Diabetes Care Volume 39, September 2016 1635

Kristen J. Nadeau,1 Barbara J. Anderson,2

Youth-Onset Type 2 Diabetes Erika G. Berg,3 Jane L. Chiang,3
Hubert Chou,4 Kenneth C. Copeland,5
Consensus Report: Current Status, Tamara S. Hannon,6 Terry T.-K. Huang,7
Jane L. Lynch,8 Jeff Powell,9
Challenges, and Priorities Elizabeth Sellers,10
Diabetes Care 2016;39:1635–1642 | DOI: 10.2337/dc16-1066 William V. Tamborlane,11 and
Philip Zeitler1

CONSENSUS REPORT
Type 2 diabetes is a significant and increasing burden in adolescents and young
adults. Clear strategies for research, prevention, and treatment of the disease in
these vulnerable patients are needed. Evidence suggests that type 2 diabetes in
children is different not only from type 1 but also from type 2 diabetes in adults.
Understanding the unique pathophysiology of type 2 diabetes in youth, as well as
the risk of complications and the psychosocial impact, will enable industry,
academia, funding agencies, advocacy groups, and regulators to collectively
evaluate both current and future research, treatment, and prevention approaches.
This Consensus Report characterizes type 2 diabetes in children, evaluates the
fundamental differences between childhood and adult disease, describes the cur-
1
rent therapeutic options, and discusses challenges to and approaches for developing Department of Pediatrics, University of Colorado
new treatments. School of Medicine, and Department of Endocrinology,
Children’s Hospital Colorado, Aurora, CO
2
Section of Psychology, Department of Pediat-
Youth-onset type 2 diabetes is an emerging disorder in children, adolescents, and rics, Baylor College of Medicine Education at
young adults with unique challenges in both research and clinical care. Type 2 di- Texas Children’s Hospital, Houston, TX
3
American Diabetes Association, Alexandria, VA
abetes has a disproportionate impact on youth of ethnic/racial minorities and from 4
Clinical Development, Daiichi Sankyo, New York,
disadvantaged backgrounds (Fig. 1) and occurs in complex psychosocial and cultural NY
5
environments that make durable lifestyle change elusive and adherence to medical Department of Pediatrics and Harold Hamm
recommendations a struggle. Furthermore, these complexities hinder successful Diabetes Center–Children’s, The University of
recruitment into and completion of research programs (1), leaving large gaps in Oklahoma College of Medicine, Oklahoma City,
OK
knowledge on pathophysiology and treatment optimization. 6
Indiana University School of Medicine, Indian-
Type 2 diabetes in youth clearly differs from type 1 diabetes and more closely apolis, IN
7
resembles the pathophysiology in adults: insulin resistance and nonautoimmune School of Public Health, The City University of
b-cell failure. However, youth-onset type 2 diabetes displays unique aspects, such New York, New York, NY
8
as rapidly progressive b-cell decline (Fig. 2) and accelerated development of di- The University of Texas Health Science Center at
San Antonio, San Antonio, TX
abetes complications. Treatment options for youth-onset type 2 diabetes are in- 9
Pediatrics and Community Health, Northern
adequate, limited to two approved drugs (insulin and metformin) and the Navajo Medical Center, Navajo Area Indian
promotion of healthy lifestyles. Comprehensive, coordinated, and innovative strat- Health Service, Shiprock, NM
10
egies for the investigation, prevention, and treatment of youth-onset type 2 di- Department of Pediatrics, Health Sciences Cen-
tre Winnipeg, Winnipeg, Canada
abetes are urgently needed. 11
Department of Pediatric Endocrinology and
Yale Center for Clinical Investigation, Yale School
OBJECTIVES of Medicine, New Haven, CT
The American Diabetes Association, in collaboration with the American Academy Corresponding author: Philip Zeitler, philip.
of Pediatrics, International Society for Pediatric and Adolescent Diabetes, and [email protected].
Pediatric Endocrine Society, conducted a consensus conference. The goal was to © 2016 by the American Diabetes Association.
review the current state of knowledge and controversies surrounding youth- Readers may use this article as long as the work
is properly cited, the use is educational and not
onset type 2 diabetes, including similarities and differences between childhood for profit, and the work is not altered. More in-
and adult disease, current therapeutic options, and unmet clinical and research formation is available at http://diabetesjournals
needs, in order to make specific recommendations regarding research priorities .org/site/license.
