting for approximately 5% of all MODY cases. Phenotypically, MODY1 due to heterozygous HNF4α mutation manifests as progressive insulin deficiency, similar to that observed in MODY3. Fetal HNF4α heterozygosity results in macrosomia due to hyperinsulinemia in utero and subsequent neonatal transient or persistent hypoglycemia, which is responsive to diazoxide.37 Glycosuria is not observed in MODY1, in contrast to MODY3. Hyperinsulinism associated with MODY1 generally remits during infancy, followed by a gradual decrease in endogenous insulin production and the emergence of diabetes in adolescence.14 Moreover, HNF4α has been associated with triglyceride metabolism, and mutation carriers may exhibit reduced levels of apolipoproteins (apoAII, apoCIII, and apoB).38 Maturity-Onset Diabetes Of The Young Essay
The transcription factor HNF1β is involved in the organogenesis of the kidney, genito-urinary tract, liver, lungs, gut, and pancreas.39 Accordingly, renal malformations, including renal cysts, renal dysplasia, urinary tract malformation, and hypoplastic glomerulonephritic kidney disease,40 are seen in the majority of HNF1β mutation carriers and constitute the main presentation of MODY5 in children, regardless of the hyperglycemia status14 HNF1β mutation also causes renal cysts and diabetes syndrome, and these renal abnormalities are evident from the 17th week of gestation.41 Affected patients will develop renal dysfunction by 45 years of age, and half of these patients will progress to end-stage renal disease without developing diabetic kidney disease.42 Accordingly, MODY5 should be suspected in patients with diabetes and nondiabetic renal disease. Genito-urinary tract malformations (especially uterine abnormalities), liver dysfunction, and pancreatic hypoplasia have also been reported.43 Although diabetes associated with MODY5 develops in early adulthood, carriers of HNF1β mutations have significantly reduced birth weights.44 Phenotypically, MODY5 differs from MODY3. Patients with MODY5 present with dyslipidemia, including a low high-density lipoprotein level and elevated triglyceride level. Diabetes develops during adolescence or early adulthood and usually progresses to an insulin-dependent state due to pancreatic hypoplasia, with hepatic insulin resistance, relatively earlier period of the disease.11,14 Patients harboring HNF1β mutations exhibit highly variable phenotype and clinical manifestations even within affected families. Accordingly, the diagnosis of MODY5 should be made in consultation with not only diabetes specialists but also other specialists, such as nephrologists, gynecologists, and urologists.14 Maturity-Onset Diabetes Of The Young Essay
PDX1 is a homeodomain-containing transcription factor that acts in both the exocrine and endocrine pancreatic developmental programs and affects pancreatic development and INS expression.45 Homozygous mutations in PDX1 cause pancreas agenesis and hypoplasia and permanent neonatal diabetes,46 whereas heterozygous mutations lead to β-cell impairment and hyperglycemia, including permanent neonatal diabetes. MODY4 is a very rare subtype.
NEUROD1 is a basic-loop-helix transcription factor involved in pancreatic and neuronal development. It plays an important role in pancreatic β-cell maturation and maintenance. Islets lacking NEUROD1 respond poorly to glucose and show a glucose metabolic profile similar to immature β-cells. Heterozygous mutations in NEUROD1 induce childhood- or adult-onset diabetes, while homozygous mutations can cause neonatal diabetes, neurological abnormalities, and learning difficulties.47–49 Maturity-Onset Diabetes Of The Young Essay
The ages of onset, degrees of hyperglycemia, involvement of special tissues, and clinical features of other subtypes of MODY are shown in Table 1.
How can be MODY diagnosed correctly?
