Pathophysiology and Treatment of Prediabetes and Type 2 Diabetes in Youth.

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by "prediabetes," a disease phase where defects in ß-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, the precipitous decline of ß-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 in the predisposition and progression of these conditions and present current management strategies and the advances in therapeutic approaches. These must adapt to meet the unique needs of the individual patient and family. Significant knowledge gaps remain that need to be addressed in future research.

Insulin Dynamics and Pathophysiology in Youth-Onset Type 2 Diabetes.

Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic ß-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.

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.

Listening to the community: identifying obesity prevention strategies for rural preschool-aged children.

Multi-level interventions promoting healthy weight in rural preschool children aged 2-5 years are limited. With the goal of developing a community-informed obesity prevention intervention for rural preschool-aged children, the purpose of this descriptive study was to identify: (1) community settings and intervention strategies to prioritize for an intervention; (2) potential implementation challenges and solutions; and (3) immediate interventions the study team and community partners could collaboratively implement. Workshops occurred in two rural communities in Indiana (2 workshops) and North Carolina (2 workshops), with high obesity rates. A guide was developed to moderate discussions and participants voted to rank community settings and intervention strategies. There were 9-15 participants per workshop, including parents, childcare providers, and representatives of community organizations. Community settings identified as priorities for child obesity prevention included the home, educational settings (preschools), food outlets, recreational facilities, and social media. Priority intervention strategies included providing nutrition and physical activity education, increasing access to healthy foods and physical activity in the built environment, and enhancing food security. Potential intervention implementation challenges centered on poor parental engagement; using personalized invitations and providing transportation support to families were proffered solutions. Immediate interventions to collaboratively implement focused on making playgrounds esthetically pleasing for physical activity using game stencils, and nutrition education for families via quarterly newsletters. This participatory approach with community partners provided insight into two rural communities' needs for child obesity prevention, community assets (settings) to leverage, and potential intervention strategies to prioritize. Findings will guide the development of a multi-level community-based intervention.

Predictors of glycemic worsening in the next year in adults with screen-detected type 2 diabetes.

Background and Aims: Identifying simple markers of risk for worsening glucose can allow care providers to target therapeutic interventions according to risk of worsening glycemic control. We aimed to determine which routine clinical measures herald near-term glycemic worsening in early type 2 diabetes(T2D). Methods: The Early Diabetes Intervention Program (EDIP) was a clinical trial in individuals with screendetected T2D [HbA1C 6.3+0.63%(45+5mmol/mol)]. During the trial some participants experienced worsening fasting blood glucose (FBG). We investigated the time course of FBG, HbA1c, weight, and other clinical factors to determine which might herald glycemic worsening over the next year. Results: Progressors (62/219, 28.5%) had higher FBG than non-progressors at baseline [118 vs 130mg/dL (6.6 vs 7.2 mmol/L), p=<0.001]. FBG was stable except in the year of progression, when progressors exhibited a large 1-year rise [mean change 14.2mg/dL(0.79 mmol/L)]. Current FBG and antecedent year change in FBG were associated with progression(p<0.01), although the magnitude of change was too small to be of clinical utility (0.19 mg/dL; 0.01 mmol/L). Current or antecedent year change in HbA1c, weight, TG or HDL were not associated with progression. In the year of glycemic worsening, rising glucose was strongly associated with a concurrent increase in weight (p<0.001). Conclusions: Elevated FBG but not HbA1c identified individuals at risk for imminent glycemic worsening; the subsequent large rise in glucose was associated with a short-term increase in weight. Glucose and weight surveillance provide actionable information for those caring for patients with early diabetes.

A co-designed, community-based intensive health behavior intervention promotes participation and engagement in youth with risk factors for type 2 diabetes.