1636 Consensus Report Diabetes Care Volume 39, September 2016

EPIDEMIOLOGY
The incidence of type 2 diabetes in
youth has increased dramatically over
the past 20 years. In the U.S., estimates
are as high as 5,000 new cases per year
(3). Prevalence increases with age, tri-
pling from age 10–14 years to 15–18
years (4). Although rates in adult men
and women are similar, adolescent girls,
for reasons that remain unclear, have a
60% higher prevalence rate than boys
(4). Disadvantaged racial/ethnic groups
are at higher risk of disease at all ages,
but the association is especially strong in
Figure 1—Prevalence of youth-onset type 2 diabetes by race/ethnicity. 2009 prevalence of youth (4) (Fig. 1).
type 2 diabetes among youth, as published by the SEARCH for Diabetes in Youth study (4). Indigenous children around the world
Prevalence is reported per 10,000 population at risk for type 2 diabetes (ages 10–19 years). bear the greatest burden of youth-onset
AA, African American; AI, American Indian; API, Asian Pacific Islander; H, Hispanic; NHW, non- type 2 diabetes (5). American Indians
Hispanic white.
have the highest rates of youth-onset
type 2 diabetes in the U.S. (6). More-
and creation of a sustainable clinical behavior, and severe weight gain. R.Y.’s over, in the SEARCH for Diabetes in
research infrastructure that supports mother wondered if R.Y.’s diabetes Youth (SEARCH) study, a population-
treatment development. diagnosis was due to gestational dia- based registry of youth with diabetes
betes mellitus, witnessing physical from five representative U.S. catchment
A CASE STUDY: THE FACE OF abuse, or social inequalities. The return sites, nearly half of American Indian
YOUTH-ONSET TYPE 2 DIABETES to the Native American community youth with diabetes had an A1C .9.5%
R.Y., an 11-year-old youth of American benefitted R.Y., with improvements in (7). Available global data indicate con-
Indian heritage, was diagnosed with R.Y.’s school performance, relation- siderable variation in incidence and
type 2 diabetes during a routine school ships, and disciplinary issues, as well prevalence, depending on ethnicity
physical exam. Her mother had re- as improvement in family cohesion. and geographical region. Rates of youth-
cently moved the family from a stressful However, the family continued to face onset type 2 diabetes are lowest in
urban environment of domestic vio- barriers to adopting a healthy life- Europe. The increasing incidence re-
lence, financial distress, frequent school style: long drives to school, a health ported in China and India is of particular
changes, unstable housing, and lack of clinic, or grocery store; financial strains; concern, given their large populations
consistent parental supervision back and few safe outdoor areas. R.Y. exem- (8,9).
home to her childhood community. plifies the complexity of the social
Before the move, R.Y. had developed milieu common to youth with type 2
PATHOPHYSIOLOGY
poor school performance, oppositional diabetes (2).
The Treatment Options for type 2 Dia-
betes in Adolescents and Youth (TODAY)
study was a multicenter trial that exam-
ined the durability of glycemic control in
699 U.S. youth randomized to metfor-
min, metformin plus rosiglitazone, or
metformin plus an intensive lifestyle in-
tervention for up to 6 years, while also
providing pathophysiological insight
into the disease (10,11). Surprisingly,
loss of glycemic control was rapid in
many of the participants, despite a
mean baseline diabetes duration of
only 7.8 months. Lower initial b-cell
reserve and higher A1C following initia-
tion of metformin were significant inde-
Figure 2—b-Cell failure rates in adults versus youth with type 2 diabetes. A comparison of pendent predictors of loss of glycemic
medication treatment failure rates and percent change in surrogate measures of insulin sensi- control (12,13).