Cases of MODY are often misdiagnosed as type 1 or type 2 diabetes at presentation.13,14,19 Accordingly, an improvement in diagnostic significance will require targeted selection of subjects for genetic testing, particularly in scenarios with limited resources. Various algorithms have been proposed to select candidates for genetic testing.13,50 According to a recent diagnostic criteria,4 MODY is characterized by onset before 25 years of age, presence of diabetes in two consecutive family generations, absence of β-cell autoantibodies, and preserved endogenous insulin secretion with a serum C-peptide level of >200 pmol/L. These diagnostic criteria have been well accepted for distinguishing MODY from type 1 and type 2 diabetes. Shields et al.50 further proposed a model in which an age younger than 30 years at diagnosis was the most useful discriminator between MODY and type 2 diabetes. In that model, a family background of diabetes increased the probability of diagnosis of MODY by 23 times among patients who were first diagnosed with type 1 diabetes.51 Maturity-Onset Diabetes Of The Young Essay
The costs and limitations of genetic testing have encouraged the discovery of nongenetic biomarkers that might be used to identify appropriate subjects for molecular diagnosis. For example, high-sensitivity C-reactive protein (hs-CRP) may be a useful biomarker in the differential diagnosis of MODY3, as affected patients have a significantly lower level of hs-CRP than those with type 1 or type 2 diabetes or MODY2.52–54 A recent study suggested that microRNAs may be useful biomarkers in carriers of MODY3-related gene mutations.55 However, some causative genes for MODY subtypes have also been associated with other forms of diabetes. KCNJ11, ABCC8, PDX1, PAX4, and NEUROD1 have been associated with permanent neonatal diabetes and type 2 diabetes, while INS is associated with both type 1 and type 2 diabetes.56,57 Moreover, variants of HNF1α, HNF4α, HNF1β, and GCK might be associated with an increased risk of type 2 diabetes.57 It is often difficult to differentiate between an incompletely penetrant MODY mutation and a rare variant of type 2 diabetes, and such distinction may be a matter of semantics.58,59 Therefore, genetic testing is not sufficient to confirm a diagnosis of MODY, which should also include clinical observation, laboratory testing (serum C-peptide, β-cell autoantibodies, and specific biomarkers). Figure 2 presents a diagnostic algorithm used to identify candidates with diabetes who should undergo genetic testing to confirm the diagnosis of MODY.Maturity-Onset Diabetes Of The Young Essay
Figure 2 Diagnostic algorithm for maturity-onset diabetes of the young (MODY).
Treatment of MODY
Correct determination of the MODY subtype is important, as this informs decisions regarding appropriate treatment and prognosis. Children and adolescents diagnosed with diabetes may initially be treated with insulin, and this regimen often continues even after the stabilization of glycemia. However, in some patients with MODY, hyperglycemia can be controlled by prescribing OADs (eg, sulfonylureas, without using insulin. Additionally, the selection of appropriate treatments for these patients is important to improve their quality of life.
The majority of patients with MODY2 exhibit mildly elevated fasting plasma glucose levels but do not exhibit postprandial hyperglycemia; in other words, they secrete sufficient insulin in response to an increase in plasma glucose after consuming a meal. Therefore, dietary intervention alone is usually advised for these patients, as pharmacological intervention is not required to control hyperglycemia and prevent diabetic complications.11,14 However, some Japanese patients with MODY2 eventually require pharmacological treatment. In a study of 55 patients, Kawakita et al.60 reported that seven were treated with OADs, two with sulfonylureas, one with metformin, and two with α-glucosidase inhibitors. Asians face a risk of insulin resistance, characterized by a higher Homeostatic Model Assessment (HOMA-IR) at a relatively low body mass index (BMI),18,61 possibly due to a greater amount of visceral fat than that observed in Caucasians.62,63 Accordingly, some Japanese patients who consume carbohydrate-rich foods and have sedentary lifestyles require OADs. Asians also exhibit a relatively lower level of insulin release in response to an increase in glucose, as well as a lower homeostasis model assessment for β-cell function (HOMA-β).62,63 This pattern may also lead to an increased requirement for OADs. During pregnancy, insulin might be offered to patients with MODY2 to prevent fetal overweight.Maturity-Onset Diabetes Of The Young Essay
MODY3 (HNF1α-MODY) and MODY1 (HNF4α-MODY)
