Screening of prediabetes and Type 2 Diabetes in Pediatrics
- Executive Summary
➡️Introduction
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. It was formerly known as adult-onset diabetes or non-insulin dependent diabetes.
➡️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. 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.
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.
Worldwide incidence and prevalence of T2D in children and adolescents vary substantially among countries, age categories and ethnic groups. Epidemiologic studies have shown variations in the incidence of T2D in children and adolescents ranging from 1 to 51 per 1000
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.
➡️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. According to the IDF, the annual prevalence increment rate of T2D in Egypt is 266%. Moreover, Egypt is thought to jump from the 9th to the 7th rank among the countries with highest prevalence of T2D worldwide by 2030 with a prevalence of 12.4 millions. Data about the prevalence of T2D in children and adolescents are sparse. Studies showed increasing prevalence rates varying from 0.01% in 2002 to 0.3% recently in 2018.
➡️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. The pathophysiology of T2D in children is more complex than that in adults. Beta-cell dysfunction occurs more rapidly in children than in adults.
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% .
Maternal overweight and obesity were found to be associated with T2DM in offspring, irrespective of various confounding pre-existing or pregnancy-related conditions. 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. 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. Not only overt GDM but also prediabetic conditions during pregnancy have been linked to glucose abnormalities and insulin resistance in the offspring. 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.
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.
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. Breastfeeding was found to have a strong protective effect against childhood T2DM especially among high-risk populations. 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.
In an earlier review in 2007 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.
The optimal approach to screening and diagnosis of prediabetes and diabetes in youth is uncertain. In a recent cross-sectional analysis conducted by Wallace et al 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.
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
➡️Methods of prevention of progression and possible reversal of the disease condition
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.
Regarding adolescents, school-based interventions have proven more effective when the adolescents were addressed directly.
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.
➡️Scope
- This guideline focuses on screening and diagnosis of pre-diabetes and type 2 Diabetes with its comorbidities.
➡️ GUIDELINE OBJECTIVES
1) Screening for early detection of prediabetes allowing the opportunity to prevent or delay progression to type 2 diabetes and its comorbidities.
2) Early detection of type 2 diabetes in high-risk groups, to prevent or delay serious diabetes complications during adolescence and early adulthood.
3) Screening for early diagnosis of comorbidities or complications in adolescents with prediabetes and type 2 diabetes to prevent serious disabilities during adolescence and early adulthood.
➡️ Health/Clinical Question (PIPOH)
- P (patients, target population):
Gender: both genders.
Age group: adolescents and preadolescents in the age group of 10-19 years.
Disease/ condition: prediabetes and type 2 diabetes (T2DM).
Comorbidity: obesity with one or more of the following:
Hypertension, dyslipidemia, NACLD, PCOS, and other organ affection (clinical features suggestive of metabolic syndrome).
Exclusion criteria: other types of diabetes or hyperglycemic states (e.g. type 1 diabetes, MODY, secondary diabetes, and drug-induced diabetes).
- I (interventions and practices considered/ guideline category):
Screening (clinical and laboratory) for prediabetes and type 2 diabetes in adolescents (age group from 10 to 19 years).
Screening for early detection of comorbidities associated with those at risk of prediabetes or type 2 diabetes.
- P (Professionals / intended or target users and clinical specialties):
-Primary health care physicians at Ministry of Health (MOH).
-General pediatricians and school physicians.
-Family medicine physicians.
- O (major outcomes):
Primary outcome:
Early detection and prompt referral of prediabetes and type 2 diabetes in adolescents to pediatric endocrinologist care.
Secondary outcome:
- Prevention of progression of prediabetes to type 2 diabetes.
- Early detection of associated comorbidities of prediabetes and type 2 diabetes.
- H (Healthcare settings):
➡️Type: primary and secondary.
➡️Health care sector: governmental, non-governmental and private sectors.
➡️Guideline development process and methods
After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):
1- ISPAD guidelines
(2022)
We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)
- Adoption for most of the guideline recommendations.
