Diabetes Spectrum
Volume 13 Number 2, 2000, Page 95
From Research to Practice / Diabetes and Adolescents

Type 2 Diabetes Mellitus in Teens

Stephen W. Ponder, MD, CDE, Susan Sullivan, RN, CDE,
and Grete McBath, RD, LD, CDE


.

In Brief

Included in this comprehensive discussion of type 2 diabetes in teens is a brief review of definitions of type 1 and forms of non-type 1 diabetes, the epidemiology of type 2 diabetes in teens, and the scope of related problems. Management considerations including pharmaceutical interventions for teens with type 2 diabetes are described.

The end of the 20th century witnessed a dramatic rise in the incidence of type 2 diabetes in children. Although considered uncommon a few decades ago, type 2 diabetes in adolescents now represents one of the most rapidly growing forms of diabetes in the United States and perhaps worldwide.

Not surprisingly, the incidence of type 2 diabetes in adolescents has paralleled the epidemic of childhood obesity now occurring in Westernized societies.1 It is believed that the genetic and lifestyle factors that increase the risk of developing type 2 diabetes in adolescents and adults are similar. This article provides an overview of this problem, plus provides direction for clinicians caring for these children.

DEFINITIONS
In 1997, the American Diabetes Association (ADA) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus categorized four major forms of diabetes and revised the metabolic parameters for diagnosis.2 Type 1, type 2, gestational diabetes mellitus (GDM), and a category labeled "other specific types" constitutes the current etiological classification scheme. It is reasonable to speculate that, as more is learned from studies of the molecular genetics of type 1, type 2, and GDM, better defined clinical subtypes will emerge. Although the ADA diagnostic criteria were developed primarily from data obtained from adults, they are to be applied equally to children and adolescents.

The categories of type 1 and type 2 diabetes are clinically defined. While this allows flexibility in assigning type to a given patient based on clinical presentation, it sometimes requires revision as the clinical course may alter the assignment (and perhaps the choice of therapeutic options) over time. For example, some overweight adolescents initially presenting with classic signs and symptoms of type 1 diabetes may actually have type 2 diabetes. Medical management with oral agents after an initial period of stabilization with insulin is often possible. If type 2 diabetes is suspected, clinicians are cautioned to not make hasty statements regarding the long-term need for insulin therapy.

For now, the designation of type 1 diabetes suggests a chronic, immune-mediated destruction of functional beta.gif (968 bytes)-cell mass with characteristic laboratory measures in serum of beta.gif (968 bytes)-cell autoimmunity (anti-glutamic acid decarboxylase [GAD], anti-insulin, and antibodies to tyrosine phosphatases IA-2 and IA-2 beta.gif (968 bytes)) found in the majority of cases. In type 1 diabetes, insulin therapy is always indicated and is the only appropriate pharmacological option. Oral agents are contraindicated, although the presence of residual insulin secretory capacity at time of diagnosis (i.e., the honeymoon phase) may lead inexperienced practitioners to attempt therapy with them with potentially disastrous consequences.

Nonimmune forms of diabetes in children and adolescents include "idiopathic" type 1 diabetes, type 2 diabetes with insulin resistance, atypical diabetes mellitus, maturity onset diabetes of youth (MODY), genetic defects in insulin action, and secondary diabetes (e.g., cystic fibrosis).

Idiopathic Type 1 Diabetes
This form is clinically indistinguishable from type 1 diabetes due to autoimmune-mediated beta.gif (968 bytes)-cell destruction. In fact, it can only be diagnosed by the failure to demonstrate evidence of serum markers of beta.gif (968 bytes)-cell-directed autoimmunity (e.g., anti-GAD antibodies). The cause(s) are unknown. The management is the same as with any patient with type 1 diabetes.

Type 2 Diabetes and the Insulin Resistance Syndrome
The insulin resistance syndrome is the metabolic state characterized by fasting and/or postprandial hyperinsulinemia plus one or more of the following: hypertension (initially systolic >diastolic), dyslipidemia (hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol fraction), obesity (abnormal weight for height or body mass index [BMI] > 25, menstrual disturbances, and hirsutism secondary to ovarian hyperandrogenism. The expression of this syndrome may be seen as early as 2 years of age with the appropriate genetic background and environmental milieu.

