Diabetes & Metabolic Syndrome: Clinical Research & Reviews 15 (2021) 102253

Contents lists available at ScienceDirect

Diabetes & Metabolic Syndrome: Clinical Research & Reviews

journal homepage: www.elsevier.com/locate/dsx

Review

The increasing trend of Type 2 diabetes in youth: An overview

Emily Buttermore a, Veronica Campanella b, Ronny Priefer a, *
a
Massachusetts College of Pharmacy And Health Sciences, BOSTON, MA, 02115, USA
b
Children's National Hospital, Washington, DC, 20010, USA

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Pediatric Type 2 Diabetes Mellitus (T2DM) is increasing in incidence, largely in correlation
Received 28 June 2021 with global childhood obesity crisis.
Received in revised form Complications: Early detection and treatment are vital as diabetes has been shown to progress rapidly
11 August 2021
and aggressively amongst children.
Accepted 12 August 2021
Etiology: Higher than expected insulin levels compared to adults, leads to more rapid b cell decline.
Treatments: New treatments to control glycemic levels among youth with T2DM are being evaluated.
Keywords:
This review summarizes the current understanding of causes, complications, and treatments for youth
Children
T2DM
diagnosed with T2DM. OR.
Adolescents Pediatric Type 2 Diabetes Mellitus (T2DM) is increasing in incidence, largely in correlation with the
Obesity global childhood obesity crisis. With increase in cases comes new challenges for medical professionals.
Metformin Early detection and treatment are vital as the disease has been shown to progress aggressively and bring
complications to children at a rapid rate. New treatments are currently being studied to control glycemic
levels among youth with T2DM, as current options are not as effective chronically in children as in adults.
This review summarizes the current understanding of causes, complications, and treatments for youth
diagnosed with T2DM.
© 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Diabetes Mellitus refers to a group of diseases affecting the
body's ability to respond to elevated blood glucose levels. Diabetes
Mellitus can be distinguished into various types including Type 1
Diabetes Mellitus (T1DM), Type 2 Diabetes Mellitus (T2DM),
Gestational Diabetes, and prediabetes. T1DM is characterized by
the destruction of b cells in the pancreas leading to the inability to
produce insulin and is generally diagnosed during
childhoodehence previously being referred to as juvenile diabetes.
Conversely, T2DM usually occurs later in life and is the result of
either insufficient insulin secretion by the b cells or insulin resis-
tance. Because T2DM is often diagnosed later in life, it was previ-
ously referred to as Adult Onset Diabetes. Once a very uncommon
diagnosis among children and adolescents, the incidence of T2DM
in this age group has been on the rise: between 2002 and 2015, the
rate of youth T2DM cases in the United States has risen 4.8% per
year compared to a 1.9% increase in T1DM [1]. The SEARCH for
* Corresponding author.
E-mail address: ronny.priefer@mcphs.edu (R. Priefer).
Diabetes in Youth Study has provided the bleak projection that
youth T2DM may climb to 84,000 cases in the United States by 2050
compared to 20,000 in 2010 [2].
The upward trend of pediatric T2DM cases (Fig. 1) has been
linked to a variety of factors. One of the largest appears to be the
childhood obesity crisis which has continued to worsen in recent
years [3]. It has been reported that children from minority families
may be at higher risk of developing T2DM, as diagnosis rates are
higher among American Indians, African Americans, Asians, and
Hispanics [4]. Socioeconomic status has been reported to play a role
in this early development of T2DM [5]. Genetics is a factor in
childhood T2DM, with a frequency of T2DM in a first or second-
degree relative ranging from 74% to 100% [6]. The lifetime risk of
developing T2DM is 40% in an offspring affected by one parent and
70% if affected by both parents (with shared environmental factors
confounding as well), unlike T1DM where only 5% have a first de-
gree relative with diabetes [7]. Other risk factors include female
gendereeven more so in females with premature adrenarche, an
infant born small for gestational age, or infants born with macro-
somia from a diabetic mother [8]. These risk factors demonstrate
T2DM's multifactorial etiology, which includes social, behavioral,
environmental, and genetic susceptibility [8].

https://doi.org/10.1016/j.dsx.2021.102253
1871-4021/© 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.
E. Buttermore, V. Campanella and R. Priefer
Fig. 1. Rates of new diagnosed cases of Type 1 and 2 diabetes among children and
teens. Taken from the Centers for Disease Control and Prevention. CDC.gov. 2020. [1].
