Pathophysiology and Treatment of Prediabetes and Type 2 Diabetes in Youth

Type 2 diabetes in youth is a heterogeneous disorder that primarily occurs in adolescents and is associated with defects in insulin secretion in the setting of severe insulin resistance. Genetic predisposition to the disease is suggested by high heritability and discovery of several genetic loci related to obesity, insulin resistance, and β-cell function (1). Genetic susceptibility to type 2 diabetes is modulated by epigenetic, physiologic, and environmental influences that contribute to β-cell dysfunction. Preceding diabetes, a stage of measurable dysglycemia or prediabetes can be identified including impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or a combination. In this review we provide an update on the current understanding of the pathophysiology of youth-onset prediabetes and type 2 diabetes. We describe the mechanisms underlying insulin resistance, the precipitous decline of β-cell function, and the role of other hormonal abnormalities in the pathogenesis of the disease. We discuss the critical importance of social determinants of health, and the advances in therapeutic approaches.

Type 2 diabetes is characterized by progressive loss of β-cell function in the setting of insulin resistance and absence of markers of autoimmunity (pancreatic autoantibodies) (2). Deficiency in insulin secretion relative to insulin sensitivity can be detected in the prediabetes stages, although the underlying mechanisms may differ, thus translating to a differential in the risk of progression to type 2 diabetes.

Insulin resistance (reduced insulin action in skeletal, adipose, and hepatic tissues) reflects a combination of factors leading to abnormalities in glucose, lipid, and protein metabolism (3). Increased adiposity is the major risk factor for insulin resistance in youth. More than 80% of total glucose disposal occurs in skeletal muscle (4). Skeletal muscle insulin resistance develops in the context of adiposity-related increases in circulating proinflammatory cytokines and free fatty acids, which impair the signaling cascade that links the insulin receptor to the translocation of the myocellular GLUT-4 to the plasma membrane, thereby impairing glucose uptake (5). This is accompanied by impaired whole-body substrate utilization (6) and increased hepatic de novo lipogenesis (7), as well as increased circulating free fatty acids, contributing to ectopic fat deposition. Ectopic intramyocellular, visceral, and hepatic fat is associated with greater degrees of insulin resistance in youth independent of total body fat (8,9). Genetic, epigenetic, and ancestry differences contribute to the site of ectopic fat deposition and the associated metabolic dysfunction (8,10,11). Genetic contributors include genes predisposing to obesity, insulin resistance, or β-cell dysfunction (12). In utero programming from exposure to maternal diabetes, obesity, or other adverse conditions may predispose to ectopic fat deposition and impairment of insulin sensitivity (13). Importantly, environmental and socio-behavioral factors such as sedentary lifestyle with caloric excess and a diet high in processed foods and saturated fats have been directly coupled to obesity and the rising rates of youth-onset prediabetes and type 2 diabetes (14). Also, insulin sensitivity declines by 25%–30% as youth transition through puberty, with the greatest impact seen in midpuberty (15,16), likely contributing to the presentation of prediabetes and type 2 diabetes in adolescence in youth at risk. Studies on the pathophysiology of youth-onset type 2 diabetes highlight the central role of β-cell dysfunction in the pathogenesis and progression of the disease (17,18).

