INTRODUCTION
Although all types of diabetes result in hyperglycemia, the pathophysiology of each
type of diabetes is different. These guidelines summarize available data specific
to the comprehensive care of youth with type 2 diabetes. The objective is to enrich
the recognition of type 2 diabetes in youth, its risk factors, its pathophysiology,
its management, and the prevention of associated complications.
PATHOPHYSIOLOGY
Glucose homeostasis is maintained by a balance between insulin secretion from the
pancreatic β-cells and sensitivity to insulin in skeletal muscle, adipose tissue,
and liver (1). When insulin sensitivity declines, insulin secretion must increase
to maintain glucose tolerance, and, in most youth, decreased insulin sensitivity due
to puberty and/or obesity is compensated by increased insulin secretion. However,
when β-cells cannot secrete sufficient insulin to compensate for insulin resistance,
abnormalities in glucose homeostasis ensue, potentially progressing to prediabetes
and type 2 diabetes as β-cell function deteriorates further (2–9). The relationship
between β-cell function and insulin sensitivity in adults and youth has been demonstrated
to be a hyperbolic function and can be described mathematically as the product of
insulin sensitivity and β-cell function, called the disposition index (DI) (1). The
DI essentially expresses the amount of insulin being secreted relative to the degree
of insulin resistance and is a constant for a given degree of glucose tolerance in
any one individual.
Overweight and obesity are major acquired contributors to the development of insulin
resistance, particularly in the face of the physiologic insulin resistance characteristic
of puberty. Robust pancreatic β-cell compensatory insulin secretion maintains normal
glucose homeostasis. However, in adolescents with obesity who develop type 2 diabetes,
there is severe peripheral and hepatic insulin resistance, with ∼50% lower peripheral
insulin sensitivity than peers with obesity without diabetes, along with increased
fasting hepatic glucose production and inadequate first- and second-phase insulin
secretion, resulting in ∼85% lower DI (2). Additional abnormalities in youth with
type 2 diabetes include impaired glucose sensitivity of insulin secretion, lower serum
adiponectin concentrations, and reduced incretin effect (3,9–13). While upregulation
of α-cell function with hyperglucagonemia has been implicated in the pathophysiology
of type 2 diabetes in adults (14,15), there are limited data in youth with type 2
diabetes, with studies showing either hyperglucagonemia or no difference from control
subjects without diabetes (3,11,16,17).
Cross-sectional and longitudinal studies in youth with obesity along the spectrum
of glycemia from normoglycemia to prediabetes to type 2 diabetes show, as in adults,
that β-cell failure with declining insulin secretion relative to insulin sensitivity
results in prediabetes and type 2 diabetes in high-risk youth (5–9,18–21). Importantly,
however, prior to reaching the American Diabetes Association (ADA)-defined fasting
and oral glucose tolerance test (OGTT)-stimulated glycemic cut points for the diagnosis
of prediabetes, youth, like adults, already demonstrate declining β-cell function
relative to insulin sensitivity (6–8). Also, youth with A1C in the at-risk/prediabetes
category (≥5.7 to <6.5%) demonstrate impaired β-cell function compared with those
with A1C <5.7% (22). A combination of obesity, genetics, the hormonal milieu, incretins
and/or their effect, and metabolic alterations, such as glucotoxicity and/or lipotoxicity,
are likely to contribute to deteriorating β-cell function against the backdrop of
insulin resistance, eventually culminating in prediabetes and type 2 diabetes in at-risk
youth. Based on the baseline data from the Restoring Insulin Secretion (RISE) study
(23,24), there appear to be important differences in insulin sensitivity and β-cell
function between youth and adults with similar degrees of dysglycemia, including greater
insulin resistance for any degree of adiposity and greater insulin secretion for any
degree of insulin resistance in youth compared with adults.
RISK, SCREENING, AND DIAGNOSIS
Risk Factors
Nonmodifiable risk factors for youth-onset type 2 diabetes include genetics/epigenetics,
manifested as a strong family history of type 2 diabetes in first- or second-degree
relatives; being the offspring of a pregnancy complicated by gestational diabetes
mellitus (GDM); minority race/ethnicity; and physiologic insulin resistance of puberty.
Metabolic evidence of genetic susceptibility can be detected in the first decade of
life, manifested as impaired insulin sensitivity and reduced insulin secretion in
otherwise healthy youth with a family history of type 2 diabetes (25). This genetic
susceptibility, when combined with environmental factors conducive to obesity and
a sedentary lifestyle, may ultimately translate to type 2 diabetes. Indeed, in a study
of youth with obesity, a genetic risk score for β-cell dysfunction from five single
nucleotide polymorphisms was associated with a higher chance of prediabetes and type
2 diabetes (26). Dozens of specific genetic variants linked to type 2 diabetes have
been identified in adults (27,28), but these only account for about 10% of its heritability
(29,30). Particular genetic variants that predispose to diabetes in youth have been
identified in Oji-Cree Native Canadians (31) and African American youth (32), but
information in other populations is only now emerging.
Evidence from both animal and human studies suggests that maternal obesity and GDM
contribute to obesity and type 2 diabetes in youth (33,34). In the Treatment Options
for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, one-third were born after
a pregnancy complicated by preexisting diabetes or GDM (35). In the SEARCH for Diabetes
in Youth (SEARCH) study, a population-based study of the epidemiology of type 1 and
type 2 diabetes in youth in the U.S., exposure to maternal GDM or pregestational diabetes
and maternal obesity were independently associated with type 2 diabetes in adolescents,
with intrauterine exposure to these two risk factors present in 47.2% of type 2 diabetes
in the cohort (36). Age of onset of type 2 diabetes was also younger in those exposed
to diabetes during gestation.
Incidence and prevalence of type 2 diabetes are highest among youth from a minority
race/ethnicity (37), likely as a consequence of many factors, including genetics,
metabolic characteristics, cultural/environmental influences, and quality of and access
to health care. Several studies have demonstrated significant differences by race/ethnicity
in insulin sensitivity and secretion that might heighten the risk of type 2 diabetes
(38–42).
Type 2 diabetes typically occurs in adolescents at midpuberty (for example, the mean
age of diagnosis was 14 years in the TODAY study) (43), most likely precipitated by
the physiologic, but transient, pubertal insulin resistance aggravating the preexisting
metabolic challenges of obesity. Cross-sectional and longitudinal studies show that
insulin sensitivity declines by 25–30% as youth transition from prepuberty to puberty
(44–46). In the presence of normally functioning β-cells, puberty-related insulin
resistance is compensated by increased insulin secretion/hyperinsulinemia, such that
DI remains normal. In youth who are predisposed to develop prediabetes and/or type
2 diabetes, β-cell compensation is inadequate with progressive decline in the DI,
ultimately resulting in dysglycemia (46,47).
In youth-onset type 2 diabetes, the major modifiable risk factors are obesity and
lifestyle habits of excess nutritional intake, low physical activity, and increased
sedentary behaviors with decreased energy expenditure, resulting in the surplus of
energy being stored as body fat. Other potentially modifiable risk factors for type
2 diabetes in adolescents and young adults include chronic stress and/or depressed
mood (48,49) and sleep-related disorders (50–52).
Risk Assessment and Diagnostic Criteria
Recommendations
Risk-based screening for prediabetes and/or type 2 diabetes should be considered after
the onset of puberty or after 10 years of age, whichever occurs earlier, in children
and adolescents who are overweight (BMI ≥85th percentile) or obese (BMI ≥95th percentile)
and who have one or more additional risk factors for diabetes (see Table 1 for evidence
grading).
If tests are normal, repeat testing at a minimum of 3-year intervals E, or more frequently
if BMI is increasing. C
Fasting plasma glucose, 2-h plasma glucose after 75-g OGTT, or A1C can be used to
test for prediabetes or diabetes. B
Table 1
Risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and
adolescents* in a clinical setting
Criteria
Testing should be considered in youth* who are overweight (≥85%) or obese (≥95%) A
and who have one or more additional risk factors based on the strength of their association
with diabetes:
• Maternal history of diabetes or GDM during the child's gestation A
• Family history of type 2 diabetes in first- or second-degree relative A
• Race/ethnicity (Native American, African American, Latino, Asian American, Pacific
Islander) A
• Signs of insulin resistance or conditions associated with insulin resistance (acanthosis
nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age
birth weight) B
*
After the onset of puberty or after 10 years of age, whichever occurs earlier.
Risk-based screening for prediabetes and/or type 2 diabetes is timed after the onset
of puberty or after 10 years of age, whichever occurs earlier, because the majority
of youth-onset type 2 diabetes occurs during puberty, as stated above, and rarely
in prepubertal children. However, some youth with obesity may have earlier onset of
puberty than usual, necessitating screening before 10 years of age. In addition, in
North America almost all youth with type 2 diabetes are overweight/obese, hence the
recommendation to screen youth with overweight/obesity. In other parts of the world
where youth with type 2 diabetes are not necessarily overweight and/or obese, clinical
judgment should guide whom to screen. Although there is no robust evidence-based rationale
for the proposed frequency of testing, increasing BMI has been shown to be a predictor
of deteriorating glycemia and progression to type 2 diabetes (21). Therefore, clinicians
caring for youth with overweight/obesity with continued increase in their BMI should
be aware of the need for more frequent screening.