2. Complications
Children diagnosed with T2DM are at higher risk for severe
complications later in life, including cardiovascular disease, ne-
phropathy, and mortality by middle age [9,10]. After adjustment for
risk factors over time, those with T2DM vs. T1DM have a significant
higher odds of diabetic kidney disease, retinopathy, and peripheral
neuropathy at a younger age. Despite the increased risk of com-
plications in T2DM, comorbidities such as hypertension and arterial
stiffness have been shown to be similar as in those with T1DM [11].
T2DM in children begins with insulin resistance and chronic
inflammation, eventually leading to the destruction of b cells. This
process has been shown to take place more rapidly in children than
in adults, increasing the risk of further complications [12]. Children
diagnosed with T2DM typically begin treatment immediately to
minimize the risk of complications. Pediatric T2DM has also been
linked to psychological issues such as depression and anxiety
[13,14].
Since early initiation of treatment is important, it is critical to
have screening of young adolescents in place to help facilitate the
diagnosis. T1DM usually has an acute or subacute presentation in
this age group, while T2DM is a disorder of insidious onset, and may
thus remain undetected for some time [15]. This delay of symp-
tomatology challenges pediatricians to make the appropriate
diagnosis in a timely manner, thereby increasing the risk for com-
plications later in life. In 2018, the American Diabetes Association
(ADA) recommended general screening for T2DM in asymptomatic
youth ages 10 and older (or after onset of puberty) who are over-
weight and have one or more risk factor [16]. These risk factors
include non-white race, family history of T2DM, maternal gesta-
tional diabetes, or signs of insulin resistance [16]. Unfortunately,
genetic screening alone has not been a useful addition for diagnosis
in adolescents compared to clinical risk factors which include
family history [17]. The ADA's diagnosis criteria for youth with
T2DM is the same as that for adults: fasting blood glucose levels of
126 mg/dL or greater, or random blood glucose levels of 200 mg/dL
or greater [2]. The ADA has also recommended using hemoglobin
A1c (HbA1c) levels to aid in T2DM diagnosis [2]. HbA1c levels of
6.5% or above indicate a T2DM diagnosis, while those with a HbA1c
reading between 5.7% and 6.4% are at an increased risk of devel-
oping T2DM [2].
To add to the complexity, treating T2DM in children and ado-
lescents has proven more difficult than within the adult population.
Lifestyle modifications, such as a healthier diet and regular exercise
are recommended to all patients, however several expert groups
have argued that these approaches to self-management are inef-
fective for youth with T2DM. The challenges behind this approach
are multifaceted. Patients, caregivers, and healthcare professionals
2
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 15 (2021) 102253
agree that there are significant barriers for lifestyle changes
including unsupportive relationships with family and friends, and
social determinants of health such as poverty, food insecurity, and
violence [18]. Aside from lifestyle modification the only approved
treatments for pediatric T2DM are metformin and insulin. How-
ever, studies have emerged to support the use of other medications
that may be more effective for childhood T2DM. A report produced
by the TODAY Study Group found that up to 51.7% of pediatric T2DM
patients fail metformin monotherapy, while those taking rosigli-
tazone as an add-on have improved outcomes [19]. Unfortunately,
there are risks to consider with various treatment options. There is
a critical need for more effective pediatric treatment options,
however studies in this age group are lacking. Herein is a review
focused on the most common causes, complications, and treat-
ments of T2DM among children and adolescents.
3. Etiology
T1DM occurs when an autoimmune process destroys b cells in
the pancreas, ceasing their ability to produce insulin. The devel-
opment of these b cell autoantibodies is assumed to start when an
individual with a genetic predisposition is exposed to a presumed
environmental factor that triggers a loss of immune regulation [20].
This process usually presents acutely or sub-acutely in children and
young adults due to the cessation of insulin production. On the
contrary, T2DM involves a period of insulin resistance leading to
the loss of b cell function and decreased insulin production. The
development of T2DM is multifactorial, and although the rise in
obesity has correlated with the rise in T2DM, there is higher
prevalence in certain races, females, and those with a strong family
history; thus supporting genetic predisposition as another major
role in pathogenesis [7]. This process takes time, explaining why
T2DM onset usually takes place later in life.
During hyperglycemia insulin is released by pancreatic b cells,
travels to peripheral tissues, and allows for the transport of glucose
into the cells for processing. In the case of insulin resistance the
cells do not properly respond to this hormone. Although insulin
resistance is complex and has multiple suggested mechanisms, a
prominent cause is the presence of excess lipids and fatty acids in
the bloodstream and skeletal muscle tissue [21]. This leads to the
blockage of transporters that bring glucose from the bloodstream
into the cells upon insulin activation [21]. For this reason obesity is
one of the most prominent risk factors for T2DM [21].
