Screening of prediabetes and Type 2 Diabetes in Pediatrics

➡️Definition of the disease condition

Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Inadequate insulin secretion and/or diminished tissue responses to insulin in the complex pathways of hormone action result in deficient insulin action on target tissues, which leads to abnormalities of carbohydrate, fat, and protein metabolism. The etiology of diabetes is heterogeneous, however, most cases can be classified into two broad etiopathogenetic categories type 1 diabetes (T1D), which is characterized primarily by deficiency of insulin secretion; or type 2 diabetes (T2D), which results from a combination of resistance to insulin action, as well as an inadequate compensatory insulin secretory response for the degree of insulin resistance, due to progressive non-autoimmune β-cell failure (1,2).  It was formerly known as adult onset diabetes or non-insulin dependent diabetes (2).

➡️Magnitude of the problem worldwide.

While T1D remains the most common form of diabetes in children and adolescents worldwide, T2D is becoming more prevalent and imposes an increasingly important public health burden globally (3). It is stated that T2D in youth has become widespread in many regions of the world; and its frequency in the pediatric age range is increasing (4,5).

 In many countries, the incidence of T2DM in adolescents continues to increase. Similarly, the prevalence of prediabetes, defined in adults as a state of high-risk for progression to diabetes, is increasing quickly in some developing countries with the increase of overweight and obesity (6).

Worldwide incidence and prevalence of T2D in children and adolescents vary substantially among countries, age categories and ethnic groups (3). Epidemiologic studies have shown variations in the incidence of T2D in children and adolescents ranging from 1 to 51 per 1000 (7). The highest reported was in North American Indian adolescents with a prevalence of 50.9 per 1000. The Center for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) reported increasing prevalence of pediatric T2D in the United States by 35% between 2001 and 2009 with an incidence rate of 5,000 new cases per year (8).  Similar trends have been reported in many European countries, although there is a significantly lower incidence rate. Candler et al. (9) showed an incidence of T2D of 0.72/100,000 per year in British children and adolescents (9). Similarly, Schober et al. described the incidence of T2D at 0.29 cases per 100,000 per year between 1999 and 2007 in Austrian children and adolescents (10). In Korea the average incidence rate of T2D in children and adolescents was 0.75/100,000 (11). In China, they reported a T2D prevalence ranging from 2.52/100,000 to 15.64/100,000 (12).

The difference in the incidence and prevalence rates of T2D in children might be attributed to genetics and hormonal factors, environmental influences, different quality of life, and access to health care.

It has been reported that T2D disproportionately involves youth of ethnic and racial minorities, demonstrating substantial differences in insulin secretion and sensitivity that might increase the risk of T2D. It has been postulated that the complexity of psychosocial and cultural environments might influence the onset of T2D in ethnic and racial minorities, where it may be difficult to achieve healthy lifestyle modifications and self-management actions (1).

➡️Magnitude of the problem in Egypt with impact on health and economy

In Egypt, T2D is presenting a major public health care burden with a total cost of 25.2 billion EGP equivalent to 3.5 billion USD (13). According to the IDF, the annual prevalence increment rate of T2D in Egypt is 266%. Moreover, Egypt is thought to jump from the 9^th to the 7^th rank among the countries with highest prevalence of T2D worldwide by 2030 with a prevalence of 12.4 millions (14). Data about the prevalence of T2D in children and adolescents are sparse. Studies showed increasing prevalence rates varying from 0.01% in 2002 (15) to 0.3% recently in 2018 (16).

➡️Role of screening and early detection in ameliorating this impact.

T2D is a complex and multifactorial disease, characterized by an association between genetic, epigenetic, and environmental factors (17). The pathophysiology of T2D in children is more complex than that in adults. Beta-cell dysfunction occurs more rapidly in children than in adults (18).

Primary prevention approaches aiming at addressing the modifiable risk factors, starting from the intra-uterine period and extending throughout childhood, are of utmost importance in preventing T2DM. Despite the possibility of detecting the genetic susceptibility to T2DM by documenting compromised insulin secretion and insulin sensitivity in otherwise healthy children with a positive family history, it is not cost effective. Since the diagnosis of T2DM in youth is rare before puberty, it is detected more frequently during puberty when physiologic and transient insulin resistance (IR) occurs (insulin sensitivity declines by 25%–30% (19).

Maternal overweight and obesity were found to be associated with T2DM in offspring, irrespective of various confounding pre-existing or pregnancy-related conditions (20). Children born to obese or overweight women were found to have a 3.5- and 1.4-fold higher incidence of T2DM respectively, compared to those born to normal-weight women (21). Hence, one of the earliest points of childhood T2DM prevention is the reduction of maternal overweight and obese status during pregnancy. In addition, studies have documented that offspring of women with gestational diabetes (GDM) are at increased risk of T2DM and obesity, irrespective of the mother’s weight status during pregnancy (22). Not only overt GDM but also prediabetic conditions during pregnancy have been linked to glucose abnormalities and insulin resistance in the offspring (23). Protection of the fetus from intrauterine glycemic derangements is, therefore, of paramount importance to prevent prediabetic conditions and T2DM in childhood and adolescence. Other risk factors such as maternal diet, maternal smoking, and paternal obesity should also be considered (24-26).