- Adaptation for 2 recommendations according to GRADE criteria to be suitable to our Economic implications (Evidence-to-Decision (EtD) table was done)
- Development of Good Practice Statements
➡️Recommendations and Good Practice Statements (GPS)
This version of the CPG includes recommendations and good practice statements on the following:
➡️Diagnosis of Pre-diabetes and Type 2 Diabetes
The guideline covers Adolescents and preadolescents in the age group of 10-19 This Guideline emphasis on:
2) Early detection of type 2 diabetes in high-risk groups, to prevent or delay serious diabetes complications during adolescence and early adulthood.
3) Screening for early diagnosis of comorbidities or complications in adolescents with prediabetes and type 2 diabetes to prevent serious disabilities during adolescence and early adulthood.
➡️We can summarize the guidelines’ recommendations for Type 2 Diabetes in the following:
Adolescents at risk that should be screened for prediabetes or type 2 diabetes in primary health care setting or general pediatric department or outpatient clinic?
Risk factors to develop type 2 diabetes (High, Strong) :
Obesity (BMI > 95th percentile for age and sex), intrauterine growth retardation with rapid infant weight gain, first-degree family history of type 2 diabetes, maternal history of diabetes or gestational diabetes during child's gestation, high-risk ethnicity, polycystic ovary syndrome (PCOS).
Risk-based screening for prediabetes and/or type 2 diabetes should be considered after the onset of puberty or after 10 years of age, whichever occurs earlier in children and adolescents who are overweight (BMI > 85th percentile) or obese (BMI > 95th percentile) and who have one or more additional risk factors for diabetes (Refer to table (1) in implementation tools for details and level of evidence) (High, Strong).
Assessment for dysglycemia in obese at-risk youth should occur in the setting of clinical assessment of other obesity-related comorbidities (metabolic dysfunction-associated steatotic liver disease (MASLD)), dyslipidemia, elevated blood pressure [BP], and polycystic ovary syndrome) that are more prevalent than dysglycaemia (Refer to Q 6) below) (High, Strong).
➡️Tests recommended for screening of prediabetes or type 2 diabetes in primary health care setting or general pediatric department or outpatient clinic:
Fasting plasma glucose, 2-h plasma glucose after 75-g OGTT, and HbA1C can be used to test for prediabetes or diabetes (Intermediate, Strong).
Recommend using a combination of A1C and fasting or random blood glucose to screen for type 2 diabetes in children and youth with risk factors.
“A 2-hour OGTT may be considered as an initial screening test in children and youth with 3 or more risk factors and should be done in those in whom there is a discrepancy between the A1C and fasting or random blood glucose results” (Good Practice Statement).
➡️Positive screening test result for prediabetes or type 2 diabetes in primary health care setting or general pediatric department?
Criteria for considering diagnosis of prediabetes according to ADA definitions (High, Strong):
• Impaired fasting glycemia (IFG): FPG ≥100-125 mg/dL
• Impaired Glucose tolerance (IGT): Post-challenge plasma glucose is ≥140-199 mg/dL
• Hemoglobin A1c ˂5.7% normal, 5.7% to 6.4% prediabetes.
(Should be laboratory-based, DCCT aligned, NGSP certified methodology).
Criteria for diagnosis of type 2 diabetes (High, Strong):
a) Symptoms of diabetes (polyuria, polydipsia, nocturia, and unexplained weight loss) and a random plasma glucose ≥200 mg/dL OR
• Fasting blood glucose ≥126 mg/dL OR
• 2-hour blood glucose concentration during an oral glucose tolerance test (OGTT) ≥200 mg/dL OR
• Hemoglobin A1c (HbA1c) ≥ 6.5%
(Should be laboratory-based, DCCT aligned, NGSP certified methodology).
Point-of-care measurement of HbA1c is not acceptable for diagnosis.
In the absence of symptoms, testing should be confirmed with a repeat test on a different day (Intermediate, Strong).
Measurement of insulin or C-peptide is NOT recommended as part of routine evaluation.