The laboratory glycemia-based diagnostic criteria for diabetes and prediabetes are
the same for youth and adults, regardless of type of diabetes (Table 2) (53). However,
these criteria are extrapolated from adults, and the epidemiological studies that
formed the basis for both glucose and A1C definitions of diabetes did not include
pediatric populations. Therefore, the exact relevance of these definitions for pediatric
populations remains unclear until more data become available.
Table 2
Criteria for the diagnosis of prediabetes and diabetes
Prediabetes
A1C 5.7% to <6.5% (39 to <48 mmol/mol). The test should be performed in a laboratory
using a method that is NGSP certified and standardized to the DCCT assay.
IFG: fasting glucose ≥100 but <126 mg/dL (≥5.6 but <7.0 mmol/L).
IGT: 2-h plasma glucose ≥140 but <200 mg/dL (≥7.8 but <11.1 mmol/L) during an OGTT.
The test should be performed as described by the World Health Organization, using
a glucose load containing the equivalent of 1.75 mg/kg (max 75 g) anhydrous glucose
dissolved in water.*
Diabetes
A1C ≥6.5% (≥48 mmol/mol). The test should be performed in a laboratory using a method
that is NGSP certified and standardized to the DCCT assay.*
OR
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least
8 h.*
OR
2-h plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed
as described by the World Health Organization, using a glucose load containing the
equivalent of 1.75 mg/kg (max 75 g) anhydrous glucose dissolved in water*
OR
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random
plasma glucose >200 mg/dL (11.1 mmol/L).
FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose
tolerance; max, maximum.
*
In the absence of unequivocal hyperglycemia, result should be confirmed by repeat
testing.
The A1C test is universally available and can be performed any time of the day without
need for fasting. However, several studies have questioned its validity in the pediatric
population because of poor sensitivity for identifying children with dysglycemia and
underestimation of the prevalence of prediabetes and diabetes (54–56). Fasting and
OGTT criteria have not been validated in youth, either. Studies using continuous glucose
monitoring (CGM) in youth with obesity demonstrated that A1C and OGTT are equally
effective at identifying glycemic abnormalities on CGM, but the glycemic patterns
differ (57); abnormal A1C was associated with higher overall and nighttime average
glucose on CGM, while abnormal OGTT was associated with more time spent above the
normal glucose range during the day. Institution of A1C screening in a large primary
care network increased provider adherence to screening recommendations compared with
OGTT screening while identifying the same prevalence of type 2 diabetes (58). Furthermore,
in this cohort, the progression to clinically confirmed diabetes was substantially
more likely for those with A1C >6% (18.4%) than for those with levels 5.7–6.0% (1.3%).
Therefore, screening with fasting glucose, OGTT, or A1C is an acceptable approach
but should be based on sound clinical judgment, recognition of the strengths and weaknesses
of each test, and the facilities and resources available.
Confirming Diabetes Type
Recommendations
Children and adolescents with overweight/obesity in whom the diagnosis of type 2 diabetes
is being considered should have a panel of pancreatic autoantibodies tested to exclude
the possibility of autoimmune type 1 diabetes. B
Genetic evaluation to exclude monogenic diabetes should also be based on clinical
characteristics and presentation. B
As stated above, youth with type 2 diabetes in the U.S. are characteristically overweight
and/or obese, in mid- to late puberty, with overrepresentation of minority ethnic/racial
groups and females (4,43,59). The clinical presentation varies widely from asymptomatic
or minimally symptomatic, diagnosed incidentally during routine laboratory testing,
to a severe presentation with symptomatic hyperglycemia, weight loss, metabolic decompensation,
diabetic ketoacidosis (DKA), or hyperglycemic hyperosmolar nonketotic (HHNK) syndrome
(4).
Obesity is a consistent feature of youth-onset type 2 diabetes in the U.S. However,
because of the escalating rates of obesity in the general population, children with
both type 1 diabetes and monogenic diabetes are also more likely to be overweight/obese
than in the past (60), making the clinical distinction between type 2 diabetes and
obese type 1 or monogenic diabetes difficult. This was illustrated in the TODAY study
in which, of the 1,206 youth clinically diagnosed with type 2 diabetes and screened
for circulating GAD65 and IA2 antibodies, 118 (9.8%) were antibody positive (Ab+)
(61). Even though these Ab+ individuals had clinical characteristics that overlapped
with the antibody-negative (Ab−) youth, they were less likely to be obese, have features
of metabolic syndrome, have a family history of diabetes, be female, or be from a
minority race/ethnicity, indicating a phenotype more similar to their peers with type
1 diabetes. Pathophysiologically, Ab− youth with obesity are more insulin resistant
than Ab+ youth with obesity, while Ab+ youth have more severe insulin deficiency (61–64).
Fasting and stimulated C-peptide are significantly lower in Ab+ youth with obesity
and diabetes, though with appreciable overlap (63). Moreover, Ab− youth are more likely
to exhibit features of the metabolic syndrome (elevated systolic blood pressure and
ALT), while Ab+ youth have significantly more frequent ketonuria at initial presentation
(61,64). The reported rates of positive pancreatic autoantibodies in youth clinically
diagnosed with type 2 diabetes vary from 10% to 75% (4,62), likely depending on the
ratio of type 1 and type 2 diabetes in the population. The clinical distinction between
youth with type 2 diabetes and youth with obesity and type 1 or monogenic diabetes
is further blurred because youth with type 2 diabetes often present with some degree
of ketosis, including DKA (65).
The distinction between these forms of diabetes in youth with obesity has important
implications for treatment (66), since Ab+ youth present more like individuals with
type 1 diabetes, progressing to insulin requirement more rapidly (61), and are at
risk for other autoimmune disorders. Therefore, measurement of pancreatic autoantibodies
is recommended in all youth with clinical characteristics of type 2 diabetes. This
testing should include GAD65 and IA2 antibodies, along with insulin autoantibody in
individuals who have not yet been exposed to exogenous insulin. The benefit of measurement
of ZnT8 antibody in individuals with phenotypic type 2 diabetes is not yet clear.
We further recommend that antibodies be measured in a laboratory aligned with the
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Pancreatic
Autoantibody Standardization Program because currently available commercial assays
may not be sufficiently sensitive or specific. However, in all cases, clinical judgment
and the presence of other risk factors for type 1 diabetes or type 2 diabetes should
be considered in making the diagnosis, and the health care team should remain open
to reconsidering the initial diagnosis. Since 4.5–8.0% of youth with clinical features
suggestive of type 2 diabetes have been found to have monogenic diabetes, genetic
testing for monogenic forms of diabetes should be considered as well (67–69).
GLYCEMIC TARGETS
Recommendations
A1C should be measured every 3 months. E
A reasonable A1C goal for most children and adolescents with type 2 diabetes treated
with oral agents alone is <7%. More stringent A1C goals (such as <6.5%) may be appropriate
for selected individual patients if they can be achieved without significant hypoglycemia
or other adverse effects of treatment. Appropriate patients might include those with
short duration of diabetes and lesser degrees of β-cell dysfunction and patients treated
with lifestyle or metformin only who achieve significant weight improvement. E
A1C targets for youth on insulin should be individualized, taking into account the
relatively low rate of hypoglycemia in youth-onset type 2 diabetes. E
Home self-monitoring of blood glucose (SMBG) regimens should be individualized, taking
into consideration the pharmacologic treatment of the patient. E
Previous target A1C guidelines by the ADA and the International Society for Pediatric
and Adolescent Diabetes for youth with type 2 diabetes ranged from <6.5% to <7.0%
(70,71) and <7.5% (72), mostly based on expert opinion and extrapolated from youth
with type 1 diabetes and adults with type 2 diabetes. However, accumulating evidence
provides support for more appropriate goals. The TODAY study showed that hypoglycemia
is rare in adolescents with type 2 diabetes, even with insulin therapy (73), suggesting
that more stringent A1C targets are acceptable. Also in TODAY, individuals with an
A1C of >6.3% after 3 months of metformin or an increasing A1C, even in the nondiabetes
range (74), had a substantially increased risk for loss of glycemic control, likely
reflecting a greater degree of β-cell dysfunction (75,76). Furthermore, individuals
with youth-onset type 2 diabetes have high rates of complications (77–79), many of
which are associated with poor glycemic control, and rapid deterioration with increasing
A1C. Finally, youth with type 2 diabetes can be expected to have long disease duration
and, therefore, continued risk for accumulation of glycemia-related complications.