β-Cell dysfunction manifested by a reduction in insulin secretion relative to insulin sensitivity is central to the onset and progression of prediabetes and type 2 diabetes. For maintenance of glycemia, insulin resistance is compensated by a proportionate increase in insulin secretion so that the disposition index (DI) (the product of insulin sensitivity and first-phase insulin secretion), which reflects the hyperbolic relationship between insulin secretion and insulin sensitivity, remains constant. The DI has been demonstrated to be a major predictor of the risk of progression to diabetes (19). Defects in β-cell function with reduced DI can be detected in the prediabetes stage (20,21). Among the prediabetes stages (Table 1), IFG is associated with hepatic insulin resistance and impaired first-phase insulin secretion (22). IGT is associated with significant whole-body insulin resistance and delayed or blunted insulin response, insufficient to compensate for the reduced insulin action (22). Combined IFG/IGT indicates whole-body insulin resistance with defects in first- and second-phase insulin responses and conveys the highest risk for progression to type 2 diabetes (21). The defect in β-cell function is more profound in those with type 2 diabetes, with 86% lower DI in comparison with normoglycemic peers of similar adiposity, sex, and pubertal stage (23) (Fig. 1). Moreover, β-cell function is the major determinant of glycemia and response to therapy. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, β-cell function at randomization in the study within a few months of the diagnosis of diabetes was the most important determinant of long-term glycemia (24). Overall, 45.6% of TODAY participants did not maintain glycemia, with a median time to treatment failure of 11.5 months (25). Irrespective of the randomized treatment arm (metformin alone, metformin plus lifestyle, or metformin plus rosiglitazone), those who were unable to maintain glycemia in TODAY had significantly lower β-cell function (∼50%) at randomization (18).

Compared with adult-onset, youth-onset type 2 diabetes exhibits a more severe phenotype with a greater degree of β-cell dysfunction and more severe whole-body insulin resistance (26,27). In the Restoring Insulin Secretion (RISE) study, with direct comparison of 91 youth with 132 adults with either IGT or recently diagnosed type 2 diabetes, youth demonstrated greater insulin resistance and lower insulin clearance in the setting of a degree of dysglycemia similar to that of adults, as assessed with the hyperglycemic clamp (28) or the oral glucose tolerance test (OGTT) (29,30). The greater insulin resistance in youth (28) is hypothesized to exacerbate the insulin secretory demand on the β-cell, with initial hypersecretion of insulin (30) leading to eventual rapid β-cell failure. Youth-onset type 2 diabetes is characterized by a decline in β-cell function of 20%–35% per year compared with an estimated decline of 7%–11% per year in adults (17,18). In TODAY, metformin plus rosiglitazone resulted in improvement in insulin sensitivity over the first 6 months of the study and was associated with lower rates of glycemic failure (39%) in comparisons with the other two treatment arms: metformin alone (52%) and metformin plus intensive lifestyle intervention (47%) (25). However, this added benefit of rosiglitazone did not persist (31). β-Cell function continued to deteriorate rapidly in the post-TODAY observational follow-up phase (31). By 96 months, only 25.6% of the original TODAY cohort maintained glycemia (31). Similar results were reported from the RISE study (26) in which youth and adults with obesity and either IGT or recently diagnosed type 2 diabetes were randomized to glargine insulin (3 months) followed by metformin (9 months) or metformin alone for 12 months. In youth, β-cell function, measured with the hyperglycemic clamp, worsened despite treatment and continued to deteriorate after discontinuation of treatment, in contrast to stabilization or improved β-cell function in adults while on treatment (26).

Dysregulation in other hormonal (glucagon, incretins) and metabolic (adipose tissue dysfunction, chronic inflammation) pathways also contributes to the pathogenesis of youth-onset prediabetes and type 2 diabetes. Elevated glucagon concentrations in youth with obesity and impaired glucose regulation have been linked to adiposity and insulin resistance (32). Hyperglucagonemia is suspected to be an early event in the pathogenesis of dysglycemia in youth (33). Incretins, namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), hormones produced by gastrointestinal cells, account for ∼70% of postprandial glucose-dependent insulin secretion. In addition to their insulinotropic action through peripheral and central mechanisms, incretins have pleiotropic effects on satiety, glucagon secretion, and gastric emptying (34). Youth with prediabetes and type 2 diabetes have decreased incretin effect without reduction in GLP-1 and GIP concentrations (33), similar to findings in adults (35).