tivity and b-cell function as reported in the TODAY study (youth) versus adult studies (A Diabetes
A decline in b-cell function also occurs
Outcome Progression Trial [ADOPT], U.S. Department of Defense Database [US DOD], and UK
Prospective Diabetes Study [UKPDS]). Note that the studies had different primary end points and in adults with type 2 diabetes, though
therefore this is an approximate comparison, as there have been no head-to-head comparisons not as rapidly as in youth (Fig. 2) (11,
(11,12,14–16,67,68). Met, metformin; Rosi, rosiglitazone. 14–16). In particular, the rate of loss of
care.diabetesjournals.org Nadeau and Associates 1637

glycemic control on either metformin Rapid progression of complications is individual vulnerability or resilience to SES
monotherapy or combination therapy also seen; current evidence in First Na- adversity, and, conversely, social factors
with rosiglitazone in TODAY appears to be tions youth with type 2 diabetes shows can alter whether a gene is expressed or
three- to fourfold higher than published that renal and neurological complications suppressed through epigenetic pathways
rates in adults. Although the studies in begin to appear within 5 years of diagno- (30,31).
Fig. 2 had different primary end points sis, and major complications (dialysis, Youth with type 2 diabetes and their
and lacked head-to-head prospective blindness, or amputation) start to family members experience multiple
evaluations, the outcomes suggest manifest 10 years after diagnosis stressors in their daily lives. However,
that b-cell failure may be more rapid (21,22). stress and other social determinants
in youth than in adults. Thus, efforts In the TODAY study, 10% of female are poorly addressed in standard medi-
are needed to preserve b-cell function adolescents became pregnant during cal care (32). Alternate models of care
in youth before significant deterioration the first 6 years of the study despite an delivery are likely needed to address
occurs. aggressive program of preconception stress and will require broad and inten-
counseling and access to birth control sive intervention (33).
PUBERTY (23). When adolescents with type 2 di-
Puberty is associated with significant abetes become pregnant, fetuses are LIFESTYLE, COMMUNITY, AND
changes in physiology, including a tran- exposed to the metabolic consequences COORDINATED INTERVENTIONS
sient reduction in insulin sensitivity by of diabetes that likely contribute to an FOR THE PREVENTION AND
;50% in lean, healthy children as they increased risk of type 2 diabetes and TREATMENT OF YOUTH-ONSET
enter puberty (17). To compensate, in- earlier age of diagnosis in the offspring TYPE 2 DIABETES
sulin secretion must increase recipro- (24,25). Moreover, in the TODAY study Lifestyle intervention is considered the
cally, which may lead to hyperglycemia ;30% of pregnancies were complicated first-line treatment for type 2 diabetes
in youth with limited b-cell capacity due by preterm birth or fetal malformation. in adults. However, most pediatric life-
to genetic, epigenetic, and/or lifestyle style intervention studies have focused
factors. Thus puberty, similar to preg- PSYCHOSOCIAL ASPECTS AND on youth affected by obesity or predia-
nancy, creates a high-risk time for diabetes CARE DELIVERY betes (34–36), not specifically on youth
development in susceptible individuals. The World Health Organization defines with type 2 diabetes. The majority of
Furthermore, reminiscent of gestational the social determinants of health as “the interventions have examined individual-
diabetes mellitus, diabetes onset during conditions in which people are born, level behavior modification, targeting
puberty may be reversible in some youth grow, work, live, and age,” which are diet and/or physical activity with classic
due to the dynamic nature of the under- “the fundamental drivers” of many health education and social-cognitive
lying insulin resistance. Other potentially health conditions (26). Socioeconomic models. The TODAY study is the only
modifiable risk factors influencing insulin status (SES), as determined by income, trial to date combining lifestyle and
sensitivity include adiposity, diet, physical education, and employment, among drug therapy in youth with type 2 diabetes
activity, sleep, and stressdall markedly other factors, is the primary social de- (11).