Patients with MODY3 and MODY1 can initially control glycemia with diet alone, although both tend to exhibit elevated postprandial glucose levels after consuming carbohydrate-rich foods.22 Over time, however, most patients will experience deteriorating β-cell function and require pharmacological treatment. Patients with MODY3 and MODY1 are sensitive to sulfonylureas and can maintain optimal glycemic control with these drugs rather than insulin. One randomized clinical trial of gliclazide therapy demonstrated a 3.9-fold improvement in the fasting glucose levels of patients with MODY3 relative to BMI-matched patients with type 2 diabetes; this effect was particularly pronounced in children and young adults. That study also demonstrated the safety and efficacy of a switch from insulin to gliclazide despite using the former for a long duration.64 The initial sulfonylurea dose should be low to avoid hypoglycemia. Reports suggest that optimal glycemic control without problematic hypoglycemia can be maintained for decades at gliclazide doses of 20–40 mg.65,66 If hypoglycemia occurs despite dose titration, a short-acting agent (eg, meglitinide) may be considered.67 Another sulfonylurea, glimepiride, might offer a similar glucose-reducing effect with fewer episodes of hypoglycemia. It also exerts extrapancreatic effects such as decreased glucose output from the liver and enhanced sensitivity of peripheral tissues to insulin.68 Maturity-Onset Diabetes Of The Young Essay
Another therapeutic option involving a glucagon-like peptide (GLP-1) agonist with a similar glucose-lowering effect as sulfonylureas and a low frequency of hypoglycemia has been proposed for patients with MODY3.69,70 A double-blind, randomized crossover trial that compared a GLP-1 agonist (liraglutide) with a sulfonylurea (glimepiride) found no difference between the two drugs in terms of controlling the fasting plasma glucose and responsive postprandial plasma glucose relative to baseline. However, glimepiride was clearly associated with a higher incidence of hypoglycemia.70 We experienced similarly good glucose-reducing effects and a lack of hypoglycemia in children with MODY3 who were treated with liraglutide.71 Moreover, we previously reported that a switch from glimepiride to a dipeptidyl-peptidase-4 (DPP-4) inhibitor, alogliptin, yielded similar glycemic control without hypoglycemia in a girl with MODY1.72 Maturity-Onset Diabetes Of The Young Essay
During treatment, patients with MODY3 and MODY1 maintain substantial β-cell function for at least 2–4 years after diagnosis. As noted above, sulfonylureas are generally the first-line of treatment for patients with MODY3 and MODY1, despite the risk of hypoglycemia. Long-term treatment with sulfonylureas is also associated with body weight gain and the deterioration of endogenous insulin, which eventually induces insulin dependency in some patients with type 2 diabetes. In contrast, GLP-1 receptor agonists and DPP-4 inhibitors lower glucose levels and increase endogenous insulin secretion in a glucose-dependent manner. This effect occurs via a subpathway of insulin secretion in response to increased cyclic adenosine 3ʹ, 5ʹ-monophosphate (c-AMP) production, rather than by ATP production, which thus overcomes the impaired mitochondrial ATP production in response to glucose in patients with MODY3 and MODY1.28 Therefore, the mode of insulin secretion induced by GLP-1 receptor agonists and DPP-4 inhibitors may more effectively increase insulin secretion in these patients. Additionally, GLP-1 receptor agonists and DPP-4 inhibitors might prevent β-cell apoptosis and promote β-cell generation to counter the progressive impairment of β-cell function during the courses of MODY3 and MODY1.73–75 These findings suggest that GLP-1 receptor agonists and DPP-4 inhibitors may be suitable alternatives to sulfonylureas.Maturity-Onset Diabetes Of The Young Essay
Unlike patients with MODY3 and MODY1, those with MODY5 do not respond adequately to treatment with sulfonylureas, possibly due to comorbid pancreatic hypoplasia and some degree of hepatic insulin resistance.76 These patients may require intensive insulin treatment to control hyperglycemia. Additionally, microvascular complications have been described in these subjects,6 and treatment for renal disease, liver dysfunction, and dyslipidemia is necessary. Renal management is a particularly important aspect of treatment in patients harboring HNF1β mutations, as these individuals will develop renal dysfunction by 45 years of age and half will progress to end-stage renal disease.42
The current treatments of other MODY subtypes according to the molecular causes and clinical characteristics are listed in Table 1. However, standard treatments have not been established for most subtypes because of low numbers of cases and a lack of data confirming treatment efficacy. Furthermore, only metformin and insulin are approved for use in youth in the majority of countries. Sulfonylureas are approved for use in adolescents in some countries. Other OADs are not approved for use in those <18 years of age.77 Maturity-Onset Diabetes Of The Young Essay
Advanced molecular genetic analyses have led to the identification of genes associated with clinically diagnosed subtypes of MODY. Accordingly, genetic testing is useful for the correct diagnosis and appropriate treatment of patients with MODY.14 To confirm a correct diagnosis and improve prognosis, genetic testing is recommended at diagnosis or during early-stage disease, despite limitations associated with costs.