A growing body of evidence supports the role of inflammation, cytokines, and adipokines in the pathogenesis of type 2 diabetes (36). Obesity-induced inflammation promotes insulin resistance, defective insulin secretion, and other disruptions of energy metabolism (37). Adolescents with type 2 diabetes have significantly higher levels of inflammatory markers, including hs-CRP, tumor necrosis factor-α (TNF-α), and interleukin-1β in comparison with BMI-, age-, and sex-matched peers without type 2 diabetes (38). TNF-α and interleukin-1β can impair insulin signaling by affecting the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways or may directly induce β-cell apoptosis and dysfunction (37).

Mitochondrial dysfunction has also been implicated in the pathogenesis of diabetes. It is associated with reduced fatty acid oxidation and elevated reactive oxygen species and toxic lipid byproducts (diacylglycerol and ceramides) contributing to lipotoxicity and impaired insulin signaling (39) and defective insulin section (40). In adipose tissue, mitochondrial dysfunction has been associated with impaired secretion of adiponectin (41). Adiponectin suppresses hepatic glucose output and promotes β-cell function and survival (42). In youth, adiponectin concentrations are positively related to insulin sensitivity and first-phase insulin secretion and negatively with proinsulin-to-insulin ratio (43).

The social determinants of health refer to the conditions in which individuals are born, grow, and live (44). Adverse childhood experiences, potentially traumatic events, are associated with an increased likelihood of diabetes in adulthood (45). Depressive symptoms and cardiometabolic dysregulation may be pathways linking adverse childhood experiences with diabetes in adulthood (46). Indeed, traumatic stress in childhood, which consists of reactions that persist after exposure to one or more traumatic events such as abuse or family violence, can lead to poor mental health (47). In turn, depressive symptoms in youth at risk predict worsening insulin resistance over time (48). Research also points to the importance of diabetes-specific and general life stress among individuals with youth-onset type 2 diabetes. Data collected in the final year of the TODAY study indicated that ∼50% of youth had experienced two or more major life stressors within the previous year (49). Major life stressors are related to greater depressive symptoms, as well as challenges in self-management and behavioral risk factors, including lower adherence to oral medication (49), smoking, and alcohol use (50). Similarly, recent observation of young adults with youth-onset type 2 diabetes from the TODAY study indicated that 24% have high diabetes distress (51), associated with greater depressive and anxiety symptoms, higher HbA_1c, and lower adherence to insulin therapy.

Youth with type 2 diabetes exhibit several cardiometabolic risk factors including dyslipidemia, elevated blood pressure, and increased micro- and macrovascular complications, including diabetic kidney disease (DKD), retinopathy, and neuropathy (52–54). Importantly, these are detected early in the disease process, inferring a more insidious course (2) and greater risk for cardiovascular disease (CVD) and early mortality in comparison with adult-onset type 2 diabetes. In the SEARCH for Diabetes in Youth (SEARCH) study, a higher age-adjusted prevalence of complications, including DKD, elevated blood pressure, arterial stiffness, retinopathy, and peripheral neuropathy, was seen for young individuals with type 2 diabetes versus those with type 1 diabetes (mean duration of diabetes 7.9 years for both) (53). In the TODAY2 follow-up study, 518 individuals (mean age 26.4 years) with youth-onset type 2 diabetes followed for an average of 10.2 years demonstrated a rapid accumulation of diabetes-related complications over a relatively short diabetes duration of 13.3 years, with a cumulative incidence of 80.1% for any microvascular complication, 67.5% for hypertension, 54.8% for DKD, 51.6% for dyslipidemia, and 32.4% for neuropathy (55). Multiple significant cardiovascular events, including myocardial infarctions and strokes, also occurred despite the relatively young age of the cohort (55), demonstrating strong evidence for a severe and progressive clinical phenotype with high risk for CVD.

The goal of therapy is to individualize the therapeutic/prevention approach to the specific underlying metabolic dysfunction and stage of the disease. Interventions need to target insulin sensitivity, β-cell function, and other hormonal disturbances while also having beneficial effects on adiposity and vascular protective effects.

