Less common forms of diabetes in young population

Introduction

Differentiating the types of diabetes mellitus (DM) has a long and unfinished history. Currently, in everyday practice, there is also a division in force since 1999, in which there are 4 types of diabetes: type 1 diabetes mellitus (associated with autoimmune destruction of pancreatic β-cells, usually leading to complete insulin deficiency; T1DM), type 2 diabetes mellitus (associated with progressive loss of adequate insulin secretion by pancreatic β-cells; T2DM), gestational diabetes (diagnosed in the second or third trimester of pregnancy, not being overt diabetes before pregnancy), and certain types of diabetes resulting from other causes, such as monogenic diabetes syndromes (neonatal diabetes and juvenile diabetes with onset in adulthood), exocrine pancreatic diseases (cystic fibrosis and pancreatitis), and diabetes caused by drugs or chemicals [1]. The results of immunological and genetic studies have broadened our knowledge on the aetiopathogenesis of glucose metabolism disorders and require a revision of the currently valid classification of diabetes [2, 3]. There are 2 basic disorders underlying the development of diabetes mellitus: impaired insulin secretion and/or insulin resistance [4].

In diabetes classified as type 2, the predominant disorder is an insulin resistance. Type 2 diabetes is usually associated with excessive accumulation of adipose tissue, and it is a component of so-called “metabolic syndrome” [5]. This type of diabetes is generally considered rare in children and adolescents. The incidence of T2DM has increased dramatically over the past decade in certain ethnic groups [6, 7]. The increased incidence of this type of diabetes mellitus has corresponded to a temporally unprecedented increase in body weight and obesity prevalence in adolescents in various ethnic populations.

Maturity-onset diabetes of the young (MODY), a type other than type 1, is characterised by early onset and autosomal dominant inheritance. MODY is mainly caused by β-cell defects, resulting in insufficient insulin secretion for a given blood glucose level.

The purpose of this article is to characterise and present other types of diabetes found in the young population.

Table I shows the clinical characteristics of T1DM, T2DM, and MODY diabetes in the child and adolescent population.

Type 2 diabetes mellitus in children and youngsters

Type 2 diabetes mellitus is the most common type of diabetes in the general population. However, distinguishing it from other forms of diabetes, including T1DM, monogenic diabetes, or diabetes with onset in adulthood or latent autoimmune diabetes in adults (LADA), is sometimes a challenge in clinical practice. Insulin resistance and hyperinsulinaemia are involved in the pathogenesis of T2DM, with consequent dysfunction of pancreatic β-cells to produce insulin [8, 9]. If suspected, the diagnosis of T2DM can be made on the basis of plasma glucose or glycated haemoglobin (HbA1c) analysis. In clinical practice, the diagnosis of T2DM is made based on the analysis of certain characteristics, such as BMI, or the diagnosis is made after ruling out other types of diabetes [10]. The prevalence of T2DM in children and adolescents correlates strongly with the prevalence of obesity, and numerous studies show that more than 85% of children with T2DM are overweight or obese at the time of diagnosis [11–13]. Determinants of prenatal life [14–16], diet and obesity [17, 18], reduced physical activity [19, 20], as well as female gender [21] and the presence of polycystic ovarian syndrome [22] in women and the presence of nonalcoholic steatohepatitis [23, 24], are considered key factors in the development of T2DM in young people. Another important aspect is that the more cases of diabetes found in the family, the younger the age of onset of T2DM. This means that the genetic risk of T2DM is associated with younger age at diagnosis and younger age at onset of insulin treatment [25]. Poor glycaemic control ultimately leads to serious health complications such as retinopathy, neuropathy and nephropathy, and cardiovascular disease. Studies show early signs of micro- and macrovascular complications, hypertension, dyslipidaemia, and hepatic steatosis in young patients with T2DM. As for the treatment of T2DM, in addition to metformin and insulin [26], the GLP-1 agonist liraglutide, and a representative of SGLT-2 inhibitors, dapagliflozin, have recently been introduced into the treatment of type 2 diabetes in adolescents over 10 years of age [27, 28]. The long-term prognosis of adolescents with T2DM is an object of observation, but it is estimated that adolescents may lose up to 15 years of life expectancy and increase their risk of serious health complications by the time they reach age 40 years, depending on their level of glycaemic control [29].