The hallmark of type 2 diabetes in adolescents, as in most adults, is insulin resistance. The development of overt glucose intolerance ultimately arises on this "foundation" of insulin resistance. For years, reduced hepatic and skeletal muscle insulin sensitivity is compensated for by increased pancreatic insulin secretion, resulting in normal glucose tolerance. In a typical adolescent with type 2 diabetes, steady increases in insulin resistance accompany the normal progression through puberty secondary to increased growth hormone secretion. This contributes to the development of postprandial hyperglycemia. Many children of predominantly non-European origin (e.g., African Americans, Hispanics, American Indians) are prone to insulin resistance which creates an even greater insulin secretory requirement. Abnormal sustained elevations in plasma glucose contribute to an erosion of insulin secretory capacity due to the phenomenon of glucose toxicity. Ultimately, fasting, as well as postprandial, hyperglycemia occurs.

In contrast to many adults who develop type 2 diabetes in middle life or later, adolescents are more likely to demonstrate early recovery of beta.gif (968 bytes)-cell function following resolution of the glucose toxic state. This has significant implications for long-term pharmacological management. The explanation for this finding may be that, in some cases, adults with type 2 diabetes may have gone undiagnosed for years, accruing irreversible beta.gif (968 bytes)-cell damage from years of insulin resistance preceding the development of overt glucose intolerance.

The prevalence of insulin resistance is high in the Hispanic community of South Texas. However, well before glucose intolerance occurs, many adolescents have already experienced years of co-morbidity due to underrecognized insulin resistance-related problems (e.g., hypertension, dyslipidemia). As a late event in the progression of the insulin resistance syndrome, type 2 diabetes truly represents the "tip of the iceberg" in regards to a much more insidious process.

Atypical Diabetes Mellitus
A form of diabetes that disproportionately affects African Americans and Asian Indians has been described as atypical diabetes mellitus.3-6 Onset of diabetes is explosive, often including diabetic ketoacidosis (DKA) as a presenting feature. Following initial stabilization, patients may be managed similar to children with type 2 diabetes.

In these cases, family history is strong for diabetes. However, obesity does not appear to be a regular feature of this condition, and insulin sensitivity is normal. A defect in first phase insulin release is associated with atypical diabetes mellitus, and the typical immunological profile found in patients with type 1 diabetes is absent.

Maturity Onset Diabetes of Youth
In 1974, the acronym MODY was created by Tattersall and Fajans to describe a mild form of diabetes that had largely gone forgotten after the discovery of insulin but was "rediscovered" following the development of oral hypoglycemic agents in the 1950s.7 After a quarter century of further investigation, we know that MODY encompasses an expanding group of specific genetic defects of beta.gif (968 bytes)-cell function. Depending on location, the relative incidence of all forms of MODY ranges between 2 and 5% compared to all other forms of type 2 diabetes.8 As a group of disorders, MODY is clinically and genetically heterogeneous.9 Clinicians unfamiliar with the term often misapply it to any child or adolescent with a noninsulin-requiring form of diabetes.

There are mutations defined in five proteins involved with the control of insulin secretion or sensitivity that characterize the known MODY subtypes. MODY 13 have fairly well-defined clinical presentations. MODY 4 is rare and has an average age of onset in middle life. MODY 5 has only been described in two Japanese families. A new MODY subtype has been recently described.10

The presenting feature of MODY is mild, occasional fasting hyperglycemia in a lean child with a prominent family history of glucose intolerance in multiple (at least three) generations. In most cases, MODY evolves slowly into overt diabetes. Clinical presentations vary according to the nature of the genetic lesion. MODY, when clinically diagnosed, can now be defined through genetic testing, but only in research laboratories. Several recent reviews have summarized the current understanding of MODY.9,11-14

Other Genetic Defects in Insulin Action
A partial list of the genetic defects in insulin action include a number of well described conditions including Type A insulin resistance, Leprechaunism, Rabson-Mendenhall syndrome, and the Lipoatrophic syndromes. The clinical course of mutations in the insulin gene has been described in several kindreds. In the cases examined so far, affected children are generally asymptomatic, and glucose intolerance or mild diabetes does not occur until adulthood. Although these conditions are often diagnosed in youth, they will not be discussed further due their extremely low prevalence.

