Genetic architecture and biology of youth-onset type 2 diabetes.

The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily1, producing a growing public health concern1 that disproportionately affects minority groups2. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear3. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant (P < 2.6 × 10-6) gene-level associations (HNF1A, MC4R, ATXN2L). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and ß-cell function. Many youth-onset T2D associations are shared with adult-onset T2D, but genetic risk factors of all frequencies-and rare variants in particular-are enriched within youth-onset T2D cases (5.0-fold increase in the rare variant and 3.4-fold increase in common variant genetic liability relative to adult-onset cases). The clinical presentation of participants with youth-onset T2D is influenced in part by the frequency of genetic risk factors within each individual. These findings portray youth-onset T2D as a heterogeneous disease situated on a spectrum between monogenic diabetes and adult-onset T2D.

Insights from rare variants into the genetic architecture and biology of youth-onset type 2 diabetes.

Youth-onset type 2 diabetes (T2D) is a growing public health concern. Its genetic basis and relationship to other forms of diabetes are largely unknown. To gain insight into the genetic architecture and biology of youth-onset T2D, we analyzed exome sequences of 3,005 youth-onset T2D cases and 9,777 ancestry matched adult controls. We identified (a) monogenic diabetes variants in 2.1% of individuals; (b) two exome-wide significant (P < 4.3×10-7) common coding variant associations (in WFS1 and SLC30A8); (c) three exome-wide significant (P < 2.5×10-6) rare variant gene-level associations (HNF1A, MC4R, ATX2NL); and (d) rare variant association enrichments within 25 gene sets broadly related to obesity, monogenic diabetes, and ß-cell function. Many association signals were shared between youth-onset and adult-onset T2D but had larger effects for youth-onset T2D risk (1.18-fold increase for common variants and 2.86-fold increase for rare variants). Both common and rare variant associations contributed more to youth-onset T2D liability variance than they did to adult-onset T2D, but the relative increase was larger for rare variant associations (5.0-fold) than for common variant associations (3.4-fold). Youth-onset T2D cases showed phenotypic differences depending on whether their genetic risk was driven by common variants (primarily related to insulin resistance) or rare variants (primarily related to ß-cell dysfunction). These data paint a picture of youth-onset T2D as a disease genetically similar to both monogenic diabetes and adult-onset T2D, in which genetic heterogeneity might be used to sub-classify patients for different treatment strategies.

Progression from prediabetes to type 2 diabetes mellitus in adolescents: a real world experience.

Background: Obesity in pediatric patients is strongly associated with increased vascular and metabolic risk. Prediabetes is present in up to 1 in 5 adolescents, aged 12-18 years-old, though is thought to remit spontaneously in a significant portion. Pediatric patients with type 2 diabetes mellitus (T2D) have a more rapid decline of beta-cell function and progression to treatment failure than adult T2D patients. Thus, there is a strong interest in better understanding the natural history of prediabetes in these youth. We aimed to evaluate the real-world rate of progression of prediabetes to T2D in adolescent patients. Methods: This is a retrospective study of 9,275 adolescent subjects aged 12-21 years-old with at least 3 years of de-identified commercial claims data and a new diagnosis of prediabetes during the observation period. Enrollees with a T2D diagnosis and/or diabetes medication use in the 1 year prior to prediabetes diagnosis or a T2D diagnosis in the 1 month following prediabetes diagnosis were excluded. Enrollees with diagnoses of type 1 diabetes (T1D) or polycystic ovarian syndrome over the 3 years were also excluded. Progression to T2D was defined by claims data of two T2D diagnoses at least 7 days apart, HbA1c ≥ 6.5%, and/or prescription of insulin without known T1D. Enrollees were followed for 2 years after prediabetes diagnosis. Results: Overall, 232 subjects (2.5%) progressed from prediabetes to T2D. There were no differences found in T2D progression based on sex or age. Progression to T2D occurred at a median of 302 days after prediabetes diagnosis (IQR 123 to 518 days). This study was limited by the lack of laboratory/anthropometric data in administrative claims, as well as the exclusion of 23,825 enrollees for lack of continuous commercial claims data over 3 years. Conclusion: In the largest sample to date on adolescent prediabetes, we found a 2.5% progression of prediabetes to T2D over a median duration of about one year.