abnormal in youth-onset type 2 diabetes terminant of health impacting youth Bright Bodies Weight Management
(18,19). and families living with type 2 diabetes. Program for Children, an intensive
Egerter et al. (27) documented how 12-month behavior modification inter-
COMPLICATIONS parental educational attainment af- vention in obese youth without diabetes,
Diabetes duration and glycemic control fects the health of all family members demonstrated significant treatment-
are closely associated with the develop- through impacts on the parents’ insur- induced reductions in BMI, total choles-
ment of microvascular complications ance options, the safety and social sup- terol, and insulin resistance estimated by
in type 1 diabetes and in adult-onset port available, choices for housing, and HOMA of insulin resistance; results
type 2 diabetes. However, evidence of opportunities for healthy eating and were sustained at 12-month postinter-
microvascular complications and risk physical activity in the neighborhood. vention (37). In addition, when applied
markers for macrovascular complica- In 50% of the TODAY study families, over 6 months to youth with prediabe-
tions are often present at the time of the highest educational level attained tes, Bright Bodies showed significantly
diagnosis of type 2 diabetes in youth. by a parent was a high school diploma more reduction in 2-h glucose com-
At enrollment into the TODAY study, or less (18). Globally, many populations pared with standard care participants
14% of participants had a blood pres- at high risk for youth-onset type 2 dia- (38). However, among children already
sure at the 95th percentile or greater, betes also have high rates of poverty diagnosed with type 2 diabetes, the ev-
13% had microalbuminuria, 80% had a and low parental educational attainment idence for lifestyle intervention effects
low HDL cholesterol level, and 10% had (28). is limited and less clear. In the TODAY
high triglycerides (18). Similarly, in McEwen and Stellar (29) introduced study, lifestyle strategies in combina-
Canadian First Nations youth with the concept of “allostatic load” to de- tion with metformin therapy did not
type 2 diabetes, 37% had elevated triglyc- scribe how chronic exposure to social perform better than metformin alone
erides and apolipoprotein B levels and and environmental stressors negatively in delaying progression of hyperglycemia
12% and 14% of male and female youth, impact body weight, metabolism, blood (11).
respectively, had systolic blood pressure pressure, and the sympathetic nervous Given the complex social and environ-
greater than the 95th percentile (20). system. Genetics also plays a role in mental context surrounding youth with
1638 Consensus Report Diabetes Care Volume 39, September 2016

type 2 diabetes, individual-level lifestyle neity, algorithms to predict disease from pharmaceutical sponsors to com-
interventions may not be sufficient to trajectory would enable customized plete an assessment of safety and effi-
target the complex interplay of family approaches to patients. cacy in pediatric patients for all new
dynamics (39), mental health (40,41), Research is needed to better under- active ingredients, indications, or dos-
community readiness (42), and the stand what diabetes complications may age forms as a condition of new drug ap-
broader environmental system (43). require pediatric-specific approaches. proval (with similar mandates in Europe)
The few pediatric obesity interventions Nonalcoholic fatty liver disease occurs (http://www.fda.gov/downloads/drugs/
to date with psychosocial outcomes in both youth and adults with type 2 guidancecomplianceregulatoryinformation/
have reported mixed findings, including diabetes (53), but the pathological phe- guidances/ucm079756.pdf). Therefore,
decreased anxiety (44) and improved notype is unique and appears more numerous new drug pharmacokinetic
psychosocial functioning and social aggressive in youth. The kidney func- studies and safety and efficacy trials in
performance (45) but no change in tion measures for adults are inappro- youth-onset type 2 diabetes are currently
perceived or measured stress (46). priate for youth (54), and little is known under way or are committed by pharma-
One alternate model of pediatric care about the long-term outcomes for youth- ceutical sponsors as a prerequisite for
delivery, the patient-centered medi- onset dyslipidemia, hypertension, kidney new drug approval in adults. However,
cal home, is designed specifically to disease, nonalcoholic fatty liver disease, the mandated pediatric trials are having
address the social context of pa- and cardiovascular dysfunction (55). The substantial difficulty completing enroll-
tient care (32) by including three key impact on glycemic control of the sleep ment. As a consequence, individuals
componentsdcomprehensive, interdis- abnormalities endemic among adoles- with youth-onset diabetes have benefit-
ciplinary care; patient/family-centered cents is also unknown (56). ted minimally, if at all, from the develop-
care; and coordinated caredwith all ment of new therapeutic agents. Barriers
health and community resources housed to study execution include the small num-
under one roof. A related approach is RECRUITMENT CHALLENGES IN ber of available study participants, restric-
to increase community readiness by CLINICAL AND TRANSLATIONAL tive study eligibility criteria, small number
assessing a community’s self-identified RESEARCH of research sites with dedicated resources
needs, mobilizing community leaders Despite the development of more than for pediatric type 2 diabetes trials, socio-
and internal and external resources, 10 different classes of antidiabetes economic challenges inherent in the af-
increasing public knowledge, and medications since the U.S. Food and fected population, and growing number
cultivating a sense of priority in the Drug Administration (FDA) approval of of trials competing for the limited pool of
community (47). Environmental strate- sulfonylurea agents in 1984, metfor- available patients (Fig. 3).