Patients with type 1 diabetes require insulin treatment for survival and metabolic control, whereas those with MODY do not usually require long-term insulin treatment. Therefore, misdiagnosis can lead to inappropriate treatment. MODY should be suspected in the presence of mild to moderate, nonketosis-prone hyperglycemia in usually nonobese patients with a strong family history of diabetes. The importance of genetic testing is emphasized by the effect of a general increase in the prevalence of obesity, which may complicate a differential diagnosis including both type 2 diabetes and MODY. Correct diagnosis of MODY is also important with respect to genetic counseling and the prevention of developing the disease.78 Rapid advances in the fields of molecular analysis and laboratory technology are expected to improve the correct diagnosis of MODY and the provision of appropriate treatment based on the individual medical condition.Maturity-Onset Diabetes Of The Young Essay
MODY, maturity-onset diabetes of the young; HNF, hepatocyte nuclear factor; GCK, glucokinase; PDX1, pancreatic and duodenal homeobox 1; NEUROD1, neurogenic differentiation 1; KLF11, Kruppel-like factor 11; CEL, carboxyl ester lipase; PAX4, paired-box-containing gene 4; INS, insulin; BLK, B-lymphocyte kinase; ABCC8, adenosine triphosphate (ATP)-binding cassette, sub-family C (CFTR/MRP) member 8; KCNJ 11, potassium channel, inwardly rectifying subfamily J, member 11; APPL1, adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1; OAD, oral antidiabetic drug; OGTT, oral glucose tolerance test; HOMA-IR, homeostasis model assessment for insulin resistance; BMI, body mass index; HOMA-β, homeostasis model assessment for β-cell function; hs-CRP, high-sensitivity C-reactive protein; GLP-1, glucagon-like peptide; DPP-4, dipeptidyl-peptidase-4; c-AMP, cyclic adenosine 3ʹ, 5ʹ-monophosphate.Maturity-Onset Diabetes Of The Young Essay
Diabetes refers to a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both . The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Diabetes is currently the fastest-growing epidemic and has been ascribed to a collision between genes and the environment.India and China have the highest reported prevalences of diabetes. More than 90% of these cases are considered as T2D making T2D the fastest-increasing disease worldwide [2,3]. The T2D epidemic can largely be ascribed to the worldwide increase in obesity during the last 30 years.. This has been ascribed to a collision between genes and the environment. The social determinants of environmental factors tend to vary across populations and have changed rapidly over the last decades. A traditional high energy-burning lifestyle has been replaced by a Western sedentary lifestyle with little or no exercise and consumption of an energy-dense diet. Meanwhile, genetic factors evolve at a slower rate across generations, and tend to favor selection of “energy-saving thrifty genotypes,” which might have been beneficial for individuals living in times of unstable food supply by storing energy in times of surplus .Maturity-Onset Diabetes Of The Young Essay
Genes play a vital role in the development of Diabetes Mellitus.Type II DM is a polygenic disorder with multiple genes located on different chromosomes resulting in this condition.The major issue to address in Diabetes biology is to identify the genetic changes in the disease and their occurrence in different populations. Until recently, type 2 diabetes was typically regarded as a disease of the middle-aged and elderly. Though this age-group maintains a higher risk than younger adults, evidence is accumulating that even children and adolescents aged less than 30 years are now becoming caught up in the diabetes epidemic, which has mainly been attributed to the high level of obesity in these groups. The decrease in the age of onset of diabetes is of great concern as future generations may be burdened with morbidity and mortality at the height of their productivity, potentially affecting the workforce and healthcare resources of the countries across the world. So the present review is written with a view to summarise the various genetic markers involved in typeII Diabetes Mellitus among South Indian Population.Maturity-Onset Diabetes Of The Young Essay
ROLE OF GENES IN TYPE II DM
It has long been known that T2D is, in part, inherited. Family studies have revealed that first degree relatives of individuals with T2D are about 3 times more likely to develop the disease than individuals without a positive family history of the disease . T2D has a strong genetic component.