Diseases of the Exocrine Pancreas
Secondary diabetes in adolescence as a result of cystic fibrosis (CF) deserves special mention. As therapies for CF extend the longevity of children with this disease, the rate of glucose intolerance and overt diabetes has increased.

Therapy for CF diabetes requires special attention to patients' nutritional needs, since daily caloric intake is increased to offset diminished intestinal absorption, even with proper enzyme replacement therapy. Because the impairment in glucose tolerance stems from insulinopenia due to diminished functional pancreatic mass (impacting exocrine and endocrine functions), the only effective pharmacological agent available for glucose control is insulin.

Since extinction of all functional beta.gif (968 bytes)-cell activity is gradual, the quality of glycemic control is often better than in children with type 1 diabetes of comparable duration. Problems frequently encountered in this population include depression and increased nonadherence. Coordinated management by the diabetes and CF teams is strongly indicated.

EPIDEMIOLOGY AND RISK FACTORS

The remainder of this article will focus on type 2 diabetes associated with insulin resistance and its co-morbidities. Children and adolescents of predominantly American Indian, Hispanic, African-American, and Asian origin display increasing prevalence of type 2 diabetes.15-18 In every population studied, increasing incidence parallels increasing rates of childhood obesity. In an area of South Texas known to have a high risk of type 2 diabetes in Mexican-American adults,19 the incidence of undiagnosed type 2 diabetes in a middle school population was determined to be 1% (William J. Riley, personal communication). All of these children were obese at the time of diagnosis. Type 2 diabetes in children is on the rise worldwide. Increasing incidence figures have been reported in Japanese, Canadian, Australian, and Libyan children.20-22 The general consensus is that the combination of increased caloric intake combined with diminishing levels of physical activity is the most likely explanation. However, these lifestyle-related factors require a foundation of insulin resistance for disease expression.

Obesity is the sentinel risk factor for type 2 diabetes in adolescents as well as in adults. Obesity is well known to have a strong familial tendency. If both parents are obese, the risk of having offspring with obesity is ~ 66%. This falls to a 50% risk for obesity if only one parent is obese. However, if neither parent is overweight, the risk is only 9% for having an obese offspring. Identical twins are highly likely to have adult weights that are similar, even if raised separately.

Genetic factors aside, reason dictates that the sudden increased incidence in child and adolescent obesity is largely due to changes in the living environment. The lifestyle of most children who develop type 2 diabetes is a study in poor nutritional habits and sedentary activity levels. This was recently illustrated in a study by the Kaiser Family Foundation, which reported that the typical child spends more than 38 hours a week using electronic media outside of school.23

Many parents lack good nutritional information regarding what foods to feed their children. Parents obtain much of their practical nutritional information from various forms of media (television, radio, and print advertising). In a typical American household, over 10,000 food advertisements are viewed each year. Virtually all of these enticing food messages provide poorly balanced nutritional information and are aimed at increasing sales and consumption. Nutrition education is not taught in primary or secondary schools and is often minimally addressed (if at all) in most medical school curricula. In fact, school lunch menus are notoriously high in fat and concentrated sugars. It is easy to see how the constant bombardment of commercial food messages pass with minimal to no rebuttal to children and their parents, most of whom were brought up with similar messages.

In the past two decades, children have grown up in an era of enhanced portion size (e.g., SuperSize ™, Big Gulp ™. Due to the relative abundance, drive-through convenience, low cost (compared to conventional restaurants), and aggressive marketing strategies of fast-food restaurants, ~ 7% of the American population eats fast food on any given day. A typical fast food meal has a plethora of calories from processed sugars and is often high in fat and low in fiber.

Even if a family chooses to eat at home, fewer working parents have the time or energy to prepare a full meal from scratch. Consequently, preprocessed "fast food equivalents" can be purchased at any grocery store.

Food is also at the center of most cultural and secular celebrations. Rewards for desired behaviors are often food-based. The concept that "a fat baby is a healthy baby" is alive and well in the minds of many families.

Physical activity in children is on a steady decline. More children are living in single-parent or dual-working-parent households than ever before, resulting in an increase in "latchkey" children.

Typically, these children are entertained electronically by television or computer games. In the United States, 53% of children 2–18 years of age have a television set in their bedroom.23 Upon returning from school, children may retire for several hours of television viewing and snacking until bedtime.

