ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 diabetes in children and adolescents.

Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.

Puberty Is Associated with a Rising Hemoglobin A1c, Even in Youth with Normal Weight.

Our objective was to explore the longitudinal trajectory of hemoglobin A1c (HbA1c) in well-characterized youth (n = 84) with normal weight and obesity during puberty. HbA1c rose from early puberty to Tanner stage 5, even in healthy, normal weight youth, revealing important implications for defining normal glycemia and prediabetes in adolescents.

High prevalence of cardiometabolic risk features in adolescents with 47,XXY/Klinefelter syndrome.

Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10-17 years) were well-matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1-5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305.

Normal Hemoglobin A1c Variability in Early Adolescence: Adult Criteria for Prediabetes Should Be Applied with Caution.

American Diabetes Association adult criteria are used to screen youth for diabetes, but little is known about normal glycemia in youth. In the HEALTHY Study (total n = 8814), hemoglobin A1c was ≥5.7% in 2% of normal weight youth. This suggests need for cautious interpretation of prediabetes hemoglobin A1s in youth.

Withdrawal of medications leads to worsening of OGTT parameters in youth with impaired glucose tolerance or recently-diagnosed type 2 diabetes.

BACKGROUND: The RISE Pediatric Medication Study compared strategies for preserving ß-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability. OBJECTIVE: Evaluate OGTT measures of glucose and ß-cell response through 12 months of intervention and 9 months of medication washout. PARTICIPANTS: Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D). METHODS: A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (G→Met) or metformin alone (Met) for 12 months. We report within-group changes from baseline to end of medication intervention (M12), baseline to 9 months post-medication withdrawal (M21), and end of medication (M12) to M21. OGTT C-peptide index [CPI] paired with 1/fasting insulin evaluated ß-cell response. RESULTS: At M12, both treatments were associated with stable fasting glucose (G→Met baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2-hour glucose (G→Met baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (G→Met M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2-hour glucose (G→Met M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in ß-cell response. CONCLUSIONS: G→Met and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and ß-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued.

Evaluation of the longitudinal change in health behavior profiles across treatment groups in the TODAY clinical trial.

BACKGROUND: Individual health behaviors (ie, eating habits and sedentary lifestyle) are associated with type 2 diabetes (T2D). Health behavior profiles specific to adolescents with T2D have not been described. OBJECTIVE: To identify health behavior profiles in adolescents with T2D and examine how these profiles change over time. METHODS: Diet (via food frequency questionnaire) and activity behaviors (via 3-day physical activity recall) examined at baseline, 6 months, and 24 months from participants in the the Treatment Options for T2D in Adolescents and Youth (TODAY) study were used for this analysis. Latent profile analysis identified profiles of health behaviors within three time points, and latent transition probabilities were estimated to examine the change from baseline to 6 months (n = 450) and baseline to 24 months (n = 415). Multinomial logistic regressions were used to examine if the assigned TODAY treatment group (Metformin [Met], Met + Rosiglitazone [Rosi], or Met + Lifestyle) predicted change in health behavior profiles. RESULTS: Three profiles emerged: "most sedentary," "healthy eaters," and "active and eat most." At 6 months, 50% of males and 29% of females in the Met + Lifestyle treatment group improved in their health behavior profile. Among males only, the Met + Lifestyle treatment group were more likely to improve their profiles from baseline to 6 months (P = .01). CONCLUSIONS: Three health behavior profiles emerged and shifted over time. A high quality, lifestyle intervention had little effect on improving health behavior profiles. Optimizing outcomes in youth with T2D might require more robust and multifaceted interventions beyond family-level lifestyle, including more extensive psychosocial intervention, novel medication regimen, or bariatric surgery.

Screening for cystic fibrosis-related diabetes and prediabetes: Evaluating 1,5-anhydroglucitol, fructosamine, glycated albumin, and hemoglobin A1c.