Lifestyle management remains the mainstay therapy for youth-onset prediabetes and type 2 diabetes (2). However, evidence is lacking for lifestyle management strategies alone for sustained weight loss or effective treatment of prediabetes and type 2 diabetes in youth.

Reducing nutrient-poor carbohydrate intake by minimizing consumption of refined grains and added sugars and eliminating sugary beverages is recommended (56). Low-carbohydrate (<26% of daily energy) diet programs have reported some success with diabetes prevention and treatment in adults, but there is not convincing evidence for prescribing these in youth (57,58). Investigators of clinical trials that require significant changes to typical eating patterns report challenges with feasibility and acceptability of sustaining dietary changes (59,60). A dietary pattern that emphasizes plant-based foods high in fiber (vegetables, fruits, whole grains), lean sources of protein (poultry, fish, legumes), and mono- and polyunsaturated fats and limits sugary beverages and highly processed foods is associated with optimal glycemic and cardiometabolic risk profiles (61).

Moderate-to-vigorous physical activity totaling at least 60 min daily and limitation of sedentary time are recommended. Physical activity, independent of weight loss, decreases insulin resistance (62) and is associated with lower HbA_1c (59), BMI, and CVD risk factors for youth with type 2 diabetes (63,64).

A limited number of clinical trials have included examination of lifestyle modification for youth-onset prediabetes and type 2 diabetes. Interventions that include both physical activity and improved food choices are associated with better insulin sensitivity (65), glycemia (65–67), quality of life (66,67), and weight stabilization (65). Findings from two randomized controlled trials suggest that decreases in risk factors for type 2 diabetes may be possible in the absence of weight loss (65,66). Moreover, longitudinal observational data indicate that the prevention of further excessive weight gain decreases type 2 diabetes risk (68).

In youth at risk for diabetes, treated with metformin and an exercise program, with a structured, reduced-energy diet, resulted in improvement in adiposity and insulin sensitivity, with no differences related to the composition of the diet (69). In youth with type 2 diabetes, ≥7% weight loss is associated with decreases in HbA_1c and CVD risk factors (70,71). However, lifestyle intervention plus metformin treatment did not result in sustained weight loss or improved glycemia in comparison with metformin alone in TODAY (25). This was in part due to a lack of sustained physical activity and dietary changes in the lifestyle intervention group (59), likely related to barriers to lifestyle change in the cohort (25).

Clinical trials to study the effects of various lifestyle management programs, alone or in combination with pharmacotherapy for glycemia and/or weight loss, are needed to optimize lifestyle management strategies in youth with prediabetes or type 2 diabetes. Sweeping public health efforts to address the impact of poverty and structural racism on access to safe neighborhoods, walkable cities, and affordable nutritious foods are imperative for achievement of these recommendations on a population scale.

The relationship of depression with insulin resistance and risk for diabetes, as well as the elevated depressive symptoms and diabetes distress in youth-onset type 2 diabetes, underscores the need for a multidisciplinary approach to prediabetes and type 2 diabetes that includes psychosocial care. Validated and developmentally appropriate screening tools to assess traumatic experiences, depression, anxiety, and diabetes distress can help to identify individuals who are at risk for psychological or mental health comorbidities (72). Overall, few studies have examined psychosocial interventions targeting psychological functioning or mental health in individuals with or at risk for youth-onset type 2 diabetes. One clinical trial demonstrated that reductions in depressive symptoms are associated with improvement in insulin sensitivity (73). Among the scarce psychosocial intervention studies in youth at risk for type 2 diabetes, mindfulness-based intervention has emerged as a promising approach with improved preliminary outcomes in depressive symptoms (74). This approach includes teaching breath awareness, body scanning, mindful eating, meditation, and yoga (74). Effective psychosocial treatment of youth without diabetes who have been exposed to traumatic events includes psychoeducation about trauma, training in emotion regulation strategies (e.g., relaxation), exposure techniques, and problem-solving (75). Importantly, barriers to care among socially disadvantaged populations are rarely addressed in standard psychosocial care (76). Promising approaches to diabetes care for socially disadvantaged groups can include psychosocial care delivered by lay providers (e.g., community health workers) and high-intensity interventions delivered over a relatively longer duration (77). These strategies are important avenues for future research for psychosocial interventions focused on youth with prediabetes and type 2 diabetes. Moreover, it is likely that structural racism and poverty are important contributors, given the race disparities in youth-onset type 2 diabetes, and addressing societal challenges will be required.