Quality after-school programs that encourage physical activity are difficult to find and are often too costly for some parents. Fewer children walk or ride a bicycle to school than in the past because their neighborhoods may be considered unsafe. Sadly, more schools are cutting back on expenditures for physical education classes and after-school programs.

Obesity, family history, female gender, puberty, and a history of low birth weight appear to be the significant risk factors for type 2 diabetes in adolescents. A family history of diabetes is found in a first- or second-degree relative in 75–100% of cases. There is a slightly higher frequency of type 2 diabetes in females, which holds equally true in adults and children. Although type 2 diabetes can occur in preschool-aged children, at this time most cases are diagnosed around the time of normal puberty with most diagnoses occurring between 12 and 16 years of age.

There is growing evidence around the world in support of the thrifty phenotype hypothesis.24-27 Poor nutrition in fetal and infant life is believed to impair the normal development and function of beta.gif (968 bytes)-cells as well as insulin-responsive tissues, primarily skeletal muscle. This may contribute to the development of insulin resistance. An association between maternal diabetes, high (> 4.5 kg) as well as low birth weights (< 2.5 kg) and later development of diabetes has been reported in Pima Indians, suggesting that maternal diabetes and elevated birth weight influence development of insulin resistance much as fetal undernutrition does.

SCOPE OF THE PROBLEM

Clinicians must always keep in mind that diabetes is only one manifestation of the insulin resistance syndrome. If fact, it is often a late event relative to the other known morbidities of hyperinsulinemia. Hypertension, dyslipidemia, and menstrual irregularities are all known consequences of chronic hyperinsulinemia. Secondary morbidities include morbid obesity, orthopedic problems, depression, and obstructive sleep apnea. The recognition of acanthosis nigricans as a proxy for insulin resistance has given rise to the use of this dermatological condition as a tool for identifying patients at risk for developing type 2 diabetes.28

Hypertension
Hyperinsulinemia and obesity contribute to the early development of hypertension. Commonly, systolic pressure is elevated to a greater extent than diastolic, but eventually both pressures may be significantly elevated if obesity is not reduced. Proper cuff selection is important since the use of an undersized cuff will often result in falsely elevated pressures.

Hypertension commonly precedes the development of diabetes in children with insulin resistance. The precise pathophysiology has yet to be fully elucidated.29

Table 1. Blood Pressure Levels for the 90th and 95th Percentile of Blood Pressure for Boys 1 –17 Years of Age by Percentiles of Height
Systolic BP (mm Hg)
by percentile of height

Diastolic BP (mm Hg)
by percentile of height

Age (yr) %ile 5% 10% 25% 50% 75% 90% 95% 5% 10% 25% 50% 75% 90% 95%
1 90th
95th
94
98
95
99
97
101
99
103
101
105
102
106
103
107
  49
54
49
54
50
55
51
56
52
57
53
58
54
58
2 90th
95th
98
101
99
103
101
105
103
107
104
108
106
110
107
110
54
58
54
59
55
60
56
61
57
62
58
63
58
63
3 90th
95th
101
105
102
106
103
107
105
109
107
111
109
112
109
113
59
63
59
63
60
64
61
65
62
66
63
67
63
68
4 90th
95th
103
107
104
108
105
109
107
111
109
113
110
114
111
115
63
67
63
68
64
68
65
69
66
70
67
71
67
72
5 90th
95th
104
108
105
109
107
111
109
113
111
114
112
116
113
117
66
71
67
71
68
72
69
73
69
74
70
75
71
76
6 90th
95th
105
109
106
110
108
112
110
114
112
116
113
117
114
118
70
74
70
75
71
75
72
76
73
77
74
78
74
79
7 90th
95th
106
110
107
111
109
113
111
115
113
117
114
118
115
119
72
77
73
77
73
78
74
79
75
80
76
81
77
81
8 90th
95th
108
112
109
113
110
114
112
116
114
118
116
119
116
120
74
79
75
79
75
80
76
81
77
82
78
83
79
83
9 90th
95th
109
113
110
114
112
116
114
118
116
119
117
121
118
122
76
80
76
81
77
81
78
82
79
83
80
84
80
85
10 90th
95th
111
115
112
116
113
117
115
119
117
121
119
123
119
123
77
81
77
82
78
83
79
83
80
84
81
85
81
86
11 90th
95th
113
117
114
118
115
119
117
121
119
123
121
125
121
125
77
82
78
82
79
83
80
84
81
85
81
86
82
87
12 90th
95th
115
119
116
120
118
122
120
124
121
125
123
127
124
128
78
83
78
83
79
84
80
85
81
86
82
87
83
87
13 90th
95th
   118
121
119
122
120
124
122
126
124
128
125
129
126
130
78
83
79
83
80
84
81
85
81
86
82
87
83
88
14 90th
95th
   120
124
121
125
123
127
125
129
127
131
128
132
129
133
79
83
79
84
80
85
81
86
82
87
83
87
83
88
15 90th
95th
  123
127
124
128
126
130
128
132
130
133
131
135
132
136
80
84
80
85
81
86
82
86
83
87
84
88
84
89
16 90th
95th
  126
130
127
131
129
133
131
134
132
136
134
138
134
138
81
86
82
86
82
87
83
88
84
89
85
90
86
90
17 90th
95th
128
132
129
133
131
135
133
137
135
139
136
140
137
141
83
88
84
88
85
89
86
90
87
91
87
92
88
93