In order to prevent childhood T2DM, one should clearly focus on intrauterine life, but postnatal exposures seem to play an equally important role. Childhood obesity is among the major modifiable risk factors of T2DM in children.  Increasing BMI has been reported as a risk factor of glycemic deterioration and progression to T2DM (27).

The importance of programming in T2DM pathogenesis is growing. Dietary and environmental factors during the first 1000 days from conception to the second birthday have utmost importance in T2DM prevention (28). Breastfeeding was found to have a strong protective effect against childhood T2DM especially among high risk populations (29, 30).  Moreover, both high and low birth weight, preterm birth, as well as rapid weight gain during the first months of life have been shown to increase the risk of childhood obesity, insulin resistance and glucose metabolism disturbances, predisposing to T2DM (31-33).

In an earlier review in 2007 (34) including reports on acute and long-term comorbidities associated with type 2 diabetes in young people, microvascular complications have been identified at diagnosis, implying long-term, unrecognized hyperglycemia. Children may also present with acute decompensation in diabetic ketoacidosis (DKA) and/or hyperosmolar hyperglycemic state (HHS). This argues for a systematic screening program in children at high risk for type 2 diabetes in order to prevent an acute, life-threatening presentation and to decrease the development of chronic complications. Although not proven in children, it is generally assumed that earlier diagnosis of diabetes will lead to interventions that will improve glycemic control and reduce the related short- and long-term complications (34).

The optimal approach to screening and diagnosis of prediabetes and diabetes in youth is uncertain (35). In a recent cross-sectional analysis conducted by Wallace et al (35) including 14,119 youth aged 10 to 19 years in the 1999–2016 NHANES; it was found that HbA1c is a specific and useful non fasting test to identify high-risk youth who could benefit from lifestyle interventions to prevent diabetes and cardiovascular risk in adulthood. Sensitivity and specificity of the screening criteria for detecting any hyperglycemia were low for both HbA1c ≥ 5.7% (sensitivity = 55.5%, specificity = 76.3%) and FPG ≥ 100 mg/dL (sensitivity = 35.8%, specificity = 77.1%). Confirmed undiagnosed diabetes (HbA1c ≥ 6.5% and FPG ≥ 126 mg/dL) was rare, 0.5% of youth. Associations with cardiometabolic risk were consistently stronger and more specific for HbA1c-defined hyperglycemia (specificity = 98.6%; sensitivity = 4.0%) than FPG defined hyperglycemia (specificity = 90.1%; sensitivity = 19.4%).

For better sensitivity, a combination of A1C and fasting or random blood glucose is recommended to screen for type 2 diabetes in children and youth with risk factors; with a 2-hour OGTT to be considered as an initial screening test in children and youth with 3 or more risk factors. A 2-hour OGTT was also recommended in those who show a discrepancy between the A1C and fasting or random blood glucose results on screening (36).

Recent analyses of data from US adolescents estimate prediabetes to be present in 4–23% of adolescents, depending on criteria used, with other studies finding an 8% risk of progression from prediabetes to T2DM over a 3-year period. These data support the importance of intervention to avoid long-term sequelae, focusing on reducing degree of obesity and insulin resistance (37).

➡️Methods of prevention of progression and possible reversal of the disease condition

Healthy diet and physical activity are important in preventing childhood obesity. This is especially important in the preschool period. Rapid weight gain in preschool children was found to be associated with a high risk of overweight or obesity in adolescence, increasing the risk of childhood T2DM (38). Most programs aiming at preventing childhood T2DM are based on obesity prevention, given the etiological connection between increased childhood obesity, metabolic syndrome and T2DM. These programs mostly target dietary interventions like providing healthier school meals, reducing simple sugars, and restricting unhealthy food advertisements aimed at children. Nutritional interventions should be combined with programs targeting increased physical activity and restricting sedentary life and screen time in order to achieve the best long-term outcome (39).

Regarding adolescents, school-based interventions have proven more effective when the adolescents were addressed directly (40).

Because of the rarity and the relatively recent emergence of the problem in children and adolescents, there has been limited evidence leading to unique challenges in the diagnosis, management, and monitoring of this vulnerable population. This limited evidence base is further complicated by differences in the characteristics and presentation of the disorder and approaches to treatment in developed and developing countries. Hence we aim to provide guidelines for screening and prevention of childhood T2D in Egypt.