The evidence to date suggests that the pharmacotherapies that are effective to treat adult-onset type 2 diabetes may have reduced efficacy in children. Treatment of prediabetes and type 2 diabetes in youth will likely require early initiation of a multipronged approach to address the combined pathophysiologic defects of severe insulin resistance, β-cell dysfunction, hyperglucagonemia, and incretin defect. Assessment and treatment of CVD risk factors (e.g., dyslipidemia, hypertension), comorbidities (e.g., fatty liver disease, sleep apnea, polycystic ovary syndrome), and complications such as nephropathy and retinopathy should be instituted, as reviewed previously (2).

Pharmacotherapy in youth with prediabetes (metformin or rosiglitazone) has been tested in few studies, which were relatively small and of short duration. In the RISE study investigators tested treatment, of 91 youth with either IGT or recently diagnosed type 2 diabetes, with metformin for 12 months or insulin glargine for 3 months followed by metformin for 9 months. Neither of these strategies was effective for preventing the deterioration in β-cell function during or after the treatment period (27). Following medication withdrawal, both fasting and 2-h OGTT glucose worsened from baseline, associated with the decline in β-cell function (30). These results indicate that the medication strategies to date have not been effective for preventing the progressive β-cell dysfunction that underlies the transition from prediabetes to type 2 diabetes. Studies of newer therapeutic agents are needed.

Initial treatment of youth-onset type 2 diabetes should address the presenting pathophysiology (e.g., hyperglycemia and associated metabolic derangements) (70). Metformin is adequate for initial treatment of type 2 diabetes in adults and youth, as it is inexpensive and well studied and has an excellent safety profile. In the TODAY study, nearly all of the youth with type 2 diabetes initially achieved target range glycemia on metformin monotherapy and nearly half maintained adequate glycemia for up to 6 years (25). Consequently, asymptomatic youth with presumptive type 2 diabetes who present in a stable metabolic state and with HbA_1c <8.5% can be started on metformin as initial therapy. The starting dose of metformin is 500–1,000 mg/day, titrated weekly as tolerated to the recommended therapeutic dose of 1,000 mg twice a day (Fig. 2). Practitioners should initially treat youth with more severe symptomatic hyperglycemia without acidosis with basal insulin while concurrently initiating and titrating metformin. In patients with ketosis/ketoacidosis at diagnosis, subcutaneous or intravenous insulin should be initiated to correct the hyperglycemia and metabolic decompensation. Once acidosis is resolved and diagnosis of type 2 diabetes is confirmed, metformin can be initiated while insulin therapy is weaned as tolerated. Whether early treatment with insulin provides benefits for β-cell function remains unclear; the RISE Pediatric Medication Study did not demonstrate benefits of 3 months of basal insulin compared with metformin alone in preserving β-cell function (27).

Failure to achieve glycemic targets with metformin alone or metformin plus insulin in those with more advanced stages of the disease warrants treatment intensification, particularly given the persistent deterioration of β-cell function (18,26) and worse glycemic trajectory over time in youth requiring insulin therapy (78). The efficacy and safety data of newer therapeutic agents in the management of youth-onset type 2 diabetes are emerging with the completion of several clinical trials, summarized below and in Table 2. Their adoption in the management of the disease can be considered and individualized based on the indication, stage of the disease, and associated comorbidities (Fig. 2).

