Current Perspectives in MODY Management— A Narrative Review

Maturity-onset diabetes of the young (MODY) is associated with familially inherited monogenic diabetes. It is characterized by genetic mutations leading to pancreatic β-cell dysfunction and subsequent insulin production. Clinical features of MODY include young-onset hyperglycemia associated with a lack of beta cell autoimmunity or insulin resistance. Glucose-lowering agents are the main therapeutic options for MODY. In this review, we have outlined the particular aspects of the most common types of MODY in order to assist clinical practitioners in this eld.


Introduction
Maturity-onset diabetes of the young (MODY) is a rare form of familial diabetes with autosomal dominant transmission spanning at least three generations (grandparents, parents and children).

In
, the term MODY was rst mentioned by Fajans at the Fifth Congress of the International Diabetes Federation in Toronto [ ]. This entity includes Caucasians with normal weight, young-age onset of the disease and a therapeutic response to tolbutamide, being a form of mild diabetes mellitus (DM) [ -]. In , Cammidge observed a good evolution of DM among children, even in the absence of insulin therapy for several years. Finally, Tattersall concluded that patients with this mild type of diabetes are asymptomatic with normal weight; they do not develop ketosis and do not necessarily require insulin treatment [ ]. The World Health Organisation includes MODY in the category of other speci c types of DM, including monogenic, with genetic defects in pancreatic beta cell function. The classi cations of juvenile-onset diabetes and adult-onset diabetes are also used [ ].
The prevalence of MODY varies by geographical region, ranging from . % in Sweden to . % in Norway [ , ]. In Africa, Asia, South America and the Middle East, data on the prevalence of MODY are unclear, necessitating further study [ ]. Among children diagnosed with DM who do not have autoantibodies, . % have a speci c MODY genetic mutation [ ].

Diagnosis of MODY
MODY can be suspected in patients with DM who do not phenotypically develop features of type diabetes mellitus (T DM) or type diabetes mellitus (T DM). Most of the time, MODY is diagnosed at onset as T DM due to a lack of insulin requirements. With the increasing worldwide incidence of childhood obesity, about % of cases diagnosed with MODY are overweight; therefore, the etiological diagnosis is overlooked from the beginning. The underdiagnosis of MODY is related to the borrowing of features from T DM and T DM (Table ), in addition to the missing information needed to establish diagnoses within the family. MODY diagnosis represents a gap in clinical research due to the high cost of genetic mutation investigations [ -].
Diagnostic criteria for MODY include: • Onset of the disease under the age of years, with a history of DM in one or more family members; • Lack of insulin requirement at least -years after diagnosis; • Autosomal dominant inheritance (similar phenotype in successive generations); • Body mass index (BMI) below kg/m ; obesity is not an exclusion criterion for MODY; • Heterogeneity of insulin secretion, with values frequently within a normal range, but low in relation to blood glucose; • Lack of pancreatic autoantibody positivity.
The age of onset of the disease is a de ning criterion in suspecting the diagnosis of MODY and di erentiating it from T DM and T DM, although the clinical presentation is often atypical and it can be di cult to t it into the diagnostic criteria [ -].
Di erential diagnosis between MODY types is based on di erent therapeutic responses (