Untreated hypertension increases the risk of early atherosclerotic injury and should be managed by exercise, proper nutrition, and weight loss. Unfortunately, these are the behavior changes that are most difficult to implement, which is why antihypertensive agents are often prescribed. The treatment threshold of 140/90 is recommended for adults with diabetes. However, for children and adolescents, clinicians should use age- and sex-specific values for determining when to institute pharmacological therapy (Tables 1 and 2).30

Table 2. Blood Pressure Levels for the 90th and 95th Percentile of Blood Pressure for Girls 1 –17 Years of Age by Percentiles of Height
Systolic BP (mm Hg)
by percentile of height

Diastolic BP (mm Hg)
by percentile of height

Age (yr) %ile 5% 10% 25% 50% 75% 90% 95% 5% 10% 25% 50% 75% 90% 95%
1 90th
95th
98
101
98
102
99
103
101
104
102
106
103
107
104
108
  52
56
52
56
53
57
53
58
54
58
55
59
55
60
2 90th
95th
99
103
99
103
101
104
102
106
103
107
104
108
105
109
57
61
57
61
58
62
58
62
59
63
60
64
60
64
3 90th
95th
100
104
101
104
102
106
103
107
104
108
105
109
106
110
61
65
61
65
61
66
62
66
63
67
64
68
64
68
4 90th
95th
101
105
102
106
103
107
104
108
106
109
107
111
108
111
64
68
64
68
65
69
65
69
66
70
67
71
67
71
5 90th
95th
103
107
103
107
105
108
106
110
107
111
108
112
109
113
66
71
67
71
67
71
68
72
69
73
69
74
70
74
6 90th
95th
104
108
105
109
106
110
107
111
109
113
110
114
111
114
69
73
69
73
69
74
70
74
71
75
72
76
72
76
7 90th
95th
106
110
107
111
108
112
109
113
110
114
112
115
112
116
71
75
71
75
71
75
72
76
73
77
74
78
74
78
8 90th
95th
108
112
109
113
110
114
111
115
112
116
114
117
114
118
72
76
72
77
73
77
74
78
74
79
75
79
76
80
9 90th
95th
110
114
111
115
112
116
113
117
114
118
116
119
116
120
74
78
74
78
74
79
75
79
76
80
77
81
77
81
10 90th
95th
112
116
113
117
114
118
115
119
116
120
118
122
118
122
75
79
75
79
76
80
77
81
77
81
78
82
78
83
11 90th
95th
114
118
115
119
116
120
117
121
119
122
120
124
120
124
76
81
77
81
77
81
78
82
79
83
79
83
80
84
12 90th
95th
116
120
117
121
118
122
119
123
121
125
122
126
123
126
78
82
78
82
78
82
79
83
80
84
81
85
81
85
13 90th
95th
  118
122
119
123
120
124
121
125
123
126
124
128
124
128
79
83
79
83
79
84
80
84
81
85
82
86
82
86
14 90th
95th
  120
124
121
125
122
126
123
127
124
128
125
129
126
130
80
84
80
84
80
85
81
85
82
86
83
87
83
87
15 90th
95th
  121
125
122
126
123
127
124
128
126
130
127
131
128
131
80
85
81
85
81
85
82
86
83
87
83
88
84
88
16 90th
95th
  122
126
123
127
124
128
125
129
127
130
128
132
129
132
81
85
81
85
82
85
82
87
83
87
84
88
84
88
17 90th
95th
123
127
123
127
124
128
126
130
127
131
128
132
129
133
81
85
81
86
82
86
83
87
83
88
84
88
85
89