gies could target community access to min remains the only oral medication Why have so many diabetes drugs
healthy foods, physical activity, and approved for use in children today been studied, yet none approved for
health care (48,49). Importantly, com- (57,58). Although numerous formula- use in children? The answer is as com-
munity engagement and cocreation of tions of insulin are commonly used in plex as the environment in which youth-
both the content and implementation youth-onset type 2 diabetes, they have onset type 2 diabetes occurs. Clinical
of interventions may be key to effective not been studied for the specific in- trial recruitment for youth with type 2
and sustained impact (50,51). dication of pediatric type 2 diabetes. diabetes is a relatively new endeavor
FDA regulations require a commitment and has had limited success (59–61). As an
ADDITIONAL KNOWLEDGE GAPS
IN YOUTH-ONSET TYPE 2
DIABETES Table 1—Gaps in knowledge in youth-onset type 2 diabetes
Further limiting the development of c How do insulin resistance and insulin secretion differ between youth and adults? Do

best practices for evaluating and treat- differences in glucose/insulin physiology require a different approach to prevention and
ing youth-onset type 2 diabetes are gaps treatment?
c What are the definitions of prediabetes and diabetes in youth-onset type 2 diabetes? Current
in our understanding of normal and
definitions are based on extrapolation from adults and are not evidence based.
abnormal glucose metabolism during
c What are the implications of transient hyperglycemia seen in some youth and the rapid
adolescence and development of com- progression of b-cell dysfunction seen in others?
plications and the long-term outcomes c What are the implications of physiological barriers (cardiac, vascular, autonomic, muscle
of youth-onset type 2 diabetes (Table 1). mitochondrial dysfunction) to exercise seen in obese youth and youth with type 2 diabetes?
Indeed, even the definitions of predia- c What are the best approaches to understanding kidney function in youth with obesity and
betes and type 2 diabetes in youth are type 2 diabetes and what is the natural history of the renal hyperfiltration characteristic of
not evidence based, as they have simply these youth?
been extrapolated from glycemic indi- c How do the unique physiology of adolescent sleep and endemic poor sleep patterns of youth

ces predicting microvascular complica- contribute to development of type 2 diabetes and associated disorders?
c What is the optimal approach to management of comorbidities and complications in
tions in adults. Dysglycemia appears to
youth-onset type 2 diabetes, including lipids, blood pressure, and microalbuminuria?
be transient in some youth, who may
c What is the impact of stress and historical trauma on the development, presentation, and
not need long-term drug treatment, and management of youth-onset type 2 diabetes?
others rapidly lose glycemic control on c What are effective ways to increase compliance with lifestyle interventions and medication in
oral monotherapy and require multiple- adolescents with type 2 diabetes?
drug treatment (52). Given this heteroge-
care.diabetesjournals.org Nadeau and Associates 1639

trials, such as elevated liver enzymes,

prior ketoacidosis, or common comorbid
conditions, can further restrict the eligi-
bility pool.
The rationale for excluding partici-
pants with an A1C ,6.5% in pharma-
ceutical trials is a consequence of the
glucocentric A1C-lowering design and
the recognition that it may be difficult
to lower A1C further in patients with
already well-controlled diabetes, as
well as outstanding questions regarding
the benefit of further lowering of A1C.
However, this approach fails to take into
consideration the observation that a
substantial proportion of youth initially
in good glycemic control ultimately of-
ten fail to maintain glycemic control
(11,64) within a relatively short time
period. Therefore, studies of add-on
therapy could include adolescents with
A1C ,6.5% on metformin because
many would be expected to show an
abrupt increase in A1C over time while
on metformin alone. The superiority of
Figure 3—Few patients with youth-onset type 2 diabetes are available to participate in clinical an add-on medication could then be
trials. The population of youth-onset type 2 diabetes is small, approximately 20,000–25,000 in tested in its ability to prevent the loss
the U.S., compared with the approximately 20 million adults. Barriers to clinical trial participa-
tion include the paucity of centers with dedicated resources for pediatric type 2 diabetes trials,
of glycemic control.