GLP-1 receptor agonists (GLP-1RA) target multiple processes including improvement in glucose-mediated insulin secretion (incretin effect), inhibition of glucagon production, delay in gastric emptying, and promotion of satiety (79). They also have a favorable effect on cardiovascular and renal outcomes in adults. To date, three GLP-1RA have received U.S. Food and Drug Administration (FDA) approval for use in children with type 2 diabetes, 10–17 years of age, based on efficacy data from clinical trials. It is worth noting that the percentage of the study population receiving insulin was 18.7%, 46.3%, and 28% in the liraglutide, exenatide, and dulaglutide trials, respectively (80–82). With the relatively lower percentage of baseline insulin use in these trials, caution is required in considering the efficacy of these medications in youth with type 2 diabetes requiring insulin therapy. Mean diabetes duration was 1.9 ± 1.5 years (liraglutide trial), 2.0 ± 2.0 years (exenatide trial), and 2.0 ± 1.7 years (dulaglutide trial). The efficacy of GLP-1RA with longer duration of diabetes in youth remains unknown. Moreover, the long-term efficacy and adverse effects are not known. The percentage of participants of Hispanic ethnicity was relatively lower in the liraglutide trial (29.1%) as opposed to the exenatide (44%) and dulaglutide (55%) trials in the context of higher prevalence of youth-onset type 2 diabetes in youth of Hispanic race-ethnicity. This may have implications for the generalizability of findings, particularly from the Evaluation of Liraglutide in Pediatrics with Diabetes (Ellipse) trial, to diverse racial/ethnic groups and warrants additional study.

In 134 children enrolled in the Ellipse trial, liraglutide 0.6–1.8 mg/day s.c. demonstrated 1% reduction in HbA_1c at 26 weeks in comparison with placebo (80). Mean HbA_1c decreased by 0.64% at week 26 (primary efficacy end point) in the liraglutide group and increased by 0.42% in the placebo group (estimated treatment difference −1.06%, 95% CI −1.65 to −0.46, P < 0.001). HbA_1c estimated treatment difference was −1.30% (95% CI −1.89 to −0.70) at week 52. In the BCB114 trial, exenatide 2 mg/week s.c. showed similar reduction in HbA_1c (0.85%) at 24 weeks in comparison with placebo in 83 youth with type 2 diabetes (81). Mean HbA_1c decreased by 0.36% at week 24 in the exenatide group and increased by 0.49% in the placebo group (between-group difference −0.85%, 95% CI −1.51 to −0.19, P = 0.012). More recently, dulaglutide 0.75 mg and 1.50 mg/week s.c. demonstrated 1.4% placebo-subtracted reduction in HbA_1c (82). At 26 weeks, mean HbA_1c decreased by 0.6% and 0.9% in the dulaglutide 0.75 mg and 1.50 mg groups, respectively, and increased by 0.6% in the placebo group (estimated treatment difference between pooled dulaglutide groups and placebo −1.4%, 95% CI −1.9 to −0.8, P < 0.001). Liraglutide and dulaglutide, but not exenatide, reduced fasting plasma glucose concentrations (80–82). Unfortunately, none of these agents had a significant effect on BMI—unlike their favorable weight loss profile in adults. No significant changes in CVD risk factors were noted in these trials except improvements in lipid profile with dulaglutide (82). Liraglutide showed greater reduction in VLDL cholesterol at week 26 in comparisons with placebo, but no differences were apparent at week 52 (80). Differences in blood pressure in comparisons with the placebo groups were not significant in the liraglutide and dulaglutide groups (80,82). There was a small increase in heart rate from baseline to week 24 in both the exenatide and placebo groups without hypotension (81). For GLP-1RA, the adverse effects were mainly gastrointestinal (nausea, vomiting, and diarrhea) and were overall well tolerated (80–82). There was a higher risk of nonsevere hypoglycemia in the liraglutide group (relative risk 2.35, 95% CI 1.04–5.35) (80) and in the exenatide group (13.6% vs. 4.3%), mostly in participants on insulin at baseline (81). In the dulaglutide trial, higher incidence and annual rate of hypoglycemia were observed among participants using insulin at baseline, without differences between the dulaglutide and placebo groups and with no reports of severe hypoglycemia (82).