Taken together, this evidence suggests that a more stringent A1C target can and should
be attained in youth with type 2 diabetes.
The evidence is insufficient regarding the value of SMBG and how often testing should
be performed by youth with type 2 diabetes not on insulin therapy. Until such data
become available, the frequency of SMBG should be individualized, taking into account
patient and family burden, the value of the information obtained and how it will be
used to adjust therapy, and the associated hypoglycemia risk.
LIFESTYLE MANAGEMENT
Diabetes Education and Self-Management Skills
Recommendation
All youth with type 2 diabetes and their families should receive comprehensive diabetes
self-management education/support that is specific to youth with type 2 diabetes and
is culturally competent. B
It has been well established that diabetes education is necessary, but not sufficient,
to enhance self-management in people with diabetes (80,81). The majority of these
studies, however, focused on adults with type 2 diabetes and/or youth with type 1
diabetes. Since the population of youth with type 2 diabetes is more likely to be
of minority ethnic/racial background than those with type 1 diabetes, and materials
developed for adults may not address issues of development in youth, culturally appropriate
programs specific to youth with type 2 diabetes and their families are necessary.
Unfortunately, there are no randomized clinical trials of education and support programs
for youth with type 2 diabetes. Nonetheless, descriptive reports suggest that programs
that focus on building knowledge and skills appropriate to this population are important
in ensuring adequate self-management.
In the TODAY trial (81), the diabetes education program included content about type
2 diabetes physiology and treatment, building skills of healthy eating habits, carbohydrate
counting, portion sizes, reading food labels, glucose monitoring, and ketone testing,
as well as problem solving, risk reduction, and living with diabetes. Full mastery
of the program was achieved in an average of 5.5 90-min sessions. Factors associated
with shorter time to mastery included more recent diagnosis and not having to use
a translator, while sex, primary language of the youth and family, individual versus
group sessions, or site of delivery were not. These program materials are available
from the ADA as “Be Healthy Today” (82). Given the lack of clinical trials of various
educational approaches, it is unclear that this program is superior to other approaches.
Nonetheless, the program provides effective, engaging materials for youth with type
2 diabetes that were designed specifically for this population. Until comparative
trials of various approaches are completed, diabetes education using these materials
is appropriate (83).
Psychosocial Factors
Recommendations
Providers should assess social context, including potential food insecurity, housing
stability, and financial barriers, and apply that information to treatment decisions.
E
Use patient-appropriate standardized and validated tools to assess diabetes distress
and mental/behavioral health in youth with type 2 diabetes, with attention to symptoms
of depression and disordered eating behaviors, and refer to specialty care when indicated.
B
When choosing glucose-lowering or other medications for youth with overweight/obesity
and type 2 diabetes, consider medication adherence and treatment effects on weight.
E
Starting at puberty, preconception counseling should be incorporated into routine
diabetes clinic visits for all females of childbearing potential. A
Patients should be screened for smoking and alcohol use at diagnosis and regularly
thereafter. C
The ADA position statement on the provision of psychosocial care for people living
with diabetes recognizes the profound influence of psychosocial factors on health
outcomes and well-being (84). The recommendations herein are consistent with those
outlined in that position statement, an important resource for more detailed information
about life-course issues and assessment of psychosocial comorbidities.
Most youth with type 2 diabetes come from racial and ethnic minority groups, have
low socioeconomic status, and have a family history of diabetes (37,85,86). Families
often experience multiple stressors including food insecurity, employment and housing
instability, and difficulties with access to treatment; youth also may have been exposed
to early adversity, which has been shown to affect health over time (87). Providers
should personalize approaches to diabetes management to minimize barriers to care,
enhance adherence, and maximize response to treatment by taking into consideration
the sociocultural context of the patient and their family.
Youth with type 1 diabetes have high rates of diabetes distress and psychiatric symptoms
and diagnoses (in particular, depression and disordered eating behaviors) necessitating
ongoing surveillance of mental and behavioral health. Evidence about psychiatric disorders
and symptoms in youth with type 2 diabetes is limited (88–92), but given the sociocultural
context and the medical burden, as well as preexisting obesity-associated comorbidities
together with type 2 diabetes, ongoing surveillance of mental health/behavioral health
is also indicated in youth with type 2 diabetes.
Symptoms of depression and disordered eating are common in youth with type 2 diabetes
and associated with poorer glycemic control (89). The prevalence of clinically significant
symptoms of depression among youth with type 2 diabetes was reported to be 8.6% in
the SEARCH cohort of youth with type 1 and type 2 diabetes (89) and 14.8% in the TODAY
cohort of youth with type 2 diabetes (93). In addition, more than 25% of females and
males in the SEARCH cohort of youth with type 2 diabetes reported symptoms of disordered
eating behaviors, such as skipping insulin, vomiting, and using diet pills or laxatives,
and these behaviors were associated with poorer glycemic control in females (89).
Binge eating rates in the TODAY cohort were high (26%) and were associated with more
severe obesity, psychological symptoms of disordered eating, and symptoms of depression
(94).
More research is needed to evaluate rates of diagnosable psychiatric disorders, trauma,
victimization, and psychotropic drug use in youth with type 2 diabetes. It also is
important to elucidate the relationships among obesity, psychiatric disorders, and
medication regimens because many of the drugs prescribed for diabetes and psychiatric
disorders are associated with weight gain and increased concerns about eating, shape,
and weight (95,96).
Finally, in accord with the ADA’s Standards of Medical Care in Diabetes—2018 (97),
preconception counseling should be provided starting at puberty for all girls of childbearing
potential in order to increase understanding of risk related to diabetes and improve
health prior to conception. In the TODAY study (98), despite counseling on pregnancy
reduction designed specifically for youth with type 2 diabetes, 10.2% of the females
in the cohort became pregnant over an average of 3.8 years of study participation.
Of note, 26.4% of pregnancies ended in a miscarriage, stillbirth, or intrauterine
death, and 20.5% of the live-born infants had a major congenital anomaly. These data
confirm the importance of educating young women with type 2 diabetes to time their
pregnancies to reduce risks to themselves and their offspring. More research regarding
pregnancy outcomes in youth with type 2 diabetes is needed.
Lifestyle Modification, Weight Management, Exercise, and Nutrition
Recommendations
Youth with overweight/obesity and type 2 diabetes and their families should be provided
with developmentally and culturally appropriate comprehensive lifestyle programs that
are integrated with diabetes management aiming to achieve 7–10% decrease in excess
weight. C
Given the necessity of long-term weight control and lifestyle management for children
and adolescents with type 2 diabetes, lifestyle intervention should be based on a
chronic care model and offered in the context of diabetes care. E
Youth with diabetes, like all children, should be encouraged to participate in at
least 30–60 min of moderate to vigorous physical activity at least 5 days per week
(and strength training on at least 3 days per week) B and should be encouraged to
decrease sedentary behavior. C
Nutrition for youth with type 2 diabetes, like all children, should focus on healthy
eating patterns that emphasize consumption of nutrient-dense, high-quality foods and
decrease consumption of calorie-dense, nutrient-poor foods, particularly sugar-added
beverages. B
The utility of pharmacotherapy for weight reduction in youth with type 2 diabetes
remains limited in the absence of approved, effective, and safe medications and the
lack of clinical trials in youth with type 2 diabetes. B
Lifestyle modification programs that incorporate evidence-informed behavioral strategies
to promote changes in diet and physical activity (99) are a cornerstone of treatment
for adults with type 2 diabetes because the resulting reductions of 5–7% of initial
body weight are associated with improvements in blood glucose levels and other risk
parameters. Much less is known about the impact of lifestyle interventions in youth
with type 2 diabetes, although 90% are overweight or obese. Family-based behavioral
weight management programs in school-aged children without diabetes have a modest,
but positive, impact on weight and cardiometabolic risk factors but are less effective
in adolescents and children with more severe obesity (100–102). Intensive weight management,
when compared with usual treatment, can have sustained benefits over a 2-year period
for ethnically and racially diverse inner-city children and adolescents with an average
BMI >35 (102,103). Although BMI changes in treated youth were modest (103), those
who received usual care showed increases in BMI over the period of observation, while
the intervention group had continued improvements in body composition and insulin
resistance relative to those who did not receive weight management.
The most pertinent evidence regarding the impact of lifestyle interventions for youth
with type 2 diabetes comes from the TODAY study (104), where the goal was to achieve
7–10% decrease in percent overweight. The addition of lifestyle intervention to metformin
monotherapy was not associated with durable metabolic control beyond that of metformin
alone. Youth receiving metformin plus lifestyle intervention showed short-term, but
not sustained, weight loss and improvements in body composition relative to those
in the two other intervention groups (105). While 31% of youth who received lifestyle
intervention achieved the preplanned goal of a decrease of ≥7% in percent overweight
through 24 months of intervention, this result did not differ significantly from that
obtained with metformin monotherapy and no predictors of successful weight loss were
identified. However, irrespective of treatment assignment, sustained weight losses
≥7% of excess body weight were associated with improvements in A1C, HDL, and C-peptide
(105), indicating that obesity management remains a crucial goal.