SES challenges inherent to the population, and the many study entry requirements that exclude U.S. (FDA) and European (European
study eligibility before and after formal study screening procedures (69). T2D, type 2 diabetes. Medicines Agency) pediatric type 2 di-
*Numbers are from Imperatore et al. (69). abetes investigation plans historically
required a stand-alone pharmacokinetics/
pharmacodynamics (PK/PD) study and
example of the challenges in recruitment with type 2 diabetes appears to be het- a phase III efficacy and safety study.
in youth-onset type 2 diabetes, the erogeneous, with two large subsets This approach substantially increases
SEARCH study aimed to register pediat- and a bimodal distribution. One subset both the number of participants and
ric patients with both type 1 and type 2 has durable normalization of glycemia the time to completion required. How-
diabetes. Yet, despite the same well- on initial monotherapy with A1C in the ever, the results of stand-alone PK/PD
funded, full-time, dedicated research nondiabetic range, while another group studies to date indicate that the PK
staff, the case ascertainment time from has a rapidly progressing course and properties of diabetes drugs in adoles-
diagnosis was two times longer in youth- very elevated values requiring insulin cent patients with type 2 diabetes are
onset type 2 diabetes than in type 1 di- treatment. Thus, only a small number not significantly different from those in
abetes (62). Similarly, the duration of the of individuals remain in the range typical adults (64). As a result, more recent pe-
TODAY study recruitment had to be ex- of pharmaceutical trial inclusion criteria, diatric study plans have waived the need
tended substantially, and although the an A1C .7.0% on treatment with diet/ for a stand-alone PK study and instead
well-funded, full-time TODAY research exercise or metformin monotherapy. confirmed exposure of the predicted
staff were ultimately successful in ran- The Pediatric Diabetes Consortium dose through sparse sampling of PK pa-
domizing 699 youth, recruitment took Type 2 Diabetes Registry (63) demon- rameters embedded within the pivotal
5.5 years (18). strated that this criteria alone excludes pediatric safety and efficacy study, al-
Recruitment for pharmaceutical trials ;87% of potentially eligible partici- lowing for more rapid progress. How-
has been even less successful due to the pants. More recently, some trials have ever, some recent phase III study plans
interaction between specific regulatory changed the criteria to allow partici- continue to require the analysis of the
requirements, need to demonstrate re- pants on a stable dose of basal insulin safety and efficacy of different doses of
duction in the glycemic surrogate A1C, who have an A1C $6.5% and #10.5%. the experimental drug, again increasing
and realities of youth-onset type 2 dia- Although an improvement, these eligi- the number of required participants.
betes (18). For example, entry criteria, bility criteria still exclude ;53% of po- The clinical presentation of new-onset
such as the typical 7–10% A1C ranges, tential participants, as 38% of patients type 2 diabetes is another barrier. Youth
often do not reflect the trajectory of included in the registry have an A1C with new-onset type 1 diabetes typically
youth-onset type 2 diabetes. As noted ,6.5% and 15% have an A1C $10.5% require urgent attention and families
previously, the population of youth (63). Exclusion criteria seen in some eagerly seek opportunities to participate
1640 Consensus Report Diabetes Care Volume 39, September 2016

in clinical research in hopes of finding a type 2 diabetes will be critical to 6. Promote development of appropriate
cure. In contrast, the majority of youth potential creative regulatory ap- study design, monitoring of recruit-
with type 2 diabetes have subtler initial proaches to new drug approval ment and retention, and a central
symptoms; many families express relief based on extrapolation from adult coordinating center to support the
at what is perceived as a familiar and trials. research teams (e.g., institutional re-
less severe form of diabetes. Insulin, if 2. Increased exploration of the psycho- view board and convening logistics,
started initially, is often stopped, adding logical and SES aspects of youth-onset budgeting, supplies, certification,
to the perception of a milder disease. type 2 diabetes. An improved under- data management, and stakeholder
As a result, families may be less likely standing of the ways in which the engagement). These consortia could
to accept the potential risks of an exper- environment contributes to the use a hybrid approach to funding: a
imental medication. Furthermore, studies pathophysiology of the disorder, modest amount of committed support
must recruit youth quickly to stay within as well as to challenges in treatment at each site to build and maintain the
the pediatric age range of ,18 years and research recruitment, will be research team, supplemented by pay-
for eligibility yet may also have to wait necessary for development and de- ment for the number of participants
for the youth to fail initial metformin livery of feasible and successful enrolled in active treatment trials.