If tests are normal repeat testing at a minimum of 3-year intervals,
or more frequently if BMI is increasing, the cardiometabolic risk profile is deteriorating, there is a strong family history of T2D, or evidence of pre-diabetes (Low, Conditional).
➡️Referral to pediatric endocrinologist and diabetologist in adolescents with suspected prediabetes or type 2 diabetes in the primary health care setting or general pediatric department:
Referral to pediatric diabetologist/endocrinologist is recommended in children and adolescents suspected to have prediabetes or type 2 diabetes according to the American Diabetes Association (ADA) criteria (High, Strong).
➡️Screen for comorbidities of prediabetes and type 2 diabetes in adolescents at risk in the primary health care setting or general pediatric department or outpatient clinic:
➡️Hypertension:
Blood pressure should be monitored at every visit according to standardized techniques specific for children.
Elevated BP should be confirmed on 2 additional separate days. (High, Strong)
Hypertension is defined as an average systolic or diastolic BP > 95th percentile for age, sex, and height, with high normal BP being 90th to <95th percentile.
Initial treatment of elevated blood pressure should consist of weight loss, limitation of dietary salt, and increased physical activity (Very Low, Conditional).
Dyslipidemia:
Lipids should be measured yearly starting at diabetes onset (after optimal glycemic levels are achieved or within 3 months of diagnosis)
Initial screening for dyslipidemia does not require fasting
Goal levels for lipids are:
1. LDL-Cholesterol < 100 mg/dL
2. HDL- Cholesterol > 35 mg/dL
3. Triglycerides < 150 mg/dL (Intermediate, Strong).
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) :
Evaluation for MASLD by measuring ALT and AST should be done at diagnosis of type 2 diabetes and annually thereafter (High, Strong).
Interpretation of ALT should be based upon sex-specific upper limits of normal in children (22 U/L for girls and 26 U/L for boys) and not individual laboratory upper limits of normal (High, Strong).
➡️If liver enzymes remain >3 times the upper limit of normal after 6 months refer to a pediatric gastroenterologist for consultation to exclude other causes of elevated liver enzymes, imaging and/or liver biopsy (Moderate, Strong)
Polycystic ovary syndrome
Female patients should be asked about menstrual irregularities, and symptoms of hyperandrogenism.
Patients with menstrual irregularities should be tested for hyperandrogenism (Very Low, Conditional).
Diagnosis of PCOS in adolescents should be based on a complete picture that includes clinical signs and symptoms of androgen excess, increased androgen levels, and exclusion of other causes of hyperandrogenemia in the setting of oligomenorrhea (See appendix). If suspected refer to endocrinologist (Intermediate, Strong).
➡️Prevent progression of prediabetes to type 2 diabetes in adolescents in primary health care setting or general pediatric department:
Only lifestyle change, with decreased caloric intake and increased physical activity has been shown to be effective for adolescents with pre-diabetes (High, Strong).
Diet modification should focus on (Intermediate, Strong):
• Eliminating sugar-sweetened soft drinks and juices.
• Reducing the intake of foods made from refined, simple sugars and high fructose corn syrup.
• Limiting use of high-fat and/or high calorie dense foods.
Reducing the use of processed, prepackaged, and convenience foods (Very Low, Conditional):
• Portion control.
• Reducing meals eaten away from home.
• Increasing vegetable intake and limited use of fruit as a substitute for high-calorie and low nutrient foods.
• Changing staple foods from enriched white rice and white flour to brown rice and whole grain items with lower glycemic index to promote gradual and sustainable absorption with meals.
The Mediterranean diet which provides a carbohydrate content < 50% of daily energy and includes abundant use of poly- and mono-unsaturated fat (about 20%), mainly olive oil, was found to reverse dysglycemia (Good Practice Statement).
The use of metformin and/or insulin in youth with prediabetes is not currently recommended (High, Strong).
➡️Guideline Registration
PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((PREPARE-2022CN813)). Link: http://www.guidelines-registry.org/