After the development of insulin resistance, the need for more
insulin production forces the pancreas to work harder than their
previous baseline. Initially, the b cells release larger amounts of
insulin to combat sustained hyperglycemic levels [22]. Over time,
the b cells begin to undergo stress changes resulting in impaired
function and decreased insulin release. Eventually, the b cells die or
dedifferentiate into immature cells without function leaving the
pancreas with a decreased amount of healthy b cells [22]. This leads
to T2DM with both insulin resistance and impaired insulin pro-
duction (Fig. 2).
Although the mechanism of developing T2DM among children
is similar to adults, among adolescents the progression is more
aggressive. It has been shown that insulin resistance in youth is
generally more severe than in adults with similar comorbidities
[23]. This may explain why children have less outcomes in insulin
sensitivity when treated with metformin and lifestyle changes [23].
Children with T2DM have been found to have higher levels of in-
sulin than adults yet show a greater decrease in insulin secretion
once the disease develops [24,25]. The TODAY trial provided evi-
dence that insulin secretion from the b cells decreased 20e35% per
year in children, compared to 7e11% in adults [25]. An exact
physiological cause for this difference has yet to be identified. The
E. Buttermore, V. Campanella and R. Priefer
Fig. 2. Progression of b cell function through prolonged insulin resistance. Taken from Ref. [22].
initial rise in insulin production may contribute to the more rapid
decline of b cell function. It has been proposed that puberty may
play a role in the more rapid b cell decline seen in children [12].
Puberty itself has been reported to cause insulin resistance and
therefore increased insulin release in healthy children. This con-
tributes to the initial higher than expected insulin levels when
compared to adults, leading to more rapid b cell decline, which
causes the impaired insulin release mechanism in children with
T2DM [12]. It is hypothesized that females are 1.5e3 times more
likely to develop T2DM as children/adolescents due to the impair-
ment of the increased compensatory insulin secretion during pu-
berty in those with T2DM, and the earlier onset of puberty in
females compared to males [7]. Once T2DM has developed, chil-
dren are at higher risk for the development of complications at an
earlier stage in life with faster progression of such conditions [24].
Children are also more likely to encounter treatment failure [24].
4. Treatments
As indicated above, nonpharmacological treatments for children
diagnosed with T2DM include adjustments in diet and increased
exercise. Guidance regarding nutrition and diet can be found in the
Academy of Nutrition and Dietetics’ Pediatric Weight Management
Evidence-based Nutrition Practice Guidelines [26]. For physical
activity, the American Academy of Pediatrics recommends moder-
ate to vigorous exercise for at least 1 h per day, while developing a
Family Media Use Plan to ensure time away from media to prioritize
adequate sleep, physical activity, and other health goals [26e28].
Children with T2DM have been found to live a sedentary lifestyle,
which may contribute to their health complications [26]. The
implementation of lifestyle modifications have shown positive ef-
fects on BMI, blood pressure, serum lipoproteins, and insulin
resistance [26]. Additionally, it is believed that promoting strategies
for positive mental health is critical for children with T2DM, as
lifestyle modifications can be challenging for young patients, and
mental health disorders are commonly seen in obesity [26].
Although there are benefits to these modifications, they are difficult
to maintain in children that are under social, economic, and
physical stress. This, combined with the more aggressive progres-
sion of T2DM in children renders these adjustments ineffective as
monotherapy to treat youth with T2DM [26].
The pharmacological treatment of youth T2DM patients focuses
on controlling insulin resistance, one of the major mechanisms of
T2DM [29]. Metformin is the drug of choice for youth T2DM pa-
tients, and is the only FDA approved treatment option beyond
lifestyle therapy and insulin itself [25,30]. Although metformin has
been deemed a safe and inexpensive option, it is not as effective on
children as it is with adults [25]. The TODAY trial found that met-
formin monotherapy at a dose of 1000 mg twice daily was only
effective in about half of participants for maintaining blood glucose
levels [19,25]. This high rate of treatment failure may be attributed
to the more aggressive etiology of the disease in children [25].
3
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 15 (2021) 102253
Insulin may be added to metformin therapy if the patient is not
meeting glycemic goals [25]. Insulin may also be used to quickly
stabilize elevated blood glucose levels during cases of ketosis,
ketoacidosis, or hyperglycemic hyperosmolar syndrome followed
by metformin therapy to maintain lowered levels [25]. Patients
should be monitored frequently and the treatment regimen should
be adjusted as needed [25].