UPPARγ (peroxisome proliferator-activated receptor-γ)U. This gene has been widely studied because it is important in adipocyte and lipid metabolism. In addition, it is a target for the hypoglycemic drugs known as thiazolidinediones. One form of the PPARγ gene (Pro) decreases insulin sensitivity and increases T2D risk by several fold. Perhaps more importantly is that this variant is very common in most populations Maturity-Onset Diabetes Of The Young Essay
UABCC8 (ATP binding cassette, subfamily C, member 8)U. This gene encodes the high-affinity sulfonylurea receptor (SUR1) subunit that is coupled to the Kir6.2 subunit (encoded by UKCNJ11U, also known as the potassium channel, inwardly rectifying subfamily J, member 11). Both genes are part of the ATP-sensitive potassium channel, which plays a key role in regulating the release of hormones, such as insulin and glucagon, in the beta cell. Mutations in either gene can affect the potassium channel’s activity and insulin secretion, ultimately leading to the development of T2D. Interestingly, ABCC8 and KCNJ11 are only 4.5 kb apart, and not far from the INS gene. Variant forms of KCNJ11 (Lys) and ABCC8 (Ala) genes have been associated with T2D, as well as other diabetes-related traits. Because of the close proximity of these genes, current studies are evaluating whether they work in concert with each other, or rather have an independent effect on T2D susceptibility.Maturity-Onset Diabetes Of The Young Essay
Since PPARγ, ABCC8 and KCNJ11 are the targets of drugs used routinely in the treatment of T2D, there are pharmacogenetic implications for maintaining good glycemic control. Response to hypoglycemic therapy may actually be related one’s genotype. Thus, genetic testing may not only help determine who is at high risk for developing T2D, but may also be useful in guiding treatment regimens for T2D. 
UCAPN10 (calpain 10)U. CAPN10 encodes an intracellular calcium-dependent cysteine protease that is ubiquitously expressed (Cox et al., 2004). A haplotype that was initially linked to T2D included an intronic A to G mutation at position 43, which appears to be involved in CAPN10 transcription. Two amino acid polymorphisms (Thr504Ala and Phe200Thr) have also been associated with T2D risk. However, it has been suggested that the coding and noncoding polymorphisms do not independently influence T2D risk, but instead contribute to an earlier age at diagnosis. Physiological studies suggest that variations in calpain 10 activity effects insulin secretion, and therefore, susceptibility to T2D.Maturity-Onset Diabetes Of The Young Essay
UHNF4A (hepatocyte nuclear factor 4-α)U. Mutations in promoter and coding regions of the HNF4A gene cause MODY1. HNF4A is expressed in many tissues, including the liver and pancreas. It regulates hepatic gene expression, and influences the expression of other MODY genes such as HNF1A, which causes MODY3. In the beta cell of the pancreas, it directly activates insulin gene expression. Mutations in the HNF4A gene also have been associated with T2D .
UHNF1A (hepatocyte nucleara factor 1-α)U. MODY3, the most frequent cause of the disease, results from mutations in the HNF1A gene. HNF1A is expressed in the liver and pancreas. It can also influence HNF4A expression, indicating a connection between MODY1 and MODY3. This suggests that the MODY transcription factors form a regulatory network that maintains glucose homeostasis. In addition to causing MODY3, HNF1A mutations have been associated with T1D and T2D .Maturity-Onset Diabetes Of The Young Essay
UIPF1 (insulin promoter factor-1)U. MODY4, which is a rare form of the disease, is due to mutations in the IPF1 gene. Homozygosity for such mutations has been associated with newborn pancreatic agenesis and neonatal diabetes. Therefore, infants who carry MODY4 mutations tend to be small for gestational age. Individuals with MODY4 may also develop T2D .IPF1 regulates expression of glucokinase, insulin and other genes involved in glucose metabolism.
UHNF1B (hepatocyte nucleara factor 1-β)U. MODY5, another rare form of MODY, has also been linked with MODY1 because HNF1β regulates HNF4α. However, unlike MODY1, MODY5 is also associated with renal cysts, proteinuria and renal failure.