Because of concerns for protecting intra-glomerular pressure and reducing the risk of development of microalbuminuria, angiotensin-converting enzyme (ACE) inhibitors are considered first-line therapeutic agents under most circumstances. Calcium-channel blockers, diuretics, and central alpha agonists are also effective if side effects to ACE inhibitors are problematic or if satisfactory control is not achieved with this class of drugs. No ACE inhibitor has been shown to be clearly superior, so cost and dosing frequency usually determine choice of agent. Combination therapy may be necessary if adequate blood pressure control cannot be achieved with monotherapy.

Lipids
The same changes in lipid metabolism seen in adults with type 2 diabetes and insulin resistance occur in adolescents. Decreases in the HDL cholesterol fraction and increases in serum triglyceride levels are commonly seen.

Serum triglyceride levels >1,000 mg/dl are associated with an increased risk of pancreatitis and must be treated pharmacologically. In most cases, following appropriate analysis of the fasting lipid levels, nutritional counseling and an exercise prescription should be the first-line therapy. Nutritional recommendations should include a reduction in intake of saturated and polyunsaturated fat with an increase in intake of monounsaturated fats. Less than 30% of total calories should come from fat. Carbohydrates should compose between 50 and 60% of the total daily caloric intake. Blood glucose control using either insulin or oral agents often results in a reduction in triglyceride levels.

If first-line therapy is unsuccessful (fasting triglycerides >400 mg/dl), then pharmacological management is indicated. Due to its role as a risk factor for cardiovascular disease, aggressive management of hyperlipidemia is indicated, even in the absence of diabetes. In the case of an insulin-resistant child with hypertriglyceridemia, treatment with metformin or a thiazolidinedione may help. Unfortunately, recent reports of hepatic toxicity have curtailed the use of this latter class of agents. When hypertriglyceridemia is the primary disturbance, gemfibrozil is an effective first line agent.

If persistent hypercholesterolemia is a significant problem (primarily elevation in low-density lipoprotein [LDL] cholesterol) a staged dietary approach (i.e., Step I and Step II dietary intervention programs) is to be followed as recommended in the 1998 American Academy of Pediatrics Position Statement on Cholesterol in Childhood.31 If satisfactory control is not achieved, then bile-acid sequestrants or HMG CoA reductase inhibitors (statins) are recommended. However, statins are contraindicated in pregnancy, making it imperative to ensure that any adolescent female treated with this class of agents is using effective contraceptives.

Menstrual Problems
Menstrual irregularities (typically oligomenorrhea) secondary to hyperinsulinism are common.32 Ovarian hyperandrogenism secondary to chronic hyperinsulinemia describes the pathophysiology of the polycystic ovarian syndrome (PCOS).

An oral contraceptive agent (OCA) with low androgenic activity is preferred for reducing ovarian androgen output by suppressing gonadotropin secretion and normalizing menstrual cycles. Treatment with an insulin sensitizer (metformin or a thiazolidinedione) can also increase menstrual regularity but results in an increased risk for pregnancy in sexually active teens. OCAs and insulin sensitizers appear to be synergistic in the treatment of PCOS and are often used in tandem. Whether or not an OCA is used, contraceptive counseling is strongly indicated in teens.

Obesity
Insulin resistance contributes to the development of obesity. Obesity further exacerbates insulin resistance. Elevated plasma insulin levels have a stimulatory effect on appetite either directly or indirectly through anabolic mechanisms. While the insulin sensitivity of skeletal muscle and the liver is diminished, the insulin response of the adipocyte is relatively spared. Therefore, excess net caloric intake is associated with a brisk expansion of total body fat mass that often seems to begin in the preschool years. As obesity progresses, it leads to diminished exercise tolerance, reducing caloric expenditure relative to intake and resulting in further weight gain.