Dipeptidyl peptidase 4 (DPP-4) inhibitors enhance the endogenous incretin effect by inhibiting the enzyme DPP-4, responsible for rapid degradation of incretins (83). In a randomized controlled trial of 190 children with type 2 diabetes, sitagliptin (100 mg/day, administered by mouth [PO]) failed to show significant reduction in HbA_1c at 54 weeks compared with placebo (84). The participants in the placebo arm received metformin during the 34-week extension phase of the study, and a group difference of 0.56% in HbA_1c was observed favoring metformin over sitagliptin. In the DIabetes study of liNAgliptin and eMpagliflozin in children and adOlescents (DINAMO), with 158 children, linagliptin (5 mg/day, PO) resulted in nonsignificant reduction in HbA_1c (0.34%) at 26 weeks compared with placebo (85). The superior efficacy of GLP-1RA in reduction of HbA_1c compared with the DPP-4 inhibitors suggests that much higher and sustained increase in GLP-1 concentrations (approximately 8- to 10-fold vs. 2- to 3-fold increase with GLP-1RA vs. DPP-4 inhibitors [84,86]) are needed in youth to counter the β-cell dysfunction. Similarly, saxagliptin compared with dapagliflozin or placebo in the T2NOW trial did not result in significant HbA_1c reduction (87).

Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycemia by reducing renal tubular glucose reabsorption. In adults, SGLT2 inhibitors were associated with significant reduction in HbA_1c and body weight (88) and were consistently shown to decrease the risk of major cardiovascular events, heart failure, and kidney failure (89,90). In youth, dapagliflozin (10 mg/day, PO) failed to demonstrate a significant reduction in HbA_1c in an intention-to-treat analysis (between-group difference −0.75% [95% CI −1.65 to 0.15] and −8.2 mmol/L [−18.0 to 1.6], P = 0.1) at 24 weeks. A prespecified sensitivity analysis of protocol-adherent participants showed that placebo-subtracted HbA_1c decreased by 1.13% (95% CI −1.99 to −0.26, P = 0.012) (91). In a subsequent 26-week, phase 3 trial (T2NOW) with a 26-week extension, dapagliflozin 5–10 mg/day, PO, versus placebo resulted in adjusted mean change in HbA_1c of −1.03% (95% CI −1.57 to −0.49, P < 0.001) at 26 weeks (87). Empagliflozin (10 and 25 mg/day, PO), tested in DINAMO, showed 0.84% reduction in HbA_1c (95% CI −1.50 to −0.19, P = 0.012) at 26 weeks (85). Both dapagliflozin and empagliflozin received FDA approval for youth-onset type 2 diabetes. Neither one of these agents had a significant effect on BMI reduction in youth. Adverse effects included headaches, nasopharyngitis, hypoglycemia, and genital mycotic infections. The potential for euglycemic diabetic ketoacidosis also needs to be considered, particularly in youth with insulin-requiring diabetes in the more advanced stages of the disease.

Current clinical practice guidelines for the treatment of childhood/adolescent obesity are applicable to youth with prediabetes and type 2 diabetes. Although clinical evidence in pediatric populations with prediabetes and type 2 diabetes is lacking, antiobesity medications may be considered in combination with behavior and lifestyle therapy (92,93). Metabolic surgery for the comprehensive treatment of severe obesity has also been suggested (92).