OBJECTIVE: Dysglycemia is prevalent in cystic fibrosis (CF) but screening with annual oral glucose tolerance tests (OGTT) can be burdensome. We investigated alternate glycemic markers-hemoglobin A1c (HbA1c), 1,5-anhydroglucitol (1,5AG), fructosamine (FA), and glycated albumin (GA)-as screening tests for CF-related diabetes (CFRD) and pre-diabetes (CFPD) in youth with CF as defined by the gold-standard OGTT 2-hour glucose (2hG). METHODS: Youth 10 to 18 years with CF had a 1,5AG, FA, GA, HbA1c, and 2-hour OGTT collected. Correlations between all glycemic markers and 2hG were evaluated. Area under the receiver operative characteristic (ROC-AUC) curves were generated. Optimal cut points for predicting CFPD (2hG ≥ 140 mg/dL) and CFRD (2hG ≥ 200 mg/dL) were determined. RESULTS: Fifty-eight youth with CF were included (2hG < 140, n = 16; CFPD, n = 33; CFRD, n = 9; 41% male, mean ± SD age 14.2 ± 3.6 years, BMI z-score 0.0 ± 0.8, % predicted forced expiratory volume in 1 second [FEV1] 89.9 ± 15.1, % predicted forced vital capacity [FVC] 103.2 ± 14.6). ROC-AUC's for all alternate markers were low for CFPD (0.52-0.67) and CFRD (0.56-0.61). At a cut point of 5.5%, HbA1c had 78% sensitivity (95% CI: 0.45-0.94) and 41% specificity (95% CI: 0.28-0.55) for identifying CFRD, correlating to a ROC-AUC of 0.61 (95% CI: 0.42-0.8). CONCLUSIONS: All alternate markers tested demonstrate poor diagnostic accuracy for identifying CFRD by 2hG.

A randomized clinical trial to evaluate the single-dose pharmacokinetics, pharmacodynamics, and safety of sitagliptin in pediatric patients with type 2 diabetes.

OBJECTIVE: To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported. RESULTS: Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0-∞ , Cmax , and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. CONCLUSIONS: Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

Review of methods for measuring ß-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium.

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of ß-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of ß-cell function and changes in ß-cell function in response to interventions. In the present paper, we review approaches for measurement of ß-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of ß-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure ß-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in ß-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine.

Alternate glycemic markers reflect glycemic variability in continuous glucose monitoring in youth with prediabetes and type 2 diabetes.

OBJECTIVE: To determine whether the alternate glycemic markers, fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5AG), predict glycemic variability captured by continuous glucose monitoring (CGM) in obese youth with prediabetes and type 2 diabetes (T2D). STUDY DESIGN: Youth with BMI ≥85th%ile, 10-18 years, had collection of fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), FA, GA, and 1,5AG and 72 hours of CGM. Participants with HbA1c ≥5.7% were included. Relationships between glycemic markers and CGM variables were determined with Spearman correlation coefficients. Linear models were used to examine the association between alternate markers and CGM measures of glycemic variability-standard deviation (SD) and mean amplitude of glycemic excursions (MAGE)-after controlling for HbA1c. RESULTS: Total n = 56; Median (25th%ile, 75th%ile) age = 14.3 years (12.5, 15.9), 32% male, 64% Hispanic, 20% black, 13% white, HbA1c = 5.9% (5.8, 6.3), FA=211 mmol/L (200, 226), GA= 12% (11%, 12%), and 1,5AG = 22mcg/mL (19, 26). HbA1c correlated with average sensor glucose, AUC, SD, MAGE, and %time > 140 mg/dL. FA and GA correlated with average and peak sensor glucose, %time >140 and >200 mg/dL, and MAGE. GA also correlated with SD and AUC180. 1,5AG correlated with peak glucose, AUC180, SD, and MAGE. After adjusting for HbA1c, all 3 markers independently predicted MAGE; FA and GA independently predicted SD. CONCLUSIONS: Alternate glycemic markers predict glycemic variability as measured by CGM in youth with prediabetes and T2D. After adjusting for HbA1c, these alternate markers continued to predict components of glycemic variability detected by CGM.

Insulin Resistance of Puberty.

Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.

Screening for type 2 diabetes and prediabetes in obese youth: evaluating alternate markers of glycemia - 1,5-anhydroglucitol, fructosamine, and glycated albumin.

