Incremental Progress in Pharmacotherapy for Pediatric Type 2 Diabetes.

Type 2 diabetes is no longer an adult-only disease but, sadly, has become an established entity in youth. Globally, an estimated 41,600 youth are newly diagnosed every year.1 Underrepresented groups, migrants, and youth of lower socioeconomic status are disproportionately affected. While incidence rates are rising steeply in almost all populations, annual increases in several non-White racial populations now surpass those of type 1 diabetes.1.

Quality improvement efforts in a safety net institution: Increased diabetes screening is associated with lower HbA1c at diagnosis and improved HbA1c outcomes in youth with type 2 diabetes.

OBJECTIVES: Evaluate whether increased diabetes screening in youth is associated with lower HbA1c at T2D diagnosis and improved HbA1c outcomes in youth. RESEARCH DESIGN AND METHODS: Diabetes screening rates from 2009 to 2018 were calculated. Electronic medical records identified obese youth ages 8-18 with first HbA1c ≥6.5% from 2009 to 2018; chart review confirmed incident T2D. Demographics, BMI and HbA1c values, and use of glucometer and diabetes medications were collected. RESULTS: 142 youth had T2D. Median age was 14 years (range 8-18); 58% were female. 46% were identified on first HbA1c testing. 69 (49%) had 1st HbA1c 6.5%-6.9%, 43 (30%) 7.0%-7.9%, and 30 (21%) ≥8%. Follow-up from 1st to last HbA1c was median 2.6 years (range 0-10). 121 youth had follow-up testing ≥1 year after diagnosis; of these, 87 (72%) had persistent T2D-range HbA1c or were taking diabetes medications. 85% of youth with 1st HbA1c ≥7% had persistent T2D versus 52% of those with 1st HbA1c <7% (p < 0.001). Poorly controlled diabetes at last test was present in 19% of youth with baseline HbA1c 6.5%-6.9%, 30% with 7.0%-7.9%, and 63% with ≥8% (p < 0.001). 47 (68%) with HbA1c <7% were prescribed a glucometer; 9% of youth prescribed a meter and 41% of youth not prescribed a meter had poorly controlled diabetes at last test (p = 0.009). CONCLUSIONS: Youth with HbA1c <7% at diagnosis were less likely to have poorly controlled diabetes at follow-up. Prescription of glucometers for youth with HbA1c in this range was associated with improved HbA1c outcomes and deserves further study including components of glucometer teaching.

ß-Cell function in obese children and adolescents with metabolic syndrome compared to isolated obesity.

OBJECTIVE: To evaluate ß-cell function in obese children and adolescents meeting clinical criteria for isolated obesity (iOB), isolated components of dysmetabolism (cMD), or metabolic syndrome (MS), and in obese children and adolescents with normal glucose tolerance (NGT), impaired glucose regulation (IGR), or type 2 diabetes (T2DM). STUDY DESIGN: We undertook a prospective study of Han Chinese children and adolescents aged 8-16 years (median 11 ± 1.4) seen in an obesity clinic between May 2013 and 2018. Patients were classified as iOB (53), cMD (139), and MS (139) groups based on clinical criteria. The same patients were also classified as NGT (212), IGR (111), or T2DM (8) based on results of an oral glucose tolerance test (OGTT). The MS patients were classified as NGT [MS](59) and IGR [MS](72) for the further study. All participants also completed a mixed-meal tolerance test (MMTT). RESULTS: Compared with the iOB group, the MS group had significantly higher area under the curve of C-peptide up to the 2 hours (AUC CP) (P = .03) and peak C-peptide (P = .03), adjusted for BMI, age and Tanner stage, on MMTT. However, there was no difference in the insulinogenic index (ΔI30/ΔG30) or oral disposition index (oDI) derived from the OGTT among the three groups. However, 52% of participants with MS had IGR, compared to 28% in the cMD group. Compared with the NGT group, the individuals with IGR had significantly lower ΔI30/ΔG30 (P = .001) and oDI (P < .001). Compared with the iOB group, the NGT[MS] had significantly higher AUC CP (P = .004), peak C-peptide (P = .004) and ΔI30/ΔG30 (P = .007) adjusted for age, but no difference in oDI. Compared with the NGT[MS], the IGR[MS] had significantly lower ΔI30/ΔG30 (P = .005) and oDI (P < .001), but the AUC CP and peak C-peptide had no difference. CONCLUSION: Although the MS youth have ß-cell hyperfunction as a whole, ß-cell dysfunction is present in the early stages of dysmetabolism in obese youth with cMD or MS and worsened across the spectrum from iOB to cMD and MS, contributing to development of T2DM.