The insulin resistance of puberty further diminishes insulin response and places an even heavier demand on beta.gif (968 bytes)-cell insulin production. Intrinsic defects in beta.gif (968 bytes)-cell physiology combined with peripheral insulin resistance result in postprandial hyperglycemia and finally in fasting hyperglycemia and overt diabetes.

Psychological Issues
Many societies view overweight individuals in an unfavorable light. These biases include the belief that obese individuals lack self control, possess a tendency towards slovenliness, have jovial demeanors, and have lower intelligence. Overweight adults have lower incomes, perhaps as a result of fewer opportunities for advancement compared to their lean counterparts.

Overweight children may be relentlessly teased and harassed, resulting in reduced self esteem and, in many instances, leading to signs of clinical depression. The social burden of obesity in childhood may have lasting effects on self-esteem, body image, and economic mobility.33 Clinicians must be aware of this possibility when working with an overweight child and family. Appropriate evaluation and therapy for affective disorders can have beneficial effects on weight and glycemic control.

Sleep Apnea
With the rise in obesity also comes an increase in the incidence of obstructive sleep apnea (OSA). Much like type 2 diabetes, OSA was felt to be relatively uncommon in children 20 years ago. However, recent reports indicate a significant rise in the incidence of OSA.34

Many primary care providers and specialists have been slow to recognize this problem. OSA is commonly misdiagnosed as attention deficit disorder (ADD), and many sleep apneic children are inappropriately placed on pharmacological therapy for ADD.

The diagnosis of OSA should be considered in any obese child if there is loud breathing at night (snoring), plus any of the following: daytime somnolence (consistently falls asleep on short trips, falls asleep in class), enuresis, restless sleep, headache upon awakening, or a family history of OSA. Referral to a sleep disorder specialist for a formal sleep study is indicated.

Untreated OSA can be a major obstacle to effective weight management and compliance with any activity prescription. Chronic sleep deficit is known to result in decreased carbohydrate tolerance and increased sympathetic tone in adults, contributing to an increased risk for the development of diabetes.35

Acanthosis Nigricans
Acanthosis nigricans (AN), a dark, rough thickening of the skin on areas exposed to repeated flexion or friction, is now recognized as a cutaneous marker for hyperinsulinism in children. Histologically, AN is characterized by papillomatosis and hyperkeratosis with hyperplasia of all dermal layers.36 Because of its ease of recognition along the neckline, acanthosis nigricans is a useful clinical tool for detecting individuals with chronic hyperinsulinemia. Obese children as young as 20 months of age have been observed with this skin lesion in our center (SWP, personal observation).

Parents and even many health professionals often view AN strictly as a cosmetic problem and limit their therapeutic efforts to vigorous cleansing or application of various topical agents. When questioned, parents commonly believe that AN is due to poor hygiene.

For those patients who wish to attempt a cosmetic therapy for this problem, topical tretinoin 0.1 % gel applied twice daily for 2 weeks has been reported to be effective.37

In September 1999, the Texas state legislature mandated that school districts in nine Texas-Mexico border counties that have endemic type 2 diabetes to begin a nurse-directed AN screening program with physician referral for diabetes evaluation.38

INTERVENTIONS

Once properly diagnosed, type 2 diabetes in children should be treated with the following goals:

  1. Weight control and/or weight reduction
  2. Maintenance of normal physical growth
  3. Near-normal fasting blood glucose (<126 mg/dl)
  4. Near-normal glycosylated hemoglobin (< 7%)
  5. Effective treatment of co-morbid problems (i.e., hypertension, dyslipidemia)
  6. Prevention of complications
  7. Maintenance of emotional well- being

The principles of managing children with type 2 diabetes include:

  1. Diabetes self-management education
  2. Medical nutrition therapy
  3. Exercise prescription
  4. Pharmacological management
  5. Psychosocial considerations

Diabetes Self-Management Education
As in adults with type 2 diabetes, adolescents may be able to effectively manage this condition with lifestyle adjustments focused on choice and amount of foods ingested combined with increased physical activity. One major therapeutic goal should be maintenance of a desirable body weight. As in adults, minor reductions in weight can have dramatic results on glucose tolerance. This underscores the value of frequent access to a diabetes team that can assess, prescribe, and assist in the implementation of these children's care plans.