Particular Aspects of GCK-MODY
Glucokinase-MODY, known as MODY , has a prevalence of up to % of MODY patients. GCK is a key enzyme in glucose metabolism, stimulating insulin secretion dependent on the glucose plasma levels. The GCK gene mutation, located at chromosome , region p -p , acts as a glycemic sensor in the pancreatic beta cells; therefore, the stimulation of insulin secretion will occur at glycemic thresholds higher than physiological levels. At the hepatic level, these mutations damage the process of glycogenogenogenesis, and at the pancreatic level, they disturb glucagon secretion in hypoglycemia states. Subsequently, glucagon acts at lower hypoglycemic values than in patients with T DM [ ].
Paraclinical picture revealed by laboratory tests is characterized by mild stable fasting hyperglycemia with blood glucose ranging between and mg/dL, glycosylated hemoglobin (HbA C) between . and . % [ ]. Hence, postprandial glycemic values at OGTT are slightly increased. Blood glucose values in these patients are % higher compared to people without DM and approximately with mg/dL lower compared to patients with T DM.
Routine periodical screening can lead to the identi cation of these slightly elevated blood glucose values. Approximately % of women with gestational diabetes actually have a diagnosis of GCK-MODY [ , ], in the presence of a positive family history of hyperglycemia and mildly modi ed OGTT values. Suspicion of GCK-MODY is raised in cases with a presence of glucose metabolism disorders in at least two generations in the family [ , -].
Clinically, patients do not exhibit symptoms, obesity or insulin resistance, or associated risk factors such as hypertension, dyslipidemia and atherosclerosis [ , ].
The prevalence of diabetes complications in GCK-MODY patients is much lower compared to other genetic mutations in MODY. Microvascular complications such as diabetic retinopathy, nephropathy and neuropathy are rarely seen or even absent, whereas signi cant macrovascular complications such as peripheral arterial disease and cardiovascular disease have a low prevalence [ , ].
Treatment is not necessary in this category of patients, because they have an excellent long-term prognosis, similar to people without diabetes. If GCK-MODY is discovered during pregnancy, then two possibilities are considered. The presence of the GCK mutation only in the mother can lead to prolonged exposure of the fetus to hyperglycemia during pregnancy. At birth, the fetus may present with macrosomia, neonatal hypoglycemia and malformations, as a consequence of the early initiation of insulin therapy on the mother; frequent monitoring of the pregnancy at risk is necessary [ -].
The presence of GCK mutations in both the mother and fetus does not require insulin treatment, because the glycemic set point is similar in both, resulting in a normal birth [ , ]. , ( ),

Particular Aspects of HNF-A-MODY
The HNF-A gene is present in the liver, intestine, pancreatic beta cells and kidneys. Mutations are found on chromosome in the q . region, with a prevalence of up to -% of MODY cases.
The HNF-A gene is involved in the transcription of insulin (INS), glucose transporters and (GLUT and ) and sodium/glucose cotransporter (SGLT ) [ , ]. The pathophysiological mechanism of HNF-A mutations encompasses decreased beta-cell function with impaired glucose metabolism. Decreased renal glucose reabsorption is a consequence of reduced SGLT activity, all of which leads to glycosuria before hyperglycemia, and is an important marker used as a screening assay for this mutation. Compared with patients with T DM, they show lower insulin resistance, better lipid pro les and increased proinsulin/insulin ratios. Compared with GCK-MODY, complications occur more frequently in these patients, with a good glycemic control being more di cult to achieve [ ].
Diagnosis in the initial stages of the disease can also be sustained by OGTT, if a marked increase in blood glucose levels over mg/dL is observed two hours after glucose intake [ ].
Diagnosis of HNF-A-MODY can be suspected in patients aged up to years with initially normal blood glucose values, glycosuria and modi ed OGTT after two hours. The treatments involve low-carbohydrate diet and low-dose sulfonylureas. Due to gradual beta cell dysfunction, insulin therapy is not necessary from baseline, but can be initiated if optimal glycemic targets are not achieved or in pregnancy. Sulfonylureas are a group of drugs that act through increased insulin secretion.
In those patients who were initially treated with insulin, having been misdiagnosed with T DM, sulfonylurea therapy can be initiated without the risk of ketoacidosis, and insulin can be ceased. The e ectiveness of switching medication can be assessed by achieving a better glycemic control and a reduction in HbA C values [ ].
The advantages of this intervention include much greater exibility in mealtimes and lifestyle, and considerably lower pill prices, which can improve the patient compliance with medication and the quality of life.
Initiation of sulfonylureas (e.g., glyburide and glibenclamide) is performed at low doses to minimize the risk of hypoglycemia and to assess interindividual tolerability. Metiglinides may also be used, because they are non-sulfonylurea insulin secretagogue agents, which decrease postprandial blood glucose levels and present a reduced risk of hypoglycemia than sulfonylureas.
The glucagon-like peptide receptor agonist (GLP-RA) class is increasingly used in the management of diabetes, due to the superior cardiovascular bene ts and protection, and the reduced risk of hypoglycemia compared to sulfonylureas. They are especially recommended for obese patients, having catabolic e ects, as well as for patients with renal impairment (e.g., liraglutide) [ ].

