Glucokinase-MODY, known as MODY 2, has a prevalence of up to 70% 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 7, region 7p15-p13, 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 T2DM [31].

Paraclinical picture revealed by laboratory tests is characterized by mild stable fasting hyperglycemia with blood glucose ranging between 100 and 150 mg/dL, glycosylated hemoglobin (HbA1C) between 5.6 and 7.6% [32]. Hence, postprandial glycemic values at OGTT are slightly increased. Blood glucose values in these patients are 40% higher compared to people without DM and approximately with 100 mg/dL lower compared to patients with T2DM.

Routine periodical screening can lead to the identification of these slightly elevated blood glucose values. Approximately 3% of women with gestational diabetes actually have a diagnosis of GCK-MODY [33,34], in the presence of a positive family history of hyperglycemia and mildly modified 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 [23,35,36,37,38].

Clinically, patients do not exhibit symptoms, obesity or insulin resistance, or associated risk factors such as hypertension, dyslipidemia and atherosclerosis [39,40].

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 significant macrovascular complications such as peripheral arterial disease and cardiovascular disease have a low prevalence [41,42].

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 [43,44,45].

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 [43,46].

The HNF-1A gene is present in the liver, intestine, pancreatic beta cells and kidneys. Mutations are found on chromosome 12 in the 12q24.2 region, with a prevalence of up to 30–70% of MODY cases.

The HNF-1A gene is involved in the transcription of insulin (INS), glucose transporters 1 and 2 (GLUT 1 and 2) and sodium/glucose cotransporter 2 (SGLT2) [47,48]. The pathophysiological mechanism of HNF-1A mutations encompasses decreased beta-cell function with impaired glucose metabolism. Decreased renal glucose reabsorption is a consequence of reduced SGLT2 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 T2DM, they show lower insulin resistance, better lipid profiles and increased proinsulin/insulin ratios. Compared with GCK-MODY, complications occur more frequently in these patients, with a good glycemic control being more difficult to achieve [49].

Diagnosis in the initial stages of the disease can also be sustained by OGTT, if a marked increase in blood glucose levels over 90 mg/dL is observed two hours after glucose intake [50].

Diagnosis of HNF-1A-MODY can be suspected in patients aged 4 up to 18 years with initially normal blood glucose values, glycosuria and modified 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 T1DM, sulfonylurea therapy can be initiated without the risk of ketoacidosis, and insulin can be ceased. The effectiveness of switching medication can be assessed by achieving a better glycemic control and a reduction in HbA1C values [51].

The advantages of this intervention include much greater flexibility 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 1 receptor agonist (GLP-1 RA) class is increasingly used in the management of diabetes, due to the superior cardiovascular benefits and protection, and the reduced risk of hypoglycemia compared to sulfonylureas. They are especially recommended for obese patients, having catabolic effects, as well as for patients with renal impairment (e.g., liraglutide) [52].

HNF-1B 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-1B mutations are present on the chromosome 17, region 17 cen-q21.3, with a prevalence of 5–10% in all MODY cases.

The clinical picture at presentation is mainly dominated by renal damage: 75% 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 50% of patients may require dialysis or kidney transplantation [53]. 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 [54].

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 [55].

Therapeutic management of HNF-1B-MODY requires early therapy to prevent micro- and macrovascular complications [25,56,57], as well as long-term nephrological follow-up. In contrast to HNF-1A, sulfonylurea administration is not recommended for this category of patients.

The HNF-4A gene is expressed in the pancreas, liver and kidneys, with its mutation located at chromosome 20, region 20q12-q13.1, mainly affecting carbohydrate and lipid metabolism. Apoprotein concentrations (apoAII, apoCIII, and apoB) are lower than those met in T2DM, as well as lipoprotein lipase activity. Paraclinical features include elevated glycemic values, altered lipid profiles with increased low-density lipoprotein and decreased high-density lipoprotein and triglycerides [58].

Another important feature is the presence of neonatal transient hyperglycemia with fetal macrosomia; however, the diagnosis of DM is confirmed later in adolescence [59]. The first-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-1 RA in patients who have frequent hypoglycemia upon therapy with sulfonylureas [60].

Neonatal diabetes mellitus (NDM) is defined as part of monogenic DM, diagnosed until the age of 6 months old. It can be permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus (TNDM), the definite diagnosis being disturbed at onset because the clinical presentation is limited, and differentiation being based on extra-pancreatic features. TNDM abates within 12 weeks, but the risk of recurrence later in life remains. At onset, blood glucose levels are between 200 and 900 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 KCNJ11, ABCC8, IPF-1/PDX1, HNF-1B and GCK genes, most commonly found in KCNJ11 and ABCC8 mutations [61]. Screening of MODY during pregnancy has the potential for early diagnoses and to facilitate optimal therapeutic management [62,63]. Genetic testing is recommended in both subtypes of NDM [64].