Long-Term Retention of Young Adult Study Participants with Youth-Onset Type 2 Diabetes: Results from the TODAY2 Study.

INTRODUCTION: The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial examined the effects of three treatment arms in a group of racially and ethnically diverse adolescents and youth with type 2 diabetes mellitus. TODAY2 was an observational follow-up study reporting outcomes and complications in these participants after having diabetes for approximately 13 years. Participant retention was essential to fulfill this objective. This report describes the motivations and problems participants self-reported related to continuing in this study. METHODS: The TODAY2 retention survey was administered to participants with a mean age of 27 years, 36% non-Hispanic black, 18% non-Hispanic white, 39% Hispanic, 52% public, and 35% private healthcare coverage, who completed the last study visit (63.8% of original TODAY cohort). The survey listed potential benefits and barriers to staying in the trial. Participants indicated agreement or disagreement with each statement using a four-point Likert-type scale. RESULTS: More than 93% of survey responders agreed with the benefits listed for staying in TODAY2. The most cited reason for staying in the study was related to the strong relationship that participants had with study staff. The common barriers to attending trial visits were tending to other medical problems, fear of disappointing study staff, and school/work scheduling conflicts. Participants with public healthcare coverage were more likely to endorse benefits related to diabetes care (e.g., getting the latest test results, staying motivated to care for my diabetes) and monetary compensation, whereas participants with poor glycemic control cited that a barrier to attending study visits was "fear of disappointing" study staff. CONCLUSION: In a racially and ethnically diverse population of youth-onset type 2 diabetes, benefits and barriers associated with long-term retention are described. These findings can be used to help inform future retention strategies for young adults in clinical trials.

Cutaneous Reactions to Continuous Glucose Monitoring and Continuous Subcutaneous Insulin Infusion Devices in Type 1 Diabetes Mellitus.

BACKGROUND: Continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) are the standard of care for type 1 diabetes in children. There is little reported on device-related skin complications and treatment options. This study documents cutaneous reactions to CGM and CSII devices in children and young adults with type 1 diabetes. METHODS: One hundred and twenty-one subjects (3-25 years) with type 1 diabetes and CGM and/or CSII use were recruited over a three-month period from the Naomi Berrie Diabetes Center at Columbia University Irving Medical Center. A five-question survey was completed for each subject detailing demographic data, diabetes management, and device-related skin complications. RESULTS: Sixty percent of subjects reported skin complications related to CGM and/or CSII use. Terms most frequently used to describe cutaneous reactions were "red," "itchy," "painful," and "rash." Subjects who used both CGM and CSII were more likely to report skin problems than those who used only CSII (odds ratio 2.9, [95% confidence interval: 1.2-6.7]; P = .015). There were no associations between skin complications and sex or race/ethnicity. Twenty-two percent of subjects with adverse skin event(s) discontinued use of a device due to their skin problem. Seven percent were evaluated by a dermatologist. Eighty-one percent used a range of products to treat their symptoms, with variable perceived clinical outcomes. CONCLUSIONS: Skin complications related to CSII or CGM devices are commonly reported in pediatric patients with type 1 diabetes and may lead to interruption or discontinuation of device use. Future studies are needed to elucidate the causes of these reactions and determine the best methods for prevention.

Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure.

OBJECTIVE: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and ß-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and ß-cell function in MODY vs. non-MODY obese youth at randomization and over time. METHODS: Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and ß-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA). RESULTS: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. ß-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth. CONCLUSIONS: In TODAY, ß-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.

The association between dispositional mindfulness and glycemic control in type 1 diabetes during early adulthood: Differences by age and adverse childhood experiences.