Hemoglobin A1c (HbA1c) is increasingly performed over the oral glucose tolerance test (OGTT) as the initial screening test for type 2 diabetes in youth. However, the optimal strategy for identifying type 2 diabetes in youth remains controversial. Alternate glycemic markers have been proposed as potentially useful tools for diabetes screening. We examined the relationships among fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG) with traditional screening tests, HbA1c and OGTT. Youth 10-18 yrs, BMI ≥85th‰, and HbA1c <7.5% had a single visit with measurement of HbA1c, 1,5-AG, FA, GA, and a standard OGTT. Distributions of FA, GA, and 1,5-AG by HbA1c and 2-hour glucose (2hG) categories were compared. Receiver operating characteristic (ROC)-curves were generated to determine the cut points at which alternate markers maximized sensitivity and specificity for predicting prediabetes and diabetes. One hundred and seventeen, 62% female, 59% Hispanic, 22% White, 17% black, median 14.1 yr, and body mass index (BMI) z-score 2.3 participated. Median values of each alternate marker differed significantly between prediabetes and diabetes HbA1c and 2hG categories (p < 0.017). Only GA medians differed (p = 0.006) between normal and prediabetes HbA1c. Area under the receiver operating characteristic curves (ROC-AUCs) for alternate markers as predictors of prediabetes (0.5-0.66) were low; however, alternate marker ROC-AUCs for identifying diabetes (0.82-0.98) were excellent. Although the alternate markers were poor predictors of prediabetes, they all performed well predicting diabetes by 2hG and HbA1c. Whereas the usefulness of these markers for identifying prediabetes is limited, they may be useful in certain scenarios as second line screening tools for diabetes in overweight/obese youth.

Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study.

OBJECTIVE: The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort. RESEARCH DESIGN AND METHODS: Descriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening. MAIN OUTCOME MEASURES: Demographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures. RESULTS: Subjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation. CONCLUSIONS: Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control.

Hemoglobin A1c assay variations and implications for diabetes screening in obese youth.

BACKGROUND: Standardization of the hemoglobin A1c (A1c) assay has led to its increasing utilization as a screening tool for the diagnosis of prediabetes and type 2 diabetes in youth. However, significant A1c assay variability remains and has implications for clinical management. OBJECTIVE: To describe our center's experiences with A1c results in youth and to evaluate inter-method differences and their clinical implications. SUBJECTS: Seventy-five youth (aged 10-18 yr old), body mass index (BMI) ≥85th‰ participated. METHODS: Seventy-two participants had two A1c values performed on the same sample, one via immunoassay (DCA Vantage Analyzer, A1c1 ) and the other via high performance liquid chromatography (Bio-Rad Variant II, A1c2 ). Nineteen had A1c run on two immunoassay devices (A1c1 and Dimensions Vista, A1c3 ). RESULTS: Mean age of participants was 13.9 years, BMI% 97.89%, 33% male, 16% white, 21% black, and 61% Hispanic (H). Mean A1c1 was 5.68% ± 0.38 vs. a mean A1c2 of 5.73% ± 0.39, p = 0.049. Concordance in diabetes status between methods was achieved in 79% of subjects. Nineteen subjects with A1c3 results had testing performed an average of 22 ± 9 days prior to A1c1 . Mean A1c3 was 6.24% ± 0.4, compared to a mean A1c1 of 5.74% ± 0.31, (p < 0.0001). A1c1 was on average systematically -0.5 ± 0.28 lower compared to A1c3 . There was poor agreement in diabetes classification between A1c1 and A1c3 , with a concordance in classification between methods of only 36.8%. CONCLUSIONS: Clinically significant inter-method A1c variability exists that impacts patient classification and treatment recommendations. In the screening of obese youth for diabetes, A1c results should be interpreted with caution.

Dulaglutide and Glomerular Hyperfiltration, Proteinuria, and Albuminuria in Youth With Type 2 Diabetes: Post Hoc Analysis of the AWARD-PEDS Study.