Longitudinal follow up of dysglycemia in overweight and obese pediatric patients.

OBJECTIVE: To examine factors related to progression of dysglycemia in overweight and obese youth in a large primary care setting. RESEARCH DESIGN AND METHODS: 10- to 18-year-old youth with body mass index (BMI) > 85 percentile and first-time A1c 5.7%-7.9% (39-63 mmol/mol) were identified retrospectively through electronic medical records (EMR). Levels of dysglycemia were defined as low-range prediabetes (LRPD; A1c 5.7%-5.9% [39-41 mmol/mol]), high-range prediabetes (HRPD; A1c 6.0%-6.4% [42-46 mmol/mol]), or diabetes-range (A1c 6.5%-7.9% [48 mmol/mol]). Follow-up A1c and BMI were extracted from the EMR. Follow up was truncated at the time of initiation of diabetes medication. RESULTS: Of 11 000 youth, 547 were identified with baseline dysglycemia (mean age 14.5 ± 2.2 years, 70% Hispanic, 23% non-Hispanic Black, 7% other). Of these, 206 had LRPD, 282 HRPD, and 59 diabetes. Follow-up A1c was available in 420 (77%), with median follow up of 12-22 months depending on A1c category. At follow-up testing, the percent with diabetes-range A1c was 4% in youth with baseline LRPD, 8% in youth with baseline HRPD, and 33% in youth with baseline diabetes-range A1c. There was a linear association between BMI increase and worsening A1c for LRPD (P < .001) and HRPD (P = .003). CONCLUSIONS: Most adolescents with an initial prediabetes or diabetes-range A1c did not have a diabetes-range A1c on follow up. Moreover, prediabetes-range A1c values do not all convey equal risk for the development of diabetes, with lower rates of progression for youth with initial A1c <6%. In youth with prediabetes-range A1c, BMI stabilization was associated with improvement of glycemia.

HbA1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Type 2 Diabetes.

OBJECTIVE: To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy. RESEARCH DESIGN AND METHODS: TODAY was a randomized clinical trial of adolescents with type 2 diabetes. Two groups, including participants from all three treatments, were defined for analysis: (1) those who remained in glycemic control for at least 48 months of follow-up and (2) those who lost glycemic control before 48 months. Outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics (age, sex, race/ethnicity, socioeconomic status, BMI, waist circumference, Tanner stage, disease duration, depressive symptoms) and biochemical measures (HbA1c, C-peptide, lean and fat body mass, insulin inverse, insulinogenic index). Receiver operating characteristic curves were used to analyze HbA1c cut points. RESULTS: In multivariate models including factors significant in univariate analysis, only HbA1c and insulinogenic index at randomization remained significant (P < 0.0001 and P = 0.0002, respectively). An HbA1c cutoff of 6.3% (45 mmol/mol) (positive likelihood ratio [PLR] 3.7) was identified that optimally distinguished the groups; sex-specific cutoffs were 6.3% (45 mmol/mol) for females (PLR 4.4) and 5.6% (38 mmol/mol) for males (PLR 2.1). CONCLUSIONS: Identifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy. HbA1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy. Adolescents with type 2 diabetes unable to attain a non-diabetes range HbA1c on metformin are at increased risk for rapid loss of glycemic control.

Psychological functioning in adolescents with obesity co-morbidities.

BACKGROUND: An understanding of the relationships among obesity severity, medical co-morbidities, and psychological complications is important in the design of interventions to encourage overweight youth and families to accomplish healthy lifestyle changes. METHODS: We evaluated associations among psychological status, diagnosed medical co-morbidities consistent with components of the metabolic syndrome, and BMI among 166 obese adolescents (11-18 years) referred for endocrinology consultation. We hypothesized that there would be higher levels of psychological distress among youth with more diagnosed components of the metabolic syndrome (i.e., more medical co-morbidities associated with obesity). RESULTS: Contrary to expectation, we found that meeting criteria for extreme obesity alone was more predictive of psychological difficulties. CONCLUSIONS: The degree of obesity may be more relevant than the number of associated medical co-morbidities in impacting psychological health. It is important to recognize individual differences between patients in terms of identifying motivating goals for accomplishing weight management.