BACKGROUND: The study objective was to determine whether higher levels of dispositional mindfulness were associated with lower HbA1c levels among young adults with type 1 diabetes (T1D) and whether this association differed by age or exposure to adverse childhood experiences (ACEs). METHODS: An online cross-sectional survey, called T1 Flourish, was completed in 2017 by 423 of 743 (56.9%) young adults (19-31 years) with T1D receiving outpatient care at a diabetes specialty clinic in New York City. HbA1c levels were abstracted from medical records. Respondents were categorized by age, high and low dispositional mindfulness (median split on Cognitive and Affective Mindfulness Scale-Revised), and exposure to any of 10 ACEs. RESULTS: Respondents had a mean (SD) HbA1c of 64 (18) mmol/mol [8.0 (1.7)%]; 59.3% were female and 69.4% were non-Hispanic white. The covariate-adjusted association between dispositional mindfulness and HbA1c differed by age group and ACEs. Among 27- to 31-year-olds, those with high mindfulness had HbA1c levels that were 8 mmol/mol [0.7%] lower (95% confidence interval, 2-13 mmol/mol [0.2-1.2%]) than those with low mindfulness, and this association tended to be stronger in those with ≥1 ACEs. Weaker, non-significant associations in the same direction occurred in 23- to 26-year-olds. Among 19- to 22-year-olds, those with high mindfulness and no ACEs tended to have higher HbA1c levels. CONCLUSIONS: In young adults with T1D, higher mindfulness was significantly associated with lower HbA1c only among 27- to 31-year-olds. In early adulthood, the impact of mindfulness-based interventions on glycemic control may vary by age and childhood trauma history.

Predictors of response to insulin therapy in youth with poorly-controlled type 2 diabetes in the TODAY trial.

OBJECTIVE: To understand the factors associated with glycemic control after starting insulin in youth with type 2 diabetes following glycemic failure (persistent HbA1c ≥8%) with metformin alone, metformin + rosiglitazone or metformin + lifestyle in the TODAY study. METHODS: Change in HbA1c after add-on insulin therapy and the factors predictive of glycemic response were evaluated. At 1-year postinsulin initiation, 253 youth had a mean of 3.9 ± 1.0 visits since the time of insulin initiation. Participants were divided into three groups according to glycemic control: consistent decrease in HbA1c by ≥0.5%, change <0.5%, or consistent increase in HbA1c ≥0.5%, at 75% or more of the visits. RESULTS: Within 1-year postinsulin initiation, 33.2% of participants had a consistent HbA1c decrease of ≥0.5%, 46.2% changed HbA1c <0.5%, and 20.6% had an increase ≥0.5%. At randomization into TODAY and at time of insulin initiation, the three glycemia groups were similar in age, sex, race-ethnicity, pubertal stage, BMI z-score, diabetes duration, and insulin secretion indices. Consistent HbA1c improvement was associated with higher insulin sensitivity (1/fasting insulin) at randomization and at time of failure, higher adiponectin at randomization, and was not associated with indices of ß-cell function. CONCLUSIONS: Response to add-on insulin was highly variable among youth in TODAY. Greater insulin sensitivity and higher adiponectin concentrations at randomization were associated with improved glycemic control after initiation of insulin. Due to limited information on adherence to insulin injections, the roles of adherence to the prescribed insulin regimen or psychosocial factors are unknown.

Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial.

PurposeMonogenic diabetes accounts for 1-2% of diabetes cases. It is often undiagnosed, which may lead to inappropriate treatment. This study was performed to estimate the prevalence of monogenic diabetes in a cohort of overweight/obese adolescents diagnosed with type 2 diabetes (T2D).MethodsSequencing using a custom monogenic diabetes gene panel was performed on a racially/ethnically diverse cohort of 488 overweight/obese adolescents with T2D in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. Associations between having a monogenic diabetes variant and clinical characteristics and time to treatment failure were analyzed.ResultsMore than 4% (22/488) had genetic variants causing monogenic diabetes (seven GCK, seven HNF4A, five HNF1A, two INS, and one KLF11). Patients with monogenic diabetes had a statistically, but not clinically, significant lower body mass index (BMI) z-score, lower fasting insulin, and higher fasting glucose. Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.ConclusionThe finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management.