monotherapy. interventions. 7. Increasing the proportion of youth
As mentioned previously, the SES 3. Development of formalized collab- with type 2 diabetes who participate
challenges (65,66) of families of youth orative networks of investigators in clinical drug trials through
with type 2 diabetes decrease the ability and centers with recognized exper- a. More flexible enrollment criteria,
to obtain clinical care or prioritize re- tise in clinical studies of youth- including wider A1C and age
search participation. In addition, fami- onset type 2 diabetes. Progress in ranges (i.e., allowing a participant
lies with an existing high burden of studying, understanding, and treat- who is over 18 years but who de-
diabetes-related disease often have ing this rare disorder cannot be veloped diabetes prior to age 18
fatalistic beliefs regarding the inevitable achieved by sole investigators who years) and fewer exclusion crite-
progression of diabetes. This perception are unlikely to have access to suffi- ria (i.e., concomitant medica-
further decreases the motivation to cient numbers of affected individu- tions, hypertension, elevated liver
sustain consistent medical care or par- als. Rather, consortia, such as the enzymes);
ticipate in research, and youth are often Children’s Oncology Group, have b. Trial designs appropriate for the
lost to follow-up within a year of diagno- promoted remarkable progress in typical youth with type 2 diabetes,
sis. Past history of ethical maltreatment addressing other rare disorders and including flexibility of scheduling,
of certain ethnic groups in research also should be looked to as models. minimization of visit number and
creates attitudes of distrust and appre- 4. Collaboration among academic lead- burden, and parent and participant
hension among family members. The ers, government and charitable reimbursement, including recogni-
high risk for losing contact, combined sponsors, industry, and regulatory tion of the sacrifices of school and
with early rapid deterioration of b-cell agencies to delineate research prior- work time these studies require;
function, creates missed opportunities ities and strategies. This should in- and
to recruit youth who meet study eligibility clude consideration for treatment c. Creative strategies to overcome
criteria. strategy trials that clarify how to ap- barriers to care and research, in-
proach treatment of affected youth cluding telemedicine, mobile or
rather than only individual drug reg- community-based research sites,
SOLUTIONS istration trials. There is also a need and engagement of affected youth,
Given the realities of the epidemiology, to prioritize outcomes other than their families, and communities in
biology, and SES characteristics of glycemic control, including preserva- the research process to identify out-
youth-onset type 2 diabetes, as well as tion of b-cell function, improvement comes that are important and rele-
the experience of clinical research to in insulin sensitivity, weight control, vant to the population.
date, progress in understanding the lowering cardiovascular disease risk, 8. Increasing efficiency of pharmaceuti-
pathophysiology of the disease in youth and reduction of other diabetes cal registration studies by focusing
and successful completion of clinical tri- complications. on high-impact trials of novel agents
als for this population will require 5. Increasing research and infrastruc- and exploration of innovative trial
ture capacity for youth-onset type 2 designs, such as multi-agent studies
1. Prioritization of clinical and transla- diabetes through the development to eliminate duplicative placebo
tional research addressing the gaps of purpose-built research centers of control groups (60), and elimination
in knowledge regarding the appar- excellence that are uniquely staffed of low-priority trials, such as fixed-
ently unique physiological features and maintained. Such centers will dose combinations or new dosage
of youth-onset type 2 diabetes. In more successfully address the re- formulations.