MODY diabetes

Maturity-onset diabetes of the young (MODY) is a rare, inherited form of diabetes that results from heterozygous mutations in various transcription factors involved in the maturation of pancreatic β-cells [30], as well as mutations in enzymes involved in the detection of glucose in β-cells [31]. The defining characteristics of MODY diabetes are autosomal dominant inheritance, early onset of the disease, usually before the age of 25 years, absence of symptoms related to the autoimmune process or insulin resistance, and preservation of endogenous insulin secretion [32, 33]. The incidence of MODY is 21–45/1,000,000 in children and 100/1,000,000 in adults [34, 35]. Depending on the circular gene mutations, pathophysiology, and clinical characteristics, there are 14 subtypes of MODY diabetes [36, 37]. Table II shows the characteristics of each type of MODY diabetes. The diagnosis of MODY diabetes is based on the use of genetic testing. Direct sequencing is a technique that can diagnose MODY with up to 100% sensitivity [38]. However, performing genetic tests on individuals without specific criteria can lead to inappropriate results and is not cost-effective, which is a problem in diagnosing MODY. Various algorithms using different clinical and laboratory parameters have been developed to define MODY [36]. Correct diagnosis and differentiation of MODY from T1DM and T2DM are important in deciding patient treatment and determining prognosis, while treatment as well as the presence of long-term vascular complications depend on the MODY diabetes subtype [36]. In patients with mild hyperglycaemia at the time of diagnosis, diet is an effective treatment in most cases. In cases of progressive hyperglycaemia, drug therapy should be implemented. Molecular diagnostics are crucial for choosing the best treatment for most MODY patients. Particularly effective therapeutic options for most types of MODY diabetes are oral hypoglycaemic drugs, in particular, sulphonylureas, which bypass the molecular defect and activate the ATP-sensitive potassium channel [37].

Discussion

Correct diagnosis and distinguishing MODY from T1DM and T2DM are important in deciding patient treatment and determining prognosis, as well as detecting at-risk family members. Patients experience a delay in receiving a diagnosis of MODY from the onset of diabetes, and some patients with MODY diabetes are misdiagnosed with T1DM and T2DM at the time of diagnosis. This indicates that the diagnosis of MODY is rarely considered by many primary care physicians. In everyday practice, when the diagnosis of the type of diabetes is based on the clinical picture and basic laboratory tests, it is relatively common to encounter an incorrect diagnosis of the type of diabetes. According to many authors, in many cases, after some time, it is necessary to verify the initially established type of diabetes [39]. One of the elements constituting the basis for differentiation is the history and assessment of the dynamics of the development of symptoms of the disease. However, it is known that the dynamics of diabetes symptom development does not always allow differentiation of the type of diabetes. Another indicator taken into consideration in establishing the type of diabetes is the presence or absence of obesity. It is worth noting that overweight and obesity also occur in children with T1DM, and this differentiating sign is not as good as it used to be in diagnosing the type of diabetes. If hyperglycaemia is found in an obese or severely overweight patient, this is often, but not always, T2DM. In such cases, it should be checked if it is not diabetes of “other types”, i.e. diabetes associated with genetic syndromes, endocrinopathies, or drug-induced diabetes. Often these forms of diabetes run together with obesity. Although T1DM is most common in children and adolescents, all other forms of diabetes, including the increasingly recognised group of monogenic diabetes, may also occur in these age groups. Initial diagnosis of hyperglycaemia or verification of the diagnosis, in addition to routine monitoring of blood glucose, urine sugar and acetone, and HbA1c, includes determination of antibodies to glutamic acid decarboxylase and 1–2 of the following: pancreatic islet cell antibodies – ICA, insulin autoantibodies – IAA, insulinoma associated autoantigen 2 – IA-2, and zinc transporter family member 8 – ZnT8. Determination of C-peptide levels is also very important. This allows assessment of endogenous insulin secretion and confirmation or exclusion of autoimmunity. Determination of C-peptide levels also allows assessment of insulin resistance characteristic of many disease syndromes [40]. It has been shown that C-peptide can help differentiate between T1DM, T2DM, and MODY. C-peptide levels correlate with disease type, duration of diabetes, and age of diagnosis. In insulin-treated patients, low values were found to correlate significantly with T1DM. However, it should be borne in mind that C-peptide, especially at the onset of T1DM, may be within the normal range. C-peptide concentrations have been shown to decrease over the decades with diabetes duration, and diabetes duration was associated with c-peptide values. More recently, it has also been confirmed that c-peptide concentration decreases over time and is significantly associated with age of onset, where younger age (less than 10 years old) results in a significantly faster decline in c-peptide concentration. In contrast, a higher percentage of detectable c-peptide was found in T1DM patients over 18 years of age compared to younger individuals. C-peptide has been proposed as a useful marker in detecting MODY diabetes before genetic testing. In MODY, while there is a reduction in β-cell function, some insulin secretion is preserved compared to T1DM. It should be remembered, however, that while c-peptide is useful in classifying diabetes, it should always be interpreted in the context of disease duration, the presence of comorbidities, and family history. In particular, there are many diagnostic errors in the young adult patient group. If diabetes is diagnosed in patients between 25–30 and 55 years of age, the type of diabetes should be considered very carefully. The correct diagnosis determines the correct treatment. If no autoantibodies are found in young patients with mild diabetes, monogenic diabetes is likely to be suspected. In that case, genetic tests are decisive. Unfortunately, access to these tests is limited for the time being. The possibility of monogenic diabetes should also be considered in patients with gestational diabetes mellitus (GDM). In young patients, T1DM is the most common form of diabetes. However during the last 2 decades an increasing incidence of T2DM in children and adolescents has been observed. This coincides with an increase in the prevalence of overweight and obesity [41]. This type of diabetes differs not only from T1DM but also from T2DM found in adult patients. It is characterised by rapidly progressive β-cell decline, high treatment failure rate, and accelerated development of complications [42]. A comprehensive discussion of issues related to the prevalence of T2DM in the developmental population was recently presented by Valaiyapathi et al. [43]. These authors confirmed that in over the past 20 years, the prevalence of T2DM among children and adolescents has increased. This increase in the paediatric age group is associated with an increase in childhood obesity. Genetic conditions are an important factor. The main factors are the occurrence of insulin resistance, as well as a deficit in insulin secretion. Impaired insulin secretion is a result of defective production in β-cells as well as decreased β-cell mass. The more aggressive course of T2DM in adolescent patients is confirmed by other authors [44].