Background: Obesity among youth (children and adolescents) is associated with increased risk for youth-onset type 2 diabetes. Lifestyle change can delay or prevent the development of type 2 diabetes, yet real-world implementation of health behavior recommendations is challenging. We previously engaged youth with risk factors for type 2 diabetes, their caregivers, and professionals in a human-centered design study to co-design a lifestyle change program. Here we report the outcomes for this 16-week co-designed lifestyle change program for youth at risk for T2D and their caregivers. Research design and methods: This single-arm family-based cohort study included youth aged 7-18 years, with BMI ≥85th percentile (overweight or obese) and at least one additional risk factor for type 2 diabetes, and their caregivers. Clinical (BMI, HbA1c), self-reported physical activity, and quality of life outcomes were evaluated at baseline (B), post-intervention (M4), and 1 year (M12) following the intervention. Results: Seventy-eight youth (mean age 12.4 ± 2.7y, 67% female, 37.8% white) and 65 caregivers were included in the data analysis. Youth baseline BMI z-scores (2.26 ± 0.47) and HbA1c (5.3 ± 0.3) were unchanged at follow up time points [BMI z-scores M4 (2.25 ± 0.52), M12 (2.16 ± 0.58), p-value 0.46], [HbA1c M4 (5.3 ± 0.3), M12 (5.2 ± 0.3), p-value (0.04)]. Youth reported increased physical activity at M4 (p = 0.004), but not at M12. Youth quality of life scores increased at M12 (p=0.01). Families who attended at least one session (n=41) attended an average of 9 out of 16 sessions, and 37 percent of families attended 13 or more sessions. Conclusion: A co-designed, community-based lifestyle intervention promotes increased physical activity, improved quality of life, maintenance of BMI z-scores and HbA1c, and engagement in youth with risk factors for T2D.

Low-Carbohydrate Diets in Children and Adolescents With or at Risk for Diabetes.

Carbohydrate restriction is increasingly popular as a weight loss strategy and for achieving better glycemic control in people with diabetes, including type 1 and type 2 diabetes. However, evidence to support low-carbohydrate diets in youth (children and adolescents 2-18 years of age) with obesity or diabetes is limited. There are no guidelines for restricting dietary carbohydrate consumption to reduce risk for diabetes or improve diabetes outcomes in youth. Thus, there is a need to provide practical recommendations for pediatricians regarding the use of low-carbohydrate diets in patients who elect to follow these diets, including those with type 1 diabetes and for patients with obesity, prediabetes, and type 2 diabetes. This clinical report will: Provide background on current dietary patterns in youth, describe how moderate-, low-, and very low-carbohydrate diets differ, and review safety concerns associated with the use of these dietary patternsReview the physiologic rationale for carbohydrate reduction in youth with type 1 diabetes and for youth with obesity, prediabetes, and type 2 diabetesReview the evidence for low-carbohydrate diets in the management of youth with type 1 diabetesReview the evidence for low-carbohydrate diets in the management of youth with obesity, prediabetes, and type 2 diabetesProvide practical information for pediatricians counseling families and youth on carbohydrate recommendations for type 1 diabetes and for obesity, prediabetes, and type 2 diabetes.

Approach to the Patient: Youth-Onset Type 2 Diabetes.

Youth-onset type 2 diabetes is a growing epidemic with a rising incidence worldwide. Although the pathogenesis and diagnosis of youth-onset type 2 diabetes are similar to adult-onset type 2 diabetes, youth-onset type 2 diabetes is unique, with greater insulin resistance, insulin hypersecretion, and faster progression of pancreatic beta cell function decline. Individuals with youth-onset type 2 diabetes also develop complications at higher rates within short periods of time compared to adults with type 2 diabetes or youth with type 1 diabetes. The highest prevalence and incidence of youth-onset type 2 diabetes in the United States is among youth from minoritized racial and ethnic groups. Risk factors include obesity, family history of type 2 diabetes, comorbid conditions and use of medications associated with insulin resistance and rapid weight gain, socioeconomic and environmental stressors, and birth history of small-for-gestational-age or pregnancy associated with gestational or pregestational diabetes. Patients with youth-onset type 2 diabetes should be treated using a multidisciplinary model with frequent clinic visits and emphasis on addressing of social and psychological barriers to care and glycemic control, as well as close monitoring for comorbidities and complications. Intensive health behavior therapy is an important component of treatment, in addition to medical management, both of which should be initiated at the diagnosis of type 2 diabetes. There are limited but growing pharmacologic treatment options, including metformin, insulin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Although long-term outcomes are not fully known, metabolic/bariatric surgery in youth with type 2 diabetes has led to improved cardiometabolic outcomes.