addition to the importance of un- cruitment and retention obstacles 9. Harmonization of national and in-
derstanding the fundamental bio- characteristic of the population ternational regulatory guidelines to
logy, a fuller understanding of the than current models consisting of ensure inclusion of diverse populations,
similarities and differences be- short-term trials that enroll a few pa- broad relevance of the results, and im-
tween youth-onset and adult-onset tients per site. proved efficiency in protocol approval.
care.diabetesjournals.org Nadeau and Associates 1641

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thank the American Diabetes Association for 7. Hamman RF, Bell RA, Dabelea D, et al.; tes Care 2014;37:436–443
the inspiration and support for the development SEARCH for Diabetes in Youth Study Group. 23. Klingensmith GJ, Pyle L, Nadeau KJ, et al.;
of this conference. In addition, we would like The SEARCH for Diabetes in Youth study: ratio- TODAY Study Group. Pregnancy outcomes in
to thank the American Academy of Pediatrics, nale, findings, and future directions. Diabetes youth with type 2 diabetes: the TODAY study
Pediatric Endocrine Society, and International Care 2014;37:3336–3344 experience. Diabetes Care 2016;39:122–129
Society for Pediatric and Adolescent Diabetes 8. Fu J, Prasad HC. Changing epidemiology of 24. Dabelea D, Hanson RL, Lindsay RS, et al. In-
for their cosponsorship and collaboration. metabolic syndrome and type 2 diabetes in Chi- trauterine exposure to diabetes conveys risks
The success of the conference was due to the nese youth. Curr Diab Rep 2014;14:447 for type 2 diabetes and obesity: a study of di-
contributions of multiple individuals, and the 9. Prasad AN. Type 2 diabetes mellitus in young scordant sibships. Diabetes 2000;49:2208–2211
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Kadish (American Diabetes Association) for her 48:683–688 E, Taback S, Dean H. Obesity and type 2 diabe-
invaluable logistics support and Ashley Butler 10. Kelsey MM, Geffner ME, Guandalini C, tes mellitus in a birth cohort of First Nation
(Baylor College of Medicine) for her contribu- et al.; Treatment Options for type 2 Diabetes children born to mothers with pediatric-onset
tions to the content. The authors would also in Adolescents and Youth (TODAY) Study Group. type 2 diabetes. Pediatr Diabetes 2011;12:219–
like to acknowledge the invaluable participation Presentation and effectiveness of early treat- 228
of Janina Karras, from the European Medicines ment of type 2 diabetes in youth: lessons from 26. World Health Organization. Social Determi-
Agency, and Lisa Yanoff and Lily Mulugeta, from the TODAY study. Pediatr Diabetes 2016;17: nants of Health. The Solid Facts. 2nd edition.
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Funding and Duality of Interest. All authors 11. Zeitler P, Hirst K, Pyle L, et al.; TODAY Study from http://www.euro.who.int/en/publications/
have completed the United Competing Interest Group. A clinical trial to maintain glycemic con- abstracts/social-determinants-of-health.-the-
form at www.icmje.org/conflicts-of-interest trol in youth with type 2 diabetes. N Engl J Med solid-facts. Accessed 21 December 2015
(available upon request from E.G.B.) and de- 2012;366:2247–2256 27. Egerter S, Braveman P, Sadegh-Nobari T,
clare the following conflicts of interest. The au- 12. TODAY Study Group. Effects of metformin, Grossman-Kahn R, Dekker M. Robert Wood
thors acknowledge an unrestricted education metformin plus rosiglitazone, and metformin Johnson Foundation Commission to Build a
grant from Novo Nordisk Inc. H.C. is employed plus lifestyle on insulin sensitivity and b-cell func- Healthier America. Exploring the Social Deter-
at Daiichi Sankyo Pharma Development. K.C.C. tion in TODAY. Diabetes Care 2013;36:1749–1757 minants of Health. Education and Health, Issue
has received honoraria from Daiichi Sankyo. 13. Zeitler P, Hirst K, Copeland KC, et al.; TODAY Brief 5 [Internet], 2011. http://www.rwjf.org/
T.S.H. has received grants from the National Study Group. HbA1c after a short period of en/library/research/2011/05/education-matters-
Institutes of Health, Agency for Healthcare Re- monotherapy with metformin identifies durable for-health.html. Accessed 21 December 2015
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