In treating T2DM, as in adults, diet and increased physical activity are the cornerstones [45]. If symptoms persist despite lifestyle changes, which is common in pubertal adolescents when disease-related insulin resistance adds up to physiological insulin resistance, the inclusion of pharmacotherapy may be needed. The drug of choice was metformin, which is considered safe in children and adolescents [46]. Metformin plays an important role in the prevention of T2DM in people with abdominal obesity. It improves glucose tolerance and impedes the conversion of the pre-diabetic state to T2DM [47]. Many authors have noted its usefulness in the treatment of glucose tolerance disorders in adolescent patients [48]. This is supported by extensive randomised trials [49]. Attempts have also been made to use other drugs [50–53]. There are now reports of other drugs being used in young patients as well [54]. There are no clear recommendations for the treatment of pre-diabetic conditions in adolescent patients [55]. As mentioned earlier, liraglutide and dapagliflozin have recently been introduced for the treatment of T2DM in adolescents. The authors presented the results of a randomised trial of glucagon-like peptide-1 (GLP-1) agonists in T2DM, pre-diabetes, and obesity in children aged < 18 years. They found that GLP-1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults. The effectiveness of GLP-1 agonists therapy, especially in pre-diabetic state, is also pointed out by other authors [56]. These studies suggest that further observations are needed regarding the indications and safety of modern therapy for T2DM in adolescent patients [42]. The significant increase in the prevalence of obesity in children and adolescents over past decades caused a concomitant rise in the incidence of glucose intolerance and diabetes. Young patients develop clinical DM and complications more rapidly and aggressively. Therefore, early diagnosis, prevention, and treatment of disorders are important. Referring to the International Society for Paediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines 2022 [57], there are certain features that, taken together, may suggest monogenic diabetes in children initially suspected of having T1DM. The significant increase in obesity in children and adolescents has meant that children and adolescents with monogenic diabetes can also be obese and very difficult to distinguish from T2DM. For such cases there are also certain characteristics that can be taken into account in verifying the diagnosis.

Conclusions

Becoming more familiar with other types of diabetes in the young population is an extremely important element in daily medical practice because misdiagnosis of the type of diabetes and inadequate treatment can translate into a reduction in the patient’s quality of life and health. Thus, it is worth paying attention to the increasing prevalence of T2DM in the young population, not forgetting the monogenic types of diabetes, the clinical picture of which may confusingly resemble the most common types of diabetes.