Use of glycosylated hemoglobin increases diabetes screening for at-risk adolescents in primary care settings.

OBJECTIVE: To examine rates of diabetes screening in obese adolescents in an ethnically diverse primary care health care system before and after an internal recommendation to use HbA1c-based screening. RESEARCH DESIGN AND METHODS: Adolescents 12-18-years old with BMI > 95% were identified through electronic medical record review during two 18-month periods in 8 community health clinics and 13 school-based health centers: period 1 (P1, 19 April 2008 to 19 October 2009) and period 2 (P2, 3 May 2010 to 3 November 2011). Testing for diabetes in the 2 yr preceding the most recently elevated BMI was reviewed. RESULTS: A total of 2870 obese adolescents were identified in P1 and 3940 in P2. Ethnicity was primarily Hispanic, with smaller populations of Black and White youth. The percent of obese teens screened for diabetes increased from 40% in P1 to 47% in P2. Use of HbA1c increased 493% during P2. Older teens (>15 yr), those seen during P2, and those with BMI ≥ 30 kg/m2 were more likely to be screened. Record review confirmed equal rates of type 2 diabetes in the two periods: 8 incident (0.7%) cases in P1 and 13 (0.7%) in P2. CONCLUSIONS: The use of HbA1c, a non-fasting and logistically simpler test, was associated with increased diabetes screening in primary care. The percentage of screened patients with confirmed type 2 diabetes remained unchanged. Thus, despite potential pitfalls, the use of HbA1c for screening appears to be as successful as previous approaches in identifying adolescents with diabetes.

Obesity after pediatric liver transplantation: prevalence and risk factors.

OBJECTIVES: Pediatric obesity has become a significant public health concern. The historical focus in pediatric liver transplant (LT) has been undernutrition, with limited knowledge regarding obesity. Therefore, we sought to determine the prevalence of obesity in pediatric LT, compare it to National Health and Nutrition Examination Surveys (NHANES) data, and identify risk factors for obesity in pediatric LT. METHODS: SPLIT, which collects pediatric LT data at 39 centers, was queried for subjects ages 2 to 18 years at follow-up, LT between 1995 and 2007, and with at least 1 body mass index measured 1 to 5 years after LT. RESULTS: Of 1706 individuals included, 44% had biliary atresia (47% boys, 58% white, mean age at LT 4.6 years). Of these individuals, 19% were obese at 1 year and 18% at 3 years, higher than in the general pediatric population reported by 2003-2004 NHANES, whereas 11% obesity at 5 years after LT was similar to NHANES data. Using logistic regression, Hispanic ethnicity (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.19-2.23), steroid use at follow-up (OR 1.48, 95% CI 1.23-1.77), overweight (OR 4.34, 95% CI 2.91-6.68), and obesity (OR 10.62, 95% CI 5.9-19.65) at LT independently predicted post-LT obesity. CONCLUSIONS: These findings suggest a need to broaden standard care to include obesity assessment and intervention in routine pre- and posttransplant care.

A clinical trial to maintain glycemic control in youth with type 2 diabetes.

BACKGROUND: Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes. METHODS: Eligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin. RESULTS: Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P=0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants. CONCLUSIONS: Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328.).

Health-related quality of life in adolescents with comorbidities related to obesity.

INTRODUCTION: Psychosocial correlates of medically complex obesity are poorly understood in adolescents. METHODS: Health-related quality of life was examined among 111 obese adolescents with medical comorbidities. RESULTS AND CONCLUSION: A higher body mass index and greater number of comorbidities were associated with diminished health-related quality of life, thus underscoring the relevance of psychosocial functioning in obese youth.

Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function.