Particular Aspects of HNF-B-MODY
HNF-B is the gene which regulates organogenesis, starting in the embryonic period, and is involved in the development of the urogenital tract, liver and pancreas. HNF-B mutations are present on the chromosome , region cen-q . , with a prevalence of -% in all MODY cases. , ( ), The clinical picture at presentation is mainly dominated by renal damage: % of patients have renal cysts. Among the extra-renal manifestations, DM is present early, following renal disease, the association of DM with renal cysts is also known as renal cysts and diabetes syndrome (RCAD). The presence of structural abnormalities from birth evolves over time to impairment functions of the involved organs. Regarding kidney function, about % of patients may require dialysis or kidney transplantation [ ]. In addition to renal malformations (such as unique kidney, renal hypoplasia), patients may also present malformations of the urinary tract, internal and external genitalia, pancreatic atrophy, gout and hyperuricemia [ ].
Kidneys present single or bilateral hyperechogenic cysts with normal or low renal parenchyma. Renal function is secondarily impaired, leading to renal magnesium loss and uric acid accumulation with hyperuricemia, and later to renal stone build-up and gout [ ].
Therapeutic management of HNF-B-MODY requires early therapy to prevent micro-and macrovascular complications [ , , ], as well as long-term nephrological follow-up. In contrast to HNF-A, sulfonylurea administration is not recommended for this category of patients.

Particular Aspects of HNF-A-MODY
The HNF-A gene is expressed in the pancreas, liver and kidneys, with its mutation located at chromosome , region q -q . , mainly a ecting carbohydrate and lipid metabolism. Apoprotein concentrations (apoAII, apoCIII, and apoB) are lower than those met in T DM, as well as lipoprotein lipase activity. Paraclinical features include elevated glycemic values, altered lipid pro les with increased low-density lipoprotein and decreased high-density lipoprotein and triglycerides [ ].
Another important feature is the presence of neonatal transient hyperglycemia with fetal macrosomia; however, the diagnosis of DM is con rmed later in adolescence [ ]. The rst-line treatment is characterized by a low-carbohydrate diet and sulfonylureas, with insulin therapy being elective in pregnancy. Glycemic control can also be achieved by the administration of meglitinide or GLP-RA in patients who have frequent hypoglycemia upon therapy with sulfonylureas [ ].

Neonatal Diabetes Mellitus
Neonatal diabetes mellitus (NDM) is de ned as part of monogenic DM, diagnosed until the age of months old. It can be permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus (TNDM), the de nite diagnosis being disturbed at onset because the clinical presentation is limited, and di erentiation being based on extra-pancreatic features. TNDM abates within weeks, but the risk of recurrence later in life remains. At onset, blood glucose levels are between and mg/dL, requiring insulin treatment and ceasing after the normalization of blood glucose values. These patients require yearly follow-up; in cases of relapse, the patients can be managed with a diet either associated or not with insulin. Oral antidiabetic drugs are not a successful choice.
NDM occurs due to mutations in the KCNJ , ABCC , IPF-/PDX , HNF-B and GCK genes, most commonly found in KCNJ and ABCC mutations [ ]. Screening of MODY during pregnancy has the potential for early diagnoses and to facilitate optimal therapeutic management [ , ]. Genetic testing is recommended in both subtypes of NDM [ ].

Future Perspectives
The real incidence of patients with MODY is not fully known, due to misdiagnoses as T DM or T DM, as well as expensive genetic testing. A thorough medical history, correlated with hereditary history and paraclinical examinations, would allow a more frequent prediction of MODY patients. The gold standard in diagnosis is genetic testing, which is di cult to perform in clinical practice. MODY calculators can contribute to estimations of the possibility of identifying MODY in patients diagnosed with DM, and it is useful in diagnostic strati cation [ ].
A multidisciplinary team, including a geneticist, is essential for genetic counseling. The autosomal dominant inheritance mechanism of disease should be explained to patients and their families, and this should be considered in subsequent medical decisions.

Conclusions
MODY is a rare disease, situated within monogenic DM. The diagnosis of MODY in adulthood is overlooked because of its phenotypic similarity to T DM and T DM. Its particular features are autosomal dominant inheritance in -successive generations and a lack of insulin requirements for at least -years. For the appropriate diagnosis of patients with MODY, family screening and further investigations to establish the type of diabetes enable the initiation of proper treatment and improvements in long-term prognoses. Regarding NDM, clinical practice now advises the suspicion and search for possible signs and symptoms, so that a certain diagnosis of MODY is not overlooked. Funding: This research received no external funding.

Con icts of Interest:
The authors declare no con ict of interest.