The TODAY trial studied the advantages of adding the thiazoli-
dinedione (TZD) rosiglitazone to metformin therapy, at a dose of
4 mg twice daily [19,25]. It was found that the combination therapy
was more efficacious in maintaining glycemic levels and b cell
function than metformin alone, with a failure rate of 39% compared
to 52% with metformin monotherapy [25]. However, the use of
rosiglitazone is not recommended because TZDs can lead to serious
long-term adverse effects including weight gain, edema, and heart
failure [25]. The sulfonylurea, glimepiride was also tested by the
TODAY group as monotherapy. It had comparable efficacy to met-
formin, however it did show increased weight gain, so this is not
recommended at this time [25].
5. Conclusion
The incidence of T2DM in children and adolescence continues to
rise, and unfortunately due to its insidious onset is hard to diagnose
early. Screening at-risk patients has helped with establishing a
diagnosis, but to prevent complications that affect both patients’
morbidity and mortality requires more effective treatment mo-
dalities be available. Conducting clinical trials has shown to be
challenging among youth. Many studies have strict inclusion and
exclusion criteria, such as specific age ranges of children with
T2DM, patients that have not yet begun treatment, and patients
willing to participate for a prolonged period of time in order to
properly assess the long-term effects of the disease. [30,31].
Furthermore, children and adolescents tend to struggle with
adherence to the treatment regimen, whether it be pharmacologic
or lifestyle modifications [31,32]. This struggle is multifaceted
including unsupportive relationships and social determinants of
health as significant barriers for care. New treatment options for
T2DM are desperately needed because the currently approved
treatment optionselifestyle modifications, metformin, and
insulinedo not appear to provide long-term efficacy for treating
T2DM, a chronic condition [33].
Declaration of competing interest
The author is involved with Breath Health Inc. (GLUCAIR™)
however we made sure that there was no bias in the break-down of
the various non-invasive discussed. In fact, upon completion, it is
clear that much more was discussed regarding the other areas.
E. Buttermore, V. Campanella and R. Priefer
Acknowledgements
The authors wish to thank the School of Pharmacy at the Mas-
sachusetts College of Pharmacy and Health Sciences University for
financial support of this project.
References
[1] Centers for Disease Control and Prevention. Rates of new diagnosed cases of
type 1 and type 2 diabetes continue to rise among children, teens. CDC.gov;
2020.
[2] Van Name M, Santoro N. Type 2 diabetes mellitus in pediatrics: a new chal-
lenge. World Journal of Pediatrics 2013;9(4):293e9.
[3] Schwartz MS, Chadha A. Type 2 diabetes mellitus in childhood: obesity and
insulin resistance. J Am Osteopath Assoc 2008;108:518e24.
[4] Shaw J. Epidemiology of childhood type 2 diabetes and obesity. Pediatr Dia-
betes 2007;8(s9):7e15.
[5] Barrett JS, Bucci-Rechtweg C, Cheung SYA, Gamalo-Siebers M, Haertter S,
Karres J, Marquard J, Mulugeta Y, Ollivier C, Strougo A, Yanoff L, Yao L,
Zeitler P. Pediatric extrapolation in type 2 diabetes: future implications of a
workshop. Clin Pharmacol Therapeut 2020;108(1):29e39.
[6] American Diabetes Association. Type 2 diabetes in children and adolescents.
Pediatrics 2000;105(3):671e80.
[7] Gill-Carey O, Hattersley AT. Genetics and type 2 diabetes in youth. Pediatr
Diabetes 2007;8(s9):42e7.
[8] Temneanu OR, Trandafir LM, Purcarea MR. Type 2 diabetes mellitus in chil-
dren and adolescents: a relatively new clinical problem within pediatric
practice. Journal of Medicine and Life 2016;9(3):235e9.
[9] Solis-Herrera C, Triplitt CL, Lynch JL. Nephropathy in youth and young adults
with type 2 diabetes. Curr Diabetes Rep 2014;14(2):456.
[10] Rhodes ET, Prosser LA, Hoerger TJ, Lieu T, Ludwig DS, Laffel LM. Estimated
morbidity and mortality in adolescents and young adults diagnosed with type
2 diabetes mellitus. Diabet Med 2012;29(4):453e63.