Components of a comprehensive pediatric lifestyle intervention are well established
(106,107), including those for youth with severe obesity (108). These include the
involvement of family at a developmentally appropriate level and evidence-based behavioral
strategies to facilitate enduring changes in nutrition and physical activity. Guidelines
for physical activity and nutrition are based on those recommended by the American
Academy of Pediatrics (2007) (107) and the Endocrine Society (2017) (106). Youth with
type 2 diabetes frequently have severe obesity, and it is particularly important that
behavior change goals for diet and activity incorporate stepwise, achievable targets
developed in conjunction with the youth and family members, as appropriate.
Youth with type 2 diabetes will face increasing severity of obesity and diabetes complications
as they age (109–111). An important first step is to integrate diabetes care and education,
such as the approach used in the TODAY trial, with ongoing lifestyle intervention
for obesity management (106) to maximize the impact of medical and lifestyle interventions
over time. Comprehensive chronic care models have been recommended for youth with
obesity and chronic illness (112,113).
With the exception of orlistat, weight loss medications are not approved for use in
youth. The Endocrine Society guidelines for pediatric obesity (106) review the limited
evidence for effectiveness of current weight-loss medications and recommends that
their use be restricted to the research setting. More research into possible pharmacologic
approaches to augment lifestyle interventions and their role in type 2 diabetes in
youth is urgently needed.
Pharmacologic Approaches to Glycemic Management
Recommendations
Initiate pharmacologic therapy, in addition to lifestyle therapy, at diagnosis of
type 2 diabetes. A
In incidentally diagnosed or metabolically stable patients (A1C <8.5% and asymptomatic),
metformin is the initial pharmacologic treatment of choice if renal function is normal.
A
Youth with marked hyperglycemia (blood glucose ≥250 mg/dL, A1C ≥8.5%) without acidosis
at diagnosis who are symptomatic with polyuria, polydipsia, nocturia, and/or weight
loss should be treated initially with basal insulin while metformin is initiated and
titrated. B
In patients with ketosis/ketoacidosis, treatment with subcutaneous or intravenous
insulin should be initiated to rapidly correct the hyperglycemia and the metabolic
derangement. Once acidosis is resolved, metformin should be initiated while subcutaneous
insulin therapy is continued. A
In individuals presenting with severe hyperglycemia (blood glucose ≥600 mg/dL), assess
for HHNK syndrome. A
In patients initially treated with insulin and metformin who are meeting glucose targets
based on home blood glucose monitoring, insulin can be tapered over 2–6 weeks by decreasing
the insulin dose 10–30% every few days. B
If the glycemic target is no longer met using metformin alone, or if contraindications
or intolerable side effects of metformin develop, basal insulin therapy should be
initiated. B
If the combination of metformin plus basal insulin is ineffective at achieving or
maintaining glycemic targets, more intensive approaches to insulin therapy may be
initiated. E
The use of nonapproved medications in youth with type 2 diabetes is not recommended
outside of research trials. B
In the clinical setting, only a minority of youth with type 2 diabetes are on lifestyle
management alone (114,115) because it is often inadequate for achieving and maintaining
the desired level of glycemic control and BMI improvement, with the percentage of
patients remaining on lifestyle intervention alone declining further by 1 year (115).
Therefore, in most cases, the addition of pharmacologic intervention early in the
disease is warranted. As in adults, the pharmacologic intervention should be a stepped
process. However, since only metformin and insulin are currently approved for the
treatment of diabetes in patients under 18 years old, the approach in youth is more
limited.
Initial Treatment
Initial treatment of youth-onset type 2 diabetes should include metformin and/or insulin
alone or in combination, based on the metabolic status of the patient. Initial treatment
of the youth with obesity and diabetes must take into account that diabetes type is
often uncertain in the first few weeks of treatment owing to overlap in presentation
and that a substantial percentage of youth with type 2 diabetes will present with
clinically significant ketoacidosis (65). Therefore, immediate therapy should address
the hyperglycemia and associated metabolic derangements irrespective of ultimate diabetes
type, with adjustment of therapy once metabolic compensation has been established
and subsequent information, such as antibody results, becomes available.
Figure 1 provides an approach to initial treatment.
Figure 1
Management of new-onset diabetes in overweight youth suspected to have type 2 diabetes
based on risk factors listed in Table 1. MDI, multiple daily injections.
Metformin
Metformin is the preferred drug for initial treatment of type 2 diabetes in adults
and youth. In the TODAY study, 48.3% of youth with type 2 diabetes who were enrolled,
with less than 2 years (median 8 months) of diabetes duration, maintained adequate
glycemic control (A1C <8.0%) on metformin alone for up to 6 years (104). However,
youth were more likely than adults to require additional pharmacologic treatment to
meet glycemic targets, with the other 51.7% of youth on metformin requiring insulin
by 4 years, with a median time to treatment failure of 11.8 months.
Asymptomatic youth with presumptive type 2 diabetes who present in a stable metabolic
state and have A1C <8.5% should be started on metformin as initial therapy if renal
function is normal. Asymptomatic patients with A1C ≥8.5% may also be given an initial
trial of metformin monotherapy at the discretion of the health care provider, especially
if the patient and family situation suggest the promise of excellent adherence to
lifestyle change recommendations.
The recommended approach to metformin initiation is to start with a dose of 500–1,000
mg/day and gradually escalate it every 1–2 weeks, depending on patient tolerability,
to the recommended therapeutic dose of 1,000 mg b.i.d. Slower dosage escalation may
be needed if gastrointestinal side effects occur and, in some cases, the maximum dose
may not be achievable. Extended-release metformin may have fewer gastrointestinal
side effects and be more convenient for the patient, but there are no studies in youth
comparing extended-release metformin to the standard metformin preparation.
Metformin Plus Insulin
Youth with marked hyperglycemia (blood glucose ≥250 mg/dL and/or A1C ≥8.5%) without
acidosis at diagnosis but who are symptomatic with polyuria, polydipsia, nocturia,
and/or weight loss should be treated initially with basal insulin while concurrently
initiating and titrating metformin. In patients with ketosis/ketoacidosis at diagnosis,
treatment with subcutaneous or intravenous insulin should be initiated to rapidly
correct the hyperglycemia and the metabolic derangement. Once acidosis is resolved,
metformin should be initiated while subcutaneous insulin therapy is continued (116).
In individuals presenting with severe hyperglycemia (blood glucose ≥600 mg/dL), assess
for HHNK syndrome.
Once glycemic stability is achieved, insulin may not be needed. Limited data suggest
that adolescents with type 2 diabetes who present initially with DKA, ketosis, or
symptomatic hyperglycemia can be managed successfully with metformin alone, at least
initially after a short course of insulin therapy to establish glycemic stability
(117). For example, in the TODAY study, more than 90% of the subjects screened for
study participation were initially controlled adequately on metformin alone regardless
of prior insulin therapy (117). However, these TODAY participants were frequently
contacted and closely monitored by the research staff, a situation that may not be
feasible in a clinical setting. Whether or not early treatment with insulin provides
unique benefits in youth with type 2 diabetes remains questionable. The recently completed
RISE Pediatric Medication Study in youth with obesity with impaired glucose tolerance
or recent-onset type 2 diabetes did not demonstrate benefits of 3 months of basal
insulin glargine followed by 9 months of metformin compared with metformin alone for
12 months in preserving or restoring β-cell function (118). It remains to be determined
if longer periods of insulin treatment may prove beneficial in preserving β-cell function.
Ongoing Therapy
When the individualized glycemic target can no longer be met with metformin alone,
or if metformin intolerance or renal insufficiency develops, insulin therapy should
be initiated. This can be done alone or in combination with metformin, unless metformin
is contraindicated. Because studies indicate that adherence with insulin therapy is
a challenge in youth with type 2 diabetes (73,119), starting with a single daily dose
of a long-acting insulin analog (glargine [Lantus, Basalglar, Toujeo], detemir [Levemir],
or degludec [Tresiba]) may be preferred. Premixed insulins may be appropriate in some
circumstances.
If the combination of metformin at the maximum tolerated dose (up to 1,000 mg b.i.d.)
plus basal insulin at a maximum dose of 1.5 units/kg/day is ineffective at achieving
the glycemic target, medication adherence should be actively addressed. When combined
metformin and basal insulin therapy does not achieve targets, and in the absence of
other approved drugs to treat diabetes in youth (<18 years old), higher doses of long-acting
insulin or initiation of multiple daily injections of basal and premeal rapid-acting
insulin should be considered, though adherence to the latter may be a barrier.