CONTEXT: Cardiovascular disease is the major cause of death in adults with diabetes, yet little is specifically known about the effects of type 1 diabetes (T1D) on cardiovascular outcomes in youth. Although insulin resistance (IR) likely contributes to exercise and cardiovascular dysfunction in T2D, IR is not typically considered a contributor in T1D. OBJECTIVE: We hypothesized that cardiopulmonary fitness would be reduced in T1D youth in association with IR and cardiovascular dysfunction. DESIGN AND PARTICIPANTS: This cross-sectional study at an academic hospital included 12 T1D adolescents compared with 12 nondiabetic controls, similar in age, pubertal stage, activity level, and body mass index. OUTCOME MEASURES: Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, intramyocellular lipid by magnetic resonance spectroscopy, and body composition by dual-energy x-ray absorptiometry. RESULTS: T1D adolescents had significantly decreased VO(2)peak, peak work rate, and insulin sensitivity compared with nondiabetic adolescents. T1D youth also had reduced vascular reactivity and evidence of diastolic dysfunction and left ventricular hypertrophy. Despite their IR and reduced cardiovascular fitness, T1D youth had paradoxically normal intramyocellular lipid, waist to hip ratio, and serum lipids and high adiponectin levels. In multivariate analysis, IR primarily, and forearm blood flow secondarily, independently predicted VO(2)peak. CONCLUSIONS: T1D youth demonstrated IR, impaired functional exercise capacity and cardiovascular dysfunction. The phenotype of IR in T1D youth was unique, suggesting a pathophysiology that is different from T2D, yet may adversely affect long-term cardiovascular outcomes.

The metabolic syndrome and nonalcoholic fatty liver disease in children.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in pediatric-age individuals, in parallel with increasing obesity, and can lead to liver inflammation, fibrosis, and even cirrhosis. NAFLD appears tightly linked with features of the metabolic syndrome (MetS). This review aims to reconsider the clinical presentation, laboratory and pathologic assessment, and treatment of NAFLD, with a focus on its relationship with the MetS. RECENT FINDINGS: NAFLD occurs with a high prevalence and severity in obese, insulin-resistant adolescents, especially Hispanic males. Pediatric NAFLD may improve with lifestyle therapy and agents that improve insulin sensitivity. In youth, NAFLD appears tightly correlated with components of the MetS, especially visceral fat, which appears to predict fibrosis as well as liver fat. In addition, noninvasive techniques such as transient elastography may help provide data on fibrosis in youth with NAFLD and avoid biopsy. SUMMARY: The close association between NAFLD and the MetS supports screening for other comorbidities associated with the MetS. Further research is urgently required to best identify effective therapies to prevent and treat NAFLD, but its close association with MetS argues for a focus on strategies designed to improve insulin resistance and components of the MetS.

Addition of metformin to a lifestyle modification program in adolescents with insulin resistance.

OBJECTIVE: To evaluate whether metformin, when added to a program of personal goal setting, improves weight loss and clinical status in obese adolescents. STUDY DESIGN: In a randomized double-blind placebo controlled trial, 85 adolescents with insulin resistance were randomized to receive metformin (70%) or placebo (30%), along with monthly goal setting for diet and exercise modification. Anthropometric measures, fasting blood analysis, and glucose tolerance tests were performed at baseline and 6 months. RESULTS: Mean age was 15.7 years. Mean body mass index (BMI) was 39.7 kg/m(2). 71% were female, 58% were Hispanic, and 34% were African-American. 76% of participants completed the study. Goal setting alone did not result in significant weight loss. In addition, there were no group differences between metformin and placebo in weight loss or measures of glucose metabolism. However, among females taking metformin, there was a significant decrease in BMI not seen in the placebo group. Furthermore, metformin adherence, when accompanied by lifestyle change, was a predictor of BMI decrease of 5% or more. 60% of 10 subjects who adhered to metformin and decreased portion size decreased BMI by >5%. CONCLUSIONS: In this group of predominately minority adolescents, monthly goal setting alone did not lead to weight loss. Although the addition of metformin had no effect on weight loss overall, the agent did significantly increase weight loss among females and weight loss was predicted by degree of metformin adherence. However, weight loss was only found in those participants also reporting lifestyle change, particularly a decrease in portion sizes. These results suggest that metformin may be a useful agent to promote short-term weight loss among girls making modest lifestyle changes.