[11] Dabelea D, Stafford JM, Mayer-Davis EJ, D'Agostino Jr R, Dolan L, Imperatore G,
Linder B, Lawrence JM, Marcovina SM, Mottl AK, Black MH, Pop-Busui R,
Saydah S, Hamman RF, Pihoker C. SEARCH for Diabetes in Youth Research
Group. Association of type 1 diabetes vs type 2 diabetes diagnosed during
childhood and adolescence with complications during teenage years and
young adulthood. J Am Med Assoc 2017;317(8):825e35.
[12] Todd JN, Srinivasan S, Pollin TI. Advances in the genetics of youth-onset type 2
diabetes. Curr Diabetes Rep 2019;18(8):57.
[13] Walders-Abramson N. Depression and quality of life in youth-onset type 2
diabetes mellitus. Curr Diabetes Rep 2014;14(1):449.
[14] Schiffrin A. Psychosocial issues in pediatric diabetes. Curr Diabetes Rep
2001;1(1):33e40.
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 15 (2021) 102253
[15] Hotu S, Carter B, Watson PD, Cutfield WS, Cundy T. Increasing prevalence of
type 2 diabetes in adolescents. J Paediatr Child Health 2004;40(4):201e4.
[16] Wallace AS, Wang D, Shin J-I, Selvin E. Screening and diagnosis of prediabetes
and diabetes in US children and adolescents. Pediatrics 2020;146(3).
[17] Vassy JL, DasMahapatra P, Meigs JB, Schork NJ, Magnussen CG, Chen W,
Raitakari OT, Pencina MJ, Jamal SM, Berenson GS, Goodman E. Genotype
prediction of adult type 2 diabetes from adolescence in a multiracial popu-
lation. Pediatrics 2012;130(5):e1235e42.
[18] Protudjer JLP, Dumontet J, McGavock JM. My voice: a grounded theory anal-
ysis of the lived experience of type 2 diabetes in adolescence. Can J Diabetes
2014;38(4):229e36.
[19] TODAY Study Group. A clinical trial to maintain glycemic control in youth
with type 2 diabetes. N Engl J Med 2012;366(24):2247e56.
[20] Norris JM, Johnson RK, Stene LC. Type 1 diabetes-early life origins and
changing epidemiology. Lancet Diabetes & Endocrinology 2020;8(3):226e38.
[21] Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med
2006;119(5A):10Se6S.
[22] Christensen AA, Gannon M. The beta cell in type 2 diabetes. Curr Diabetes Rep
2019;19(9):81.
[23] Tagi VM, Giannini C, Chiarelli F. Insulin resistance in children. Front Endo-
crinol 2019;10:342.
[24] Barrett T, Jalaludin MY, Turan S, Hafez M, Shehadeh N. Rapid progression of
type 2 diabetes and related complications in children and young peopleea
literature review. Pediatr Diabetes 2020;21(2):158e72.
[25] Narasimhan S, Weinstock RS. Youth-onset type 2 diabetes mellitus: lessons
learned from the TODAY study. Mayo Clin Proc 2014;89(6):806e16.
[26] McGavock J, Dart A, Wicklow B. Lifestyle therapy for the treatment of youth
with type 2 diabetes. Curr Diabetes Rep 2015;15:568.
[27] Council on Communications and Media. Media use in school-aged children
and adolescents. Pediatrics 2016;138(5):e20162592.
[28] American Academy of Pediatrics. Family media plan. healthychildren.org. 2021.
www.HealthyChildren.org/MediaUsePlan.
[29] Meehan C, Silverstein J. Treatment options for type 2 diabetes in youth remain
limited. J Pediatr 2016;170:20e7.
[30] Jalaludin MY, Barrientos-Pe rez M, Hafez M, Lynch J, Shehadeh N, Turan S,
Weghuber D. Recommendations for improving clinical trial design to facilitate
the study of youth-onset type 2 diabetes. Clin Trials 2020;17(1):87e98.
[31] Nadeau KJ, Anderson BJ, Berg EG, Chiang JL, Chou H, Copeland KC, Hannon TS,
Huang TT-K, Lynch JL, Powell J, Sellers E, Tamborlane WV, Zeitler P. Youth-
onset type 2 diabetes consensus report: current status, challenges, and pri-
orities. Diabetes Care 2016;39:1635e42.
[32] Pulgaron ER, Delamater AM. Obesity and type 2 diabetes in children: epide-
miology and treatment. Curr Diabetes Rep 2014;14(8):508.
[33] Barr MM, Aslibekyan S, Ashraf AP. Glycemic control and lipid outcomes in
children and adolescents with type 2 diabetes. PloS One 2019;14(7):
e0219144.