Because severe insulin resistance is characteristic of youth with type 2 diabetes,
basal insulin doses above 1.5 units/kg/day may be required to achieve adequate glycemic
control, particularly for those youth with elevated A1C and glucotoxicity and youth
who are in mid- to late puberty. In these circumstances, it may be appropriate to
use more concentrated insulin preparations (U-300 glargine [Toujeo], U-200 Tresiba,
U-200 Humalog, U-500 regular) to avoid large-volume injections that may further diminish
medication adherence.
The most significant adverse effect of insulin therapy in type 2 diabetes, as in type
1 diabetes, is hypoglycemia. Although the incidence of hypoglycemia in youth with
type 2 diabetes is low, even with insulin therapy (73), patients treated with insulin
should be educated about avoidance, recognition, and treatment of hypoglycemia and
should be instructed on the use of glucagon for treatment of severe hypoglycemia.
Also, since insulin may result in weight gain, involvement of a nutritionist in patient
care and education is essential when insulin is initiated.
Other Therapies
Other than insulin and metformin, there are currently more than 25 medications in
10 general classes that are commercially available and FDA-approved for treatment
of type 2 diabetes in adults in the U.S. (Table 3). It should be noted, however, that
none of these are currently approved for use in youth (<18 years old), and while some
of these agents have undergone or are currently undergoing pharmacokinetic, pharmacodynamics,
and safety/tolerability testing in small pediatric studies, no efficacy or long-term
safety results have yet been reported in youth.
Table 3
Drugs for treating type 2 diabetes in adults (not including insulin or insulin analogs)
but not yet approved in youth except for metformin
Drug class
Available drugs in this class
Mechanism of action
Significant adverse effects
Approved in patients <18 years old
Biguanides
Metformin
Decreases insulin resistance; reduces hepatic glucose production; increases peripheral
glucose uptake; decreases gastrointestinal absorption of glucose
Gastrointestinal
Lactic acidosis
Yes
Sulfonylureas
Glipizide
Glimepiride
Glyburide
Stimulates secretion of insulin from the β-cell
Hypoglycemia
Weight gain
No
Meglitinides
Repaglinide
Nateglinide
Stimulates glucose-dependent secretion of insulin from the β-cell
Hypoglycemia
URI
Diarrhea
Headache
No
α-Glucosidase inhibitors
Acarbose
Miglitol
Delays absorption of glucose by intestines by inhibiting breakdown of complex sugars
Flatulence
Diarrhea
Abdominal cramps
No
GLP-1 agonists
Exenatide
Liraglutide
Dulaglutide
Lixisenatide
Albiglutide
Semaglutide
Incretin effect; slows gastric emptying; enhances postprandial insulin biosynthesis;
improves β-cell function; decreases appetite
Acute pancreatitis
C-cell hyperplasia/ medullary thyroid carcinoma
Nausea/vomiting
Hypoglycemia
Diarrhea
Headache
No
DPP-4 inhibitors
Saxagliptin Sitagliptin
Alogliptin
Linagliptin
Inhibits DPP-4 enzyme, reducing endogenous GLP-1 breakdown
Acute pancreatitis
URI
UTI
Nasopharyngitis
Headache
No
Amylin analog
Pramlintide
Inhibits postprandial glucagon secretion; delays gastric emptying; improves satiety
Hypoglycemia
Nausea
Anorexia
Abdominal pain
No
Thiazolidinediones
Rosiglitazone
Pioglitazone
PPAR-γ inhibitor; increases insulin sensitivity in liver, muscle, and adipose tissue;
decreases hepatic glucose output
Edema
Weight gain
Anemia
Elevated liver enzymes
No
SGLT-2 inhibitors
Canagliflozin
Dapagliflozin
Empagliflozin
Ertugliflozin
Allows more glucose to be excreted in the urine and hence lowers blood glucose
Euglycemic ketoacidosis
UTI
Candidal vulvovaginitis
No
Bile acid sequestrant
Colesevelam
Mechanism for glucose lowering is unknown
Gastrointestinal (gas, nausea, diarrhea, abdominal pain)
Weakness
Muscle pain
No
Dopamine-2 agonist
Bromocriptine (quick release)
Modulates hypothalamic regulation of metabolism; increases insulin sensitivity
Nausea/vomiting
Fatigue
Dizziness
Headache
No
DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; PPAR, peroxisome proliferator–activated
receptor; SGLT2, sodium–glucose cotransporter 2; URI, upper respiratory infection;
UTI, urinary tract infection.
Although the TODAY study demonstrated that the addition of rosiglitazone to metformin
improved the durability of glycemic control (treatment failure rate 38.6% for metformin
plus rosiglitazone vs. 51.7% for metformin alone) with no increased rate of adverse
events over a 3–6 year period in youth with recent-onset type 2 diabetes, it is premature
to recommend its widespread use in youth with type 2 diabetes, especially since its
use is not approved in the pediatric population. Even though many of the newer agents
approved in the adult population are promising and may have particular benefits in
younger individuals with diabetes, we cannot recommend widespread use of these medications
until additional studies are completed. Unfortunately, implementation and completion
of such studies have been slow and many barriers have been identified (111). Therefore,
we recommend that the use of these medications in youth with type 2 diabetes be avoided
outside of research trials. However, collaboration among investigators, pharmaceutical
sponsors, and governmental regulators is urgently needed to expand treatment options
for this population of patients.
METABOLIC SURGERY
Recommendations
Metabolic surgery may be considered for the treatment of adolescents with type 2 diabetes
who are markedly obese (BMI >35 kg/m2) and who have uncontrolled glycemia and/or serious
comorbidities despite lifestyle and pharmacologic intervention. A
Metabolic surgery should be performed only by an experienced surgeon working as part
of a well-organized and engaged multidisciplinary team including surgeon, endocrinologist,
nutritionist, behavioral health specialist, and nurse. A
Bariatric or metabolic surgery, including Roux-en-Y gastric bypass, vertical sleeve
gastrectomy, laparoscopic adjustable gastric banding, laparoscopic gastric plication,
and biliopancreatic diversion, has been shown to significantly reduce weight, BMI
(120), and cardiovascular comorbidities (121) in adults with obesity and is now considered
a standard component of care for adults with morbid obesity. Metabolic surgery is
also an effective strategy for prevention (122,123) and treatment of type 2 diabetes
in obese and severely obese (BMI ≥30 kg/m2) adults (124–129) and is now endorsed as
part of the algorithm for treating type 2 diabetes in adults (127).
Over the last decade, weight-loss surgery has been increasingly performed in adolescents
with obesity, but the long-term experience remains limited. The current guidelines
for metabolic surgery in adolescents generally include BMI >35 kg/m2 with significant
comorbidities or BMI >40 kg/m2 with or without comorbidities (106,130–140). The Endocrine
Society Clinical Practice Guideline on Pediatric Obesity discusses bariatric surgery
for the management of pediatric obesity in detail, and interested readers can refer
to it (106). Briefly, positive outcomes of metabolic surgery have included remission
of type 2 diabetes, improvements in glucose homeostasis in youth without diabetes,
improvement in surrogate markers of insulin sensitivity and secretion, resolution
of sleep apnea, improvements in nonalcoholic fatty liver disease (NAFLD), and improvements
in cardiovascular disease (CVD) risk factors, among others (106,134–141). Direct comparison
between the medical management of youth with type 2 diabetes and bariatric surgery
outcome, both short- and long-term, is very limited. A recent study compared youth
with type 2 diabetes from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS)
cohort who had undergone a bariatric surgical procedure with youth with medically
treated type 2 diabetes from the TODAY cohort. During 2 years, A1C decreased from
6.8% to 5.5% in Teen-LABS and increased from 6.4% to 7.8% in TODAY, BMI decreased
by 29% in Teen-LABS and increased by 3.7% in TODAY, elevated blood pressure decreased
from 45% to 20% of participants in Teen-LABS and increased from 22% to 41% in TODAY,
and dyslipidemia decreased from 72% to 24% in Teen-LAB versus no appreciable change
in TODAY (142).
Overall, studies in both adults and adolescents suggest that those who undergo bariatric
surgery earlier in the course of diabetes (that is, at a younger age or with higher
baseline β-cell function) have a higher remission rate despite similar weight loss
(143). Initial diabetes remission rates in adults range between 40% and 70%, whereas
in adolescents the reported initial rates are as high as 68–100% (144). The long-term
durability of these remissions is unknown and will require longer follow-up.
Short-term and long-term complications of metabolic surgery need to be taken into
consideration. In Teen-LABS, 13% of adolescents required a second operative procedure
and another 13% required an endoscopic procedure because of a complication (145).
In the recent Teen-LABS/TODAY comparison, 30% of the youth with diabetes undergoing
surgical intervention required readmission and/or reoperation (142). Postoperative
nutritional complications (vitamin B12, thiamine, and vitamin D deficiency) are also
prevalent. Long-term follow-up and further research is required to better understand
the mechanisms by which metabolic surgery improves type 2 diabetes and the short-term
and long-term benefits and risks of this procedure in youth. Quality of life and economic
(cost-benefit) analyses will also be important components of ongoing follow-up and
research (146,147).
PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS
Youth-onset type 2 diabetes is associated with significant microvascular and macrovascular
risk burden and a substantial increase in the risk of cardiovascular morbidity and
mortality at an earlier age than those individuals diagnosed later in life (148).
The higher complication risk in earlier-onset type 2 diabetes is likely to be related
to prolonged lifetime exposure to hyperglycemia and other atherogenic risk factors,
including insulin resistance, dyslipidemia, hypertension, and chronic inflammation.
These diabetes comorbidities also appear to be higher than in youth with type 1 diabetes
despite shorter diabetes duration and lower A1C (149). In addition, the progression
of vascular abnormalities appears to be more pronounced in type 2 diabetes diagnosed
earlier in life compared with type 1 diabetes of similar duration, including ischemic
heart disease and stroke (150,151).
Nephropathy
Recommendations
Blood pressure should be measured at every visit. A
Blood pressure should be optimized to reduce risk and/or slow the progression of diabetic
kidney disease. A
If blood pressure is >95th percentile for age, sex, and height, increased emphasis
should be placed on lifestyle management to promote weight loss. If blood pressure
remains above the 95th percentile after 6 months, antihypertensive therapy should
be initiated. C
Initial therapeutic options include ACE inhibitors or angiotensin receptor blockers.
Other blood pressure–lowering agents may be added as needed. C
Protein intake should be at the recommended daily allowance of 0.8 g/kg/day. E
Urine albumin/creatinine ratio (UACR) should be obtained at the time of diagnosis
and annually thereafter. An elevated UACR (>30 mg/g creatinine) should be confirmed
on two of three samples. B
Estimated glomerular filtration rate (eGFR) should be determined at the time of diagnosis
and annually thereafter. E
In nonpregnant youth with diabetes and hypertension, either an ACE inhibitor or an
angiotensin receptor blocker is recommended for those with modestly elevated UACR
(30–299 mg/g creatinine) D and strongly recommended for those with UACR >300 mg/g
creatinine and/or eGFR <60 mL/min/1.73 m2. E
For those with nephropathy, continued monitoring (yearly UACR, eGFR, serum K) may
aid in assessing adherence and detecting progression of disease. E
Referral to nephrology is recommended in case of uncertainty of etiology, worsening
UACR, or decrease in eGFR. E
Diabetic kidney disease is diagnosed in the presence of elevated albumin excretion
and decreased eGFR and is the leading cause of end-stage renal disease (152). Elevated
UACR or albuminuria, defined as >30 mg/g creatinine, and hyperfiltration, defined
as an eGFR between 120 mL/min/1.73 m2 and 150 mL/min/1.73 m2 (153,154), are early
abnormalities that indicate increased risk of progression to diabetic kidney disease
(154,155). Overt nephropathy is defined as persistent proteinuria ≥500 mg/day or UACR
≥300 mg/g creatinine and an eGFR <60 mL/min/1.73 m2.
Albuminuria and hyperfiltration detected early in youth with type 2 diabetes may occur
because of obesity before the onset of diabetes (156) and can be related to early
vascular dysfunction (157). In TODAY, the prevalence of microalbuminuria was 6.3%
at randomization (mean 7.8 months since diagnosis of diabetes) and increased to 16.6%
over 3 years (79). This coincided with progression of dyslipidemia (from 4.5% at baseline
to 11%) and hypertension (from 11.6% at baseline up to 33%) (78,79) despite standardized
therapy for these comorbidities. The main determining factor in albuminuria progression
was A1C, with 17% higher risk of developing albuminuria per 1% increase in A1C (79),
consistent with findings in other studies (149). Modifiable risk factors include obesity,
dyslipidemia, hypertension, and glycemia (152). In some ethnic groups, particularly
Pima Indians and First Nations people in Canada, the risk of nephropathy is much higher
in youth with type 2 diabetes (158–161).
Spot UACR is generally recommended for screening of urinary albumin excretion, with
an abnormal value confirmed on two of three consecutive tests obtained on different
days within a 3- to 6-month period. Results can be affected by orthostatic proteinuria,
marked hyperglycemia, exercise, menstruation, recent intercourse, and sample contamination.
eGFR can be calculated from serum creatinine and the patient’s height using the Schwartz
equation. However, recent studies suggest that this underestimates hyperfiltration,
which is highly prevalent in youth with type 2 diabetes, and a combined estimation
using serum creatinine and serum cystatin C is preferable when available (162).
In addition to optimizing glycemia, control of hypertension is important to prevent
and slow the progression of nephropathy. Therapeutic options include the use of ACE
inhibitors or angiotensin receptor blockers (152,163–165). If not tolerated, a calcium
channel blocker or diuretic or combination therapy may be required if hypertension
does not normalize on single-agent therapy.
Neuropathy
Recommendations
Youth with type 2 diabetes should be screened for the presence of neuropathy by foot
examination at diagnosis and annually. The examination should include inspection,
assessment of foot pulses, pinprick and 10-g monofilament sensation tests, testing
of vibration sensation using a 128-Hz tuning fork, and ankle reflexes. C
Prevention should focus on achieving glycemic goals. C
Diabetic neuropathy can manifest as distal polyneuropathy (DPN), mononeuropathy, and/or
autonomic neuropathy. Mononeuropathies are uncommon. DPN is usually the earliest clinically
apparent manifestation of neuropathy in persons with diabetes and most commonly presents
with paresthesia, numbness, or pain in the feet. DPN generally affects the small myelinated
fibers first with burning or stabbing pain and reduced or absent thermal and pinprick
sensation. It then progresses to larger myelinated fibers with numbness, tingling,
and poor balance along with reduced or absent reflexes, vibration perception, and
monofilament sensation. The “gold standard” for the diagnosis of DPN includes careful
neurologic examination to rule out other potential causes of neuropathy and nerve
conduction velocity studies. The Diabetes Control and Complications Trial (DCCT),
which used a combination of examination by a neurologist, nerve conduction velocity
testing, and autonomic neuropathy testing, clearly showed that improved glycemic control
reduced the incidence of diabetic neuropathy, both DPN and autonomic, by 44–60%.
However, most large prospective studies have not been able to include the gold standard
of nerve conduction studies and have utilized less invasive and less expensive approaches
to the diagnosis of diabetic neuropathy. The most commonly used is the Michigan Neuropathy
Screening Instrument (MNSI). The MNSI is a self-administered questionnaire (MNSIQ)
and an examination (MNSIE) for foot abnormalities, distal vibration perception, and
ankle reflexes; the MNSI has been validated in adults with type 1 diabetes as a screening
tool for neuropathy (166–169). It should be noted, however, that the MNSIE does not
include an assessment of small-fiber dysfunction.
Evidence of diabetic neuropathy using the MNSI was found in 26% of youth with type
2 diabetes in the SEARCH study (168) and in 21% of an Australian cohort using thermal
(small fiber) and vibration (large fiber) threshold testing (149). In addition, more
than half of the cohort had evidence of autonomic neuropathy (pupillary reactivity)
after a median duration of diabetes of 1.3 years (149). In an Indian cohort of mean
age 16 years at diagnosis, the prevalence of neuropathy increased from 3% in those
with diabetes duration <5 years to 49% in those with duration >15 years (170). In
the SEARCH study, the prevalence of abnormal MNSI was significantly higher in youth
with type 2 diabetes compared with those with type 1 diabetes after adjustment for
age and sex. This association was no longer significant after adjustment for the covariates
of diabetes duration, waist circumference, blood pressure, HDL cholesterol, and microalbuminuria
(168). In the Australian cohort, the prevalence of peripheral and autonomic neuropathy
in adolescents with type 2 diabetes was similar to that of the type 1 diabetes cohort
despite shorter diabetes duration (1.3 vs. 6.8 years) and lower A1C (7.3% vs. 8.5%)
(149). In adolescents with type 1 diabetes, data from the DCCT support the importance
of intensive glycemic therapy and reduction of A1C for the prevention of diabetic
neuropathy (171,172). So far, such data do not exist in youth with type 2 diabetes.
The ADA recommends that assessment for symmetric DPN should include a careful history
and assessment of either temperature or pinprick sensation (small-fiber function)
and vibration sensation using a 128-Hz tuning fork (for large-fiber function). All
patients should have annual 10-g monofilament testing to identify feet at risk for
ulceration and amputation (173). Since it appears that youth with type 2 diabetes
develop DPN at least as frequently as adults, youth with type 2 diabetes should be
screened at the same frequency: at diagnosis and annually.