Identifying monogenic diabetes in a pediatric cohort with presumed type 1 diabetes.

OBJECTIVE: Monogenic diabetes (MD) is rare and can often be confused with type 1 diabetes (T1D) in a pediatric cohort. We sought to determine clinical criteria that could optimally identify candidates for genetic testing of two common forms of MD that alter therapy: glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1α). RESEARCH DESIGN AND METHODS: We performed a retrospective chart review of 939 patients with a presumed diagnosis of T1D, 6 months-20 yr of age, and identified four clinical criteria that were unusual for T1D and could warrant further evaluation for MD: (i) negative pancreatic autoantibodies, (ii) evidence of prolonged endogenous insulin production, or (iii) strong family history of diabetes in multiple generations. One hundred and twenty-one patients were identified as having one or more of these high-risk clinical criteria and were offered screening for mutations in GCK and HNF1α; 58 consented for genetic testing. RESULTS: Of 58 patients with presumed T1D who underwent genetic testing, four were found to have GCK and one had HNF1α. No patients with only one high-risk feature were found to have MD. Of 10 patients who had two or more high risk criteria, five had MD (50%). CONCLUSION: A high frequency of MD from mutations in GCK/HNF1α may be identified among pediatric diabetic patients originally considered to have T1D by performing genetic testing on those patients with multiple clinical risk factors for MD.

Drowning in a sea of advice: pediatricians and American Academy of Pediatrics policy statements.

OBJECTIVE: The proliferation of policy statements from the American Academy of Pediatrics presents pediatricians with an increasing amount of health advice to deliver, yet no quantitative estimates of pediatric health advice expectations exist in the literature. The objective of this study was to quantify and characterize verbal health advice that pediatricians are expected to deliver to patients/guardians. METHODS: The authors read and coded the 344 American Academy of Pediatrics policy statements that are contained in the American Academy of Pediatrics' Pediatric Clinical Practice Guidelines and Policies, Third Edition, and identified 57 policies that contained health advice directives that are broadly relevant to pediatric practice. We extracted the individual advice text to a database in which we also coded its date of issue, its theme, and whether (1) it was duplicated in another policy, (2) a screening question was required to identify a target population for the advice, (3) handouts or other aids to delivering the advice were referenced in the policy itself, or (4) the text of the statement referred to evidence of the effectiveness of office-based delivery of the advice. RESULTS: These 57 policies were found to contain 192 discrete health advice directives that pediatricians are expected to deliver to patients/guardians. Seven (4%) of these directives originated before 1993, and 185 (96%) were created from 1993 to 2002. After removal of the 30 (16%) duplicates, safety advice composed 67%, media use composed 12%, substance abuse composed 5%, environmental health hazards composed 4%, development/emotional health composed 4%, sexuality and pregnancy composed 3%, nutrition composed 2%, and miscellaneous composed 3%. In 41% of the directives, a screening question was required to identify the target population for the advice. Aids to delivering advice were referenced in 20% of the policies. In no policy statements did the text refer to evidence that office-based counseling was an effective method to achieve the desired health or behavioral outcome. CONCLUSIONS: We examined the American Academy of Pediatrics policy statements and found 162 different verbal health advice directives on which pediatricians should counsel parents and patients throughout childhood. The expectation that delivery of all of this advice can be achieved is unrealistic. Moreover, none of the reviewed statements were found to include an evidence-based discussion of the efficacy of the suggested advice. In light of these findings, we suggest that committees should consider both the feasibility and the evidence of efficacy of office-based health advice when generating future policy statements.