OBJECTIVE: To examine changes in glomerular hyperfiltration and other measures of kidney function in youth with type 2 diabetes treated with dulaglutide or placebo. RESEARCH DESIGN AND METHODS: Post hoc analysis was performed on kidney laboratory data from 154 youths (age 10-18 years) with type 2 diabetes enrolled in a completed placebo-controlled glycemic control trial of dulaglutide. RESULTS: Mean estimated glomerular filtration rate (eGFR) decreased from baseline to 26 weeks in participants treated with dulaglutide versus placebo (-5.8 vs. -0.1 mL/min/1.73 m2; P = 0.016). Decreases in eGFR were observed primarily in participants with baseline glomerular hyperfiltration. At 26 weeks, the prevalence of both glomerular hyperfiltration and proteinuria increased with placebo but decreased with dulaglutide (P = 0.014 and 0.004 vs. placebo, respectively). CONCLUSIONS: Dulaglutide was associated with attenuated glomerular hyperfiltration and proteinuria in youth with type 2 diabetes. The impact of these changes on the risk of diabetic kidney disease is unclear.

Congenital adrenal hyperplasia and the second newborn screen.

OBJECTIVE: To evaluate the effectiveness of a second newborn screen for congenital adrenal hyperplasia (CAH) in the state of Colorado and report characteristics associated with cases identified on the first versus second screen. STUDY DESIGN: Colorado implemented newborn screening for CAH with 17-hydroxyprogesterone beginning August 2000. The first screening is performed within 72 hours of life and the second between 8 and 14 days of life. We compared infants diagnosed on the basis of the first versus second newborn screen. RESULTS: The first screen identified 29 cases of which 28 represented classical CAH. The incidence of classical CAH on the first screen was 1:24,766. The second screen identified 17 additional cases, of which 11 represented classical CAH. Combined, the incidence of classical CAH was 1:17,789. The sensitivity of the first screen was 71.79%. The false negative rate of the first screen was 28.2%. In the absence of a second screen, 1:47,824 infants would have been missed. Infants diagnosed on the first screen had higher 17-hydroxyprogesterone values compared with those diagnosed on the second screen (P = .0008). CONCLUSIONS: The use of a single newborn screen for CAH missed nearly 30% of classical CAH cases in Colorado. Addition of a second screen, therefore, can improve the operating characteristics of the newborn screening program.

Hypoglycemia in children and young adults with cystic fibrosis during oral glucose tolerance testing vs. continuous glucose monitoring.

BACKGROUND: Hypoglycemia is common in people with cystic fibrosis (pwCF) during oral glucose tolerance tests (OGTTs) and in the free-living setting, yet its pathophysiology remains unclear. OBJECTIVE: To evaluate hypoglycemia in children and young adults with CF by OGTT and continuous glucose monitoring (CGM). METHODS: A 3-h OGTT was performed in children and young adults with CF and healthy controls (HC). Individuals were classified as experiencing hypoglycemia on OGTT (glucose <70 mg/dL) or not. Insulin, C-peptide, glucose, glucagon, and incretins were measured. CGM was performed for 7 days in the free-living setting. Measures of insulin sensitivity, beta cell function accounting for insulin sensitivity, and insulin clearance were calculated. RESULTS: A total of 57 participants (40 CF and 17 HC) underwent assessment. Rates of hypoglycemia by OGTT were similar in pwCF (53%, 21/40) compared to HC (35%, 6/17), p = 0.23. PwCF compared to HC had higher A1c; on OGTT higher and later glucose peaks, later insulin peaks; and on CGM more glucose variability. CF Hypo+ versus CF Hypo- had higher lung function, higher insulin sensitivity, higher beta cell function accounting for insulin sensitivity, and decreased CGM variability. When comparing CF Hypo+ to HC Hypo+, although rates of hypoglycemia are similar, pwCF had blunted glucagon responses to hypoglycemia. OGTT hypoglycemia was not associated with CGM hypoglycemia in any group. CONCLUSION: Youth with CF have increased insulin sensitivity and impaired glucagon response to hypoglycemia on OGTT. Hypoglycemia on OGTT did not associate with free-living hypoglycemia.