Retinopathy
Recommendations
Screening for retinopathy should be performed by dilated fundoscopy or retinal photography
at or soon after diagnosis and annually thereafter. C
Optimizing glycemia is recommended to decrease the risk or slow the progression of
retinopathy. B
Less frequent examination (every 2 years) may be considered if there is adequate glycemic
control and a normal eye exam. C
Diabetic retinopathy refers to changes in the small vessels of the retina with the
occurrence of hemorrhages, microaneurysms, exudates, or abnormal vessels. The prevalence
of retinopathy in youth with type 2 diabetes is reported to be between 2% and 40%,
depending on the methodology used, the age of the participants, and the duration of
diabetes. The prevalence is higher with greater duration of the disease, although
retinopathy has been reported at diagnosis (149,170,174). In the TODAY study, the
prevalence of early retinopathy by digital fundus photography at a mean age of 18.1
years and mean duration of diabetes of 4.9 years was 13.7%, with no evidence of macular
edema or proliferative retinopathy (77). Retinopathy was associated with older age
(19.1 vs. 17.9 years), longer duration of diabetes (5.6 vs. 4.7 years), and higher
A1C (8.3% vs. 6.9%). Moreover, the odds ratio for retinopathy increased with increasing
A1C, age, and duration of diabetes (77). In the SEARCH study, the prevalence of retinopathy
using retinal photography was 42% at a mean age of 21 years and mean duration of type
2 diabetes of 7.2 years (175). A1C and LDL cholesterol were significantly higher among
those with retinopathy compared with those without. In Pima Indians, retinopathy was
detected only after age 20 years and only after 5 years of diabetes duration (158).
However, by 30 years of age, retinopathy had developed in 45% of this population (158).
NAFLD
Recommendations
Evaluation for NAFLD (by measuring ALT and AST) should be done at diagnosis of type
2 diabetes and annually thereafter. B
Referral to gastroenterology should be considered for persistently elevated or worsening
transaminases. B
The prevalence of dysglycemia in youth with NAFLD is higher than in those without
NAFLD (176). In a multicenter cohort of youth with NAFLD, primarily of Hispanic descent,
a third of the children with NAFLD had abnormalities in glucose metabolism; 23.4%
had prediabetes and 6.5% had type 2 diabetes (176). Moreover, type 2 diabetes in youth
is associated with greater NAFLD histologic severity than in adults, which may imply
a heightened risk of progression to fibrosis, cirrhosis, and hepatic failure (176,177).
Therefore, it is particularly important to evaluate for NAFLD in youth with obesity
and type 2 diabetes. For screening, transaminase levels are a clinical tool that is
widely available and has a good sensitivity for the detection of more advanced stages
of hepatitis or fibrotic changes, but these tests are not disease specific; therefore,
other causes of chronic liver disease should be ruled out (178,179). Recently, population-based
cutoffs lower than those used in clinical laboratories have been advocated to indicate
abnormality (180). Among the noninvasive diagnostic tests, MRI/MRS are currently the
preferred imaging modalities, though of limited clinical application (181). Liver
ultrasound, though a widely available clinical tool, is operator dependent and detects
liver fat >30% with sensitivity of 80%, but sensitivity is lower with lower degrees
of fatty infiltration and the presence of morbid obesity. Hence, its value in the
early diagnosis of NAFLD is limited (181). Among the noninvasive modalities, elastography
is useful in evaluating advanced fibrosis and cirrhosis (181) and is gaining wider
acceptance. Liver biopsy remains the gold standard for diagnosis and staging of liver
disease and the only way to differentiate between nonalcoholic steatohepatitis and
hepatic steatosis. Treatment options for NAFLD remain limited, with weight loss being
most effective. Therapeutic agents tested in randomized clinical trials in youth include
metformin, vitamin E, and cysteamine, with no clear established benefit on histologic
outcomes or sustained reduction in ALT (182–184).
Obstructive Sleep Apnea
Recommendation
Screening for symptoms of obstructive sleep apnea (OSA) should be done at each visit,
and referral to a pediatric sleep specialist for evaluation and a polysomnogram, if
indicated, is recommended. OSA should be treated when documented. B
Sleep disturbance (insufficient or disrupted sleep, circadian rhythm dysregulation)
and OSA are increasingly recognized as being associated with obesity (185–189), insulin
resistance in adults and children (52,190–195), and type 2 diabetes in adults (196–199),
as well as risk for future CVD (200). Experimental sleep restriction results in decreased
glucose clearance and postprandial glucose elevation (193,201), decrease in glucose
effectiveness, and variable decrease in insulin sensitivity (190,192,202). OSA may
influence glycemic regulation in individuals with diabetes; in adults with type 2
diabetes, treatment of OSA with continuous positive airway pressure has been associated
with improvement in the glycemic profile (203), decreased A1C, and improvement in
insulin sensitivity indices (204) as well as inflammation (205) in some, but not all,
studies. Further study is needed.
Polycystic Ovary Syndrome
Recommendations
Evaluate for polycystic ovary syndrome (PCOS) in female adolescents with type 2 diabetes,
including laboratory studies when indicated. B
Oral contraceptives for treatment of PCOS are not contraindicated for girls with type
2 diabetes. C
Metformin in addition to lifestyle modification is likely to improve the menstrual
cyclicity and hyperandrogenism in girls with type 2 diabetes. E
PCOS affects 5–10% of females in the reproductive age-group and is characterized by
hyperandrogenism and amenorrhea or oligomenorrhea secondary to chronic anovulation
(206,207). The prevalence of PCOS is significantly higher in adolescent girls with
obesity compared with adolescent girls without overweight/obesity (208), but the prevalence
in adolescent girls with type 2 diabetes is not well studied. Insulin resistance with
compensatory hyperinsulinemia are metabolic features in both adult women with PCOS
with and without overweight/obesity (209) and in adolescent girls with PCOS compared
with control subjects of similar age, body composition, and abdominal adiposity (210).
In adolescent girls with PCOS and obesity, this increased insulin resistance when
combined with impaired β-cell function predisposes to prediabetes and type 2 diabetes
(211), with higher prevalence of impaired glucose tolerance (30%) and type 2 diabetes
(3.7%) (212). Therefore, it is important to obtain a menstrual history and evaluate
female adolescents with type 2 diabetes for signs and symptoms of hyperandrogenism
(irregular menses, hirsutism, acne) and to initiate appropriate diagnostic evaluation
for PCOS if indicated (213,214). In the TODAY cohort, 21% of adolescent girls who
were ≥1-year postmenarche had irregular menses. Those with irregular menses versus
regular menses had higher total testosterone, free androgen index, BMI, and AST and
lower sex hormone–binding globulin and estradiol (215). Treatment of PCOS in adolescents
includes lifestyle changes (216–218), the use of oral contraceptive pills (OCPs),
and insulin sensitizers, such as metformin (213). However, the use of some OCPs has
been associated with unfavorable effects on indices of insulin sensitivity (219) and
lipid profile (220). The use of metformin therapy for 3–12 months was associated with
decrease in serum androgens, improvement in lipid profile, induction of ovulation,
and improvement in glucose tolerance and insulin sensitivity (216,221,222). Therefore,
in girls with type 2 diabetes and PCOS, treatment with metformin in addition to lifestyle
modification is likely to improve the metabolic dysfunction associated with PCOS and
may improve menstrual cyclicity and hyperandrogenism (213,218). However, for the girls
in the TODAY study, all of whom received metformin, there was no treatment group (metformin
alone, metformin plus lifestyle, and metformin plus rosiglitazone) effect on menses
or sex steroids at 12 and 24 months and no association of sex steroids with surrogate
estimates of insulin sensitivity or secretion (215). Despite the potential negative
effects of OCPs, which may not be shared by all OCPs, on metabolic status and cardiovascular
risk, hormonal contraceptive therapy is more effective at addressing the symptoms
of hyperandrogenism and anovulation and is not contraindicated in female youth with
type 2 diabetes (213).
CVD
Recommendation
Intensive lifestyle interventions focusing on weight loss, dyslipidemia, hypertension,
and dysglycemia are important to prevent overt macrovascular disease in early adulthood.