There are currently several FDA-approved medications for the treatment of obesity in children ages ≥12 years with BMI ≥95th percentile for age and sex. Orlistat is a lipase inhibitor that decreases dietary fat absorption. It is associated with significant gastrointestinal side effects, which often makes it unacceptable to youth (93). Qsymia (phentermine and topiramate extended-release capsules), an amphetamine analog in combination with an anticonvulsant, is associated with dose-dependent appetite reduction (94). It should be noted that topiramate is a teratogen and a reliable form of birth control should be used with this medication. More recently, two GLP-1RA have received FDA approval for the treatment of obesity in adolescents ≥12 years of age (95,96). In combination with lifestyle therapy, liraglutide (3 mg s.c. daily) resulted in superior reduction in BMI (4.6%) and weight (−4.5 kg) than placebo after 56 weeks (95); semaglutide (2.4 mg s.c. once weekly) resulted in −16.7% decline in BMI and −17.7 kg in weight versus placebo after 68 weeks (96).

Bariatric surgery (Roux-en-Y gastric bypass or vertical sleeve gastrectomy) are recommended for the treatment of youth with severe obesity. In a study comparing 30 adolescents with severe obesity and type 2 diabetes who underwent bariatric surgery (Teen–Longitudinal Assessment of Bariatric Surgery [Teen-LABS] cohort) with 63 participants from the TODAY study (97), BMI decreased by 29.0% in the surgery cohort compared with a 3.7% increase in TODAY participants, while HbA_1c decreased from 6.8% to 5.5% in Teen-LABS and increased from 6.4% to 7.8% in TODAY participants (97). Remission rates 5 years postsurgery were approximately 86% for type 2 diabetes and 68% for hypertension (98). Most postsurgical complications were mild, but up to 8% of adolescents have major perioperative complications (98). In addition to improvement in insulin sensitivity related to weight loss, metabolic improvements in response to metabolic surgery can be related to several mechanisms including improvement in incretins, changes in the microbiome, and increase in bile acids (99).

Findings of studies to date support 1) significant insulin resistance and progressive, rapid rates of deterioration in β-cell function in youth with type 2 diabetes; 2) that β-cell dysfunction starts in the prediabetes stage; 3) the importance of early diagnosis of youth-onset type 2 diabetes and institution of therapy to preserve the balance between insulin secretion and insulin sensitivity; and 4) the need to identify more effective therapeutic agents and prevention strategies. A multidisciplinary approach is advocated in the management of the disease, with attention to mental health and social determinants of health that may hamper efficacy of therapeutic interventions. Lifestyle intervention and metformin therapy remain adequate early in the disease process for most individuals with youth-onset type 2 diabetes. The same follow-up interval schedule (every 3 months) as for type 1 diabetes is recommended because glycemia may deteriorate rapidly. Surveillance and treatment of cardiovascular comorbidities and complications is recommended (2,70). Newer therapeutic agents can be instituted early if intensive lifestyle intervention and metformin therapy do not lead to target range glycemia. Long-term youth diabetes prevention and intervention studies are lacking. Important research questions remain as to whether we can prevent β-cell dysfunction from progressing to β-cell failure in the prediabetes stage and what constitutes effective interventions to prevent the rapid deterioration of β-cell function in youth. Additional research is needed to address these knowledge gaps and to allow more targeted prevention and treatment approaches and individualized therapies.

Funding. The effort of F.B. is supported by U.S. Department of Agriculture (USDA)/Agricultural Research Service Current Research Information System (CRIS) award 309251000-057-03S; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), grant DK134982; and Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, grant HD105104-01. The effort of M.T. is supported by NIDDK, NIH, grant K23-DK129821.

The authors are solely responsible for the contents of this article, which do not necessarily represent the official views of the USDA or the NIH.

Duality of Interest. P.S.Z. serves as a consultant for Eli Lilly and Boehringer Ingelheim. T.S.H. serves on the advisory board for Eli Lilly. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. F.B., T.S.H., and P.S.Z. designed the study. All authors reviewed the literature and contributed to the writing of different sections of the manuscript. F.B. reviewed and edited all sections of the manuscript. F.B., T.S.H., M.T., and P.S.Z. contributed to the discussion and reviewed and edited the manuscript.

Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Steven E. Kahn.