UNEUROD1 (neurogenic differentiation factor 1)U. Mutations in NEUROD1 are responsible for MODY6. MODY6 is also rare. Together, MODY4, MODY5 and MODY6 comprise less then 3% of all MODY cases. NERUOD1 is expressed in the beta cells of the pancreas, the intestine and the brain. In the pancreas, it contributes to the regulation of the expression of insulin.  Maturity-Onset Diabetes Of The Young Essay
GENETIC MARKERS AMONG INDIAN POPULATION
In Asian Indians, the D1057D genotype of insulin receptor substrate 2 (IRS-2) gene is susceptible to diabetes by interacting with obesity . Association of lipoprotein lipase Hind III (T-G) and Ser447Thr (C- G) polymorphism with dyslipidemia has been studied in Asian Indians by Radha et al.,  and it was shown that H+Ser and H-Ter were the ‘high- risk’ and ‘low-risk’ haplotypes for low HDL cholesterol and elevated triglyceride levels respectively. It has also been shown that –T93G SNP of lipoprotein lipase gene is associated with obesity but not T2D, whereas the – G53C SNP appears to be protective against both obesity and T2D . A few studies in North western Indian Punjabi populations show association of apolipoprotein E (APOE) (Hha1), angiotensin-1 converting enzyme (ACE) I/D, APOA1-CIII-AIV gene cluster with lipid levels in T2D and CHD  and Paraoxonase (PON1) activity to CAD and T2D . Studies in North Indians show genetic association of interleukin-1 beta (-511C/T) and interleukin-1 receptor antagonist (86bp repeat) polymorphism with T2D .Thr394Thr (G-A) polymorphism of peroxisome proliferator activated receptor-co-activator-1 alpha (PGC-1 alpha) gene has been shown to be associated with T2D in Asian Indian subjects and also with total, visceral and subcutaneous body fat . Two North Indian populations showed significant association of PGC-1 alpha variants (Thr394Thr & Gly482Ser) with T2D Analysis of mitochondrial G10398A/T16189C haplotypic combinations suggests susceptibility of these alleles to T2D independently as well as together .A comparison of risk genotype combinations of uncoupling protein-2 (UCP2) -866GG, mtDNA 10398A and PGC1 alpha p.Thr394Thr or p.Gly482Ser against the protective genotypes UCP2- 866XA, mtDNA 10398G and PGC1 alpha p.Thr394Thr or PGC1 alpha p.Gly482Ser showed a highly significant difference and increased ORs, showing significance of additive interaction of multiple small effects of the studied candidate gene variations in a complex disease like T2D. Among all the association studies with T2D in Indian populations, TCF7L2 has been shown to be most promising in South Indianand Western Indian ,populations, where intronic SNP (rs12255372, rs7903146, rs4506565) show association with T2D have also replicated association of eight well established genetic variants with T2D in North Western Indian populations showing higher effect size compared to the Europeans.Maturity-Onset Diabetes Of The Young Essay
GENES AND ENVIRONMENTAL INTERACTIONS
Gene interactions, or epistasis, have been suggested as a possible explanation for difficulties in replicating genetic association in complex diseases . The standard statistical methods used in association studies are usually limited to analysis of single marker effects and thereby do not account for interactions between markers. Previous attempts to study epistasis in complex diseases have focused on interactions between candidate regions [25,26]. However, the recent abundance of GWAS data has made a comprehensive search across the genome more feasible. Some studies have attempted to account for epistasis in GWAS using a two-step approach in which significant SNPs are tested against each other or against all other SNPs in the study with variable results [27,28]. The main problem when studying epistasis is power, since interaction between loci with modest effects is difficult to detect without extremely large sample sizes. However, some studies have pointed at novel tests to increase power . Thorough studies in diabetes addressing epistasis using this approach are missing. Furthermore, a recent paper by Eric Lander and co-workers provided compelling evidence that gene-gene interaction can also contribute to missing heritability by causing “phantom heritability” that inflates the estimated narrow sense heritability of the trait . Gene and environment interactions are equally difficult to study but are likely to play an important role in T2D development. The epidemic of T2D only dates back 50 years, and it is quite obvious that during this period that only the environment, and not the genes, have changed. However, the genetic architecture determines our response to the environment. Genetic variants could affect specific metabolic processes to make an individual more susceptible to the harmful effects of a poor diet but also personality traits that make an individual more or less likely to over-consume and live a sedentary lifestyle. It will however be a formidable task to identify the environmental triggers for most of the genetic variants increasing susceptibility to diabetes as this will require very large studies with precise information on diet, exercise, energy expenditure, etc.Maturity-Onset Diabetes Of The Young Essay
The genetic revolution has allowed identification of numerous genetic variants that associate with T2D. The genetic landscape of T2D susceptibility is as yet incomplete, thus far only explaining a small proportion of the total heritability of diabetes. It has already greatly contributed to our understanding of disease mechanisms by identifying pathways that could not be linked to diabetes by existing hypothetical models, even though many genetic findings are very recent and have yet to make their contribution to our knowledge about diabetes pathogenesis. However, one must bear in mind that diabetes is probably a much more diverse disease than the current subdivision into T1D and T2D implies and more precise subdivision into subgroups may both facilitate the investigation of T2D genetics and pave the way for more individualized treatment. A holistic systems biology approach will also be required to obtain a complete picture of how genetic variation leads to diabetes. Maturity-Onset Diabetes Of The Young Essay