E
Dyslipidemia
Recommendations
Lipid testing should be performed when initial glycemic control has been achieved
and annually thereafter. B
Optimal cholesterol goals are LDL <100 mg/dL (2.6 mmol/L), HDL >35 mg/dL (0.905 mmol/L),
triglycerides <150 mg/dL (1.7 mmol/L). E
If LDL cholesterol is >130 mg/dL, blood glucose control should be maximized and dietary
counseling should be provided using the American Heart Association Step 2 diet. E
If LDL cholesterol remains above goal after 6 months of dietary intervention, initiate
therapy with statin, with goal of LDL <100 mg/dL. B
If triglycerides are >400 mg/dL (4.7 mmol/L) fasting or >1,000 mg/dL (11.6 mmol/L)
nonfasting, optimize glycemia and begin fibrate, with a goal of <400 mg/dL (4.7 mmol/L)
fasting (to reduce risk for pancreatitis). C
Although there have been no long-term studies of the outcome of cholesterol-lowering
therapy in youth with type 2 diabetes, studies in youth with familial hypercholesterolemia
have shown reduction in carotid intima-media thickness (IMT) with the use of statins
(223,224), with similar efficacy and side effects as in adults. However, in a recent
multicenter, multinational study of youth with type 1 diabetes, statin use did not
have a significant effect on carotid IMT despite reductions in total LDL cholesterol
and triglyceride concentrations (225). Although longitudinal, interventional data
with statins in youth-onset type 2 diabetes are not yet available, statin therapy
in youth with type 2 diabetes who do not meet LDL targets following lifestyle change
intervention is considered a reasonable approach and aligned with overall recommendations
for dyslipidemia (226), given that dyslipidemia in youth tracks into adulthood and
is anticipated to confer increased cardiovascular risk. Similarly, though there have
been no studies of the use of fibrates in youth with type 2 diabetes and hypertriglyceridemia
to prevent pancreatitis, extrapolation from studies in adults supports the use of
these agents for severe hypertriglyceridemia in adolescents. Adolescent girls treated
with statins or fibrates should receive counseling on potential risk to the fetus
and be encouraged to use effective birth control.
Cardiac Function Testing
Recommendation
Routine screening for heart disease with electrocardiogram, echocardiogram, or stress
testing is not recommended in asymptomatic youth with type 2 diabetes. B
Macrovascular disease involves coronary, cerebral, and peripheral arterial disease.
In adults, type 2 diabetes is associated with doubling of risk for CVD, including
coronary heart disease and stroke as well as increased risk of heart failure, after
adjusting for age, sex, smoking status, BMI, and systolic blood pressure (227). Diabetes
duration is implicated as a major risk factor for CVD (228,229), though there may
also be a worsened risk of CVD with early onset of type 2 diabetes (228,230). While
overt cardiovascular events are not expected in youth with type 2 diabetes, epidemiological
and clinical studies show that the atherosclerotic process starts during childhood
(231), with strong relationships between childhood obesity, elevated blood pressure,
low HDL cholesterol, and coronary artery disease in adulthood (232–235). Furthermore,
studies of vascular function have demonstrated subclinical vascular disease in adolescents
with obesity and type 2 diabetes, including elevated aortic pulse wave velocity, a
marker of vascular stiffness (236), and increased carotid IMT, a structural measure
of atherosclerosis, compared with normoglycemic youth with and without overweight/obesity
(237). In the SEARCH study, youth with type 2 diabetes had worse arterial stiffness
than those with type 1 diabetes, attributed to greater central adiposity and hypertension
but not related to duration of diabetes or glycemic control (238). In studies of obese
youth with and without type 2 diabetes, carotid IMT was significantly related to glycemia,
while aortic pulse wave velocity was related to insulin resistance and inflammation
(239). In addition, total body and abdominal adiposity were significant determinants
of coronary artery calcifications in these youth (239). In TODAY, echocardiographic
evaluation revealed a relationship of BMI and blood pressure with adverse cardiac
measures (240), though there was a protective effect of cardiorespiratory fitness
on functional measures of cardiac structure and function in this group of largely
sedentary youth (241). Overall, studies to date indicate significant vascular dysfunction
and greater risk of progression to overt CVD in youth with obesity and type 2 diabetes.
The vascular dysfunction may begin prior to the diagnosis of type 2 diabetes as a
result of obesity and insulin resistance.
In adults, type 2 diabetes is associated with an increased risk of mortality, with
cardiac disease as a major cause of death (242); the excess mortality is related to
worse glycemic control, impaired renal function, and younger age at diabetes diagnosis
(243). Youth-onset type 2 diabetes appears to be associated with an earlier onset
of complications and an increased mortality risk compared with type 1 diabetes (109,244,245).
In a Swedish study, type 2 diabetes diagnosed between 15 and 34 years of age was associated
with a higher standardized mortality ratio than type 1 diabetes (2.9 and 1.8, respectively),
with an increased hazard ratio for males versus females (P = 0.0002) (244). Similarly,
an epidemiological study from Australia reported a significant mortality excess over
15–30 years of follow-up in individuals diagnosed with type 2 diabetes between 15
and 30 years of age compared with type 1 diabetes, with a hazard ratio of 2.0 (95%
CI 1.2–3.2), despite shorter average disease duration (26.9 vs. 36.5 years, P = 0.01)
and similar glycemic control (109). The mortality excess was related to an excess
of cardiovascular deaths in those with type 2 diabetes (50% vs. 30%, P < 0.05). In
First Nations individuals, increased mortality with type 2 diabetes is reported in
relation to end-stage renal disease (159) and is significantly higher than in individuals
with youth-onset type 1 diabetes (245). In a large cohort of 354 patients with type
2 diabetes diagnosed between 15 and 30 years of age compared with a duration-matched
cohort of 1,062 patients diagnosed between 40 and 50 years old, the negative effect
of diabetes on morbidity (albuminuria and neuropathy scores) and mortality was greatest
for those diagnosed at a young age. Standardized mortality adjusting for duration
was highest, at any chronological age, for those diagnosed between 15 and 30 years
of age (246). Taken together, these data raise significant concern regarding the long-term
outcome of youth-onset type 2 diabetes and support the importance of aggressive management
of glycemia and CVD risk factors in these youth.
Transitioning from Pediatric to Adult Care
Recommendation
Youth with type 2 diabetes should be transferred to an adult-oriented diabetes specialist
when deemed appropriate by the patient and provider. E
The process of transferring the pediatric patient to an adult health care provider
is a challenge that has only recently received attention in the literature but is
now recognized to be “important and should begin well before patients are transferred”
(247). Both the Society for Adolescent Medicine (248) and the American Academy of
Pediatrics, along with other associations (249), have position statements related
to transition of care for those with chronic diseases and special medical needs that
emphasize the importance of a gradual and collaborative process starting a year or
longer before the actual transition is to occur. Published literature on this subject
recommends progressive implementation as eight developmentally linked steps (250,251).
The ADA, in partnership with the other organizations of the ADA Transitions Working
Group (252), developed position statements in 2011 (252), in 2014 (253), and in 2018
(254). Even for youth with type 1 diabetes, deficiencies and gaps in the transition
process have been demonstrated in observational cross-sectional research. These gaps
are summarized in recent reviews (250,252,255) and include minimal empirical evidence
about the best approaches, differences in the style and approach to health care delivery
between pediatric and adult health care providers, lack of well-defined criteria of
readiness for transition or tools to assess readiness, gaps in health insurance coverage,
changing social structure as adolescents enter young adulthood, differences in learning
styles of the patient and teaching styles of the provider, and lack of health care
provider training related to transition of care.
Despite the prevailing evidence of the need for better transition of care, there are
no controlled studies of the effectiveness of such programs in patients with youth-onset
type 2 diabetes. Patients with type 1 diabetes have reduced dropout from medical care,
increased number of visits, and reduced pregnancy loss, DKA, and severe hypoglycemia
during the transition period using a “navigator” to assist young adults (18–30 years
old) (256–258).
Since emerging adults with type 2 diabetes express similar concerns related to transition
from pediatric to adult health care providers (259), the same principles discussed
above and steps to facilitate transition that apply to those with type 1 diabetes
should be considered in type 2 diabetes.
Conclusions
Even though our knowledge of youth-onset type 2 diabetes has increased tremendously
over the last two decades, robust and evidence-based data are still limited regarding
diagnostic and therapeutic approaches and prevention of complications. The current-day
information indicates that there are fundamental differences in insulin sensitivity
and β-cell function between youth and adults with prediabetes and type 2 diabetes,
which could possibly explain why some youth develop type 2 diabetes decades earlier
than adults (23,24,260,261). Youth are more insulin resistant and have β-cells that
are hyperresponsive to stimulation compared with adults (23,24,260,261). Puberty-related
physiologic insulin resistance, particularly in obese youth, may play a role in this
heightened insulin resistance. It remains an enigma, though, why some individuals
with youth-onset type 2 diabetes demonstrate durable control and others do not (74).
Furthermore, type 2 diabetes appears to be more aggressive in youth than adults, with
a faster rate of deterioration of β-cell function (76) and poorer response to glucose-lowering
medications (104). Future research should probe the mechanisms responsible for this
youth–adult contrast in the various aspects of type 2 diabetes. Lastly, complications
in youth with type 2 diabetes appear early, resulting in higher rates of morbidity
and mortality compared with type 1 diabetes. Preexisting obesity and its comorbidities
might play a key role in amplifying the complications of youth-onset type 2 diabetes.
Intervention/prevention strategies for type 2 diabetes should not be limited to youth
with dysglycemia only, but youth with obesity at large.
In closing, the present guidelines are based on current data, experience, opinion,
and gained “wisdom.” However, we anticipate that future guidelines will change as
more scientific data emerge to support evidence-based recommendations.