Since minority youth are disproportionately affected, socioeconomic factors may limit access to the same diabetes education and care that children with type 1 diabetes receive. The obstacles to optimal diabetes education and care in this special population include cultural and language barriers, lack of adequate health insurance coverage, and geographic barriers to qualified diabetes care providers.39

One particularly challenging problem in South Texas is a pervasive fatalism in the Mexican-American community, which results in a reduced adherence to treatment recommendations. Ultimately, this belief may lead to increased morbidity and mortality, which then becomes a self-fulfilling prophecy.

As with anyone with diabetes, teens with type 2 diabetes should regularly monitor blood glucose at home to assess the quality of their control. It is well known that many adolescents are poorly adherent with this self-care behavior, regardless of the nature of their diabetes. Clinicians should spend quality "face time" with teens to explain and emphasize the value of blood glucose self-monitoring.

Reviewing the monitoring data in the presence of teenage patients is a powerful illustration of its value and validates the effort the teens have made in obtaining the information. A cursory or cavalier review of the blood glucose log is a strong disincentive for teens to continuing this self-care behavior. Ongoing diabetes education provided by a certified diabetes educator can guide teens through the proper use of these data and is the best approach to promote adherence with this aspect of the self care regimen.

Since ketosis is a possible consequence for some teens with type 2 diabetes, it is imperative that proper education for sick-day care and ketosis management be provided, as it is for children with type 1 diabetes.

Smoking cessation is essential since tobacco use magnifies the risk for long-term micro- and macrovascular complications and aggravates co-morbid problems (e.g., hypertension). Teens with type 2 diabetes who abuse alcohol would also be expected to have a greater risk of nonadherence. Substance abuse is difficult to ascertain without a thorough understanding of a teen's social environment and family background.

Medical Nutritional Therapy
As in adults, weight reduction in obese adolescents with type 2 diabetes can be associated with significant improvement in glycemic control. Weight reduction also improves insulin sensitivity and may delay or prevent the onset of type 2 diabetes in individuals at risk. This makes weight control a primary goal of therapy.

Overall, the goals of medical nutrition therapy (MNT) for adolescents with type 2 diabetes are similar to those for adults, with some caveats. MNT should be targeted at maintaining balanced nutrition and promoting normal linear growth, while depleting fat stores. Depending on the age of the child, there may be remaining linear growth that may be impaired if nutritional intake were severely restricted (i.e., <1,200 kcal/day).

Some adolescents with type 2 diabetes may still undergo the pubertal growth spurt and will need additional caloric intake during puberty. Hyperinsulinemic children are tall for their chronological age and have mildly advanced skeletal and secondary sexual maturation for age. The state of hypernutrition that accompanies the hyperinsulinemic state increases free IGF-1 binding by reducing the circulating level of IGF binding proteins.40,41 Diminished metabolic control is common during this period unless medical and nutrition management is adjusted to offset puberty's effect on glycemic control. This is an age when regular physical activity should be strongly encouraged.

Although target weight can be useful, it should never be used as a goal for children. Instead, an overall plan to reduce intake and increase physical activity should be implemented.42 An experienced pediatric dietitian should provide MNT.

Strategies for weight management
Nutritional education is a cornerstone of therapy for children with type 2 diabetes. Often, these children come from a home environment with a poor understanding of healthy eating habits. Commonly reported behaviors include skipping meals, heavy snacking, and excessive television/video game/computer involvement. Like many adults, adolescents engage in nonappetite-based eating (i.e., emotional eating, television-cued eating, boredom) and on and off ("yo-yo") dieting.

Adolescents and their families must be encouraged to consistently make better food choices. This begins by teaching parents what foods to bring home and how to plan meals and snacks. Although most experts believe children are able to self-regulate eating, one must consider that adolescents with type 2 diabetes may have lost this ability and may lack parental involvement to support effective behavior change. Behavior modification should start by helping children recognize eating cues and satiety factors. Parents can help by learning appropriate serving sizes for children.

Changing food habits is one of the most challenging aspects of care and demands regular follow-up with an experienced pediatric dietitian. Infrequent visits are associated with a high probability of continued weight gain.

Probably the most overlooked aspect of weight management is determining when a child, teen, and family is ready to change. There are many types of readiness-to-change questionnaires. The most basic tool is to just ask. Readiness and motivation can change at any point for the better or worse. Level of commitment should be addressed at each visit.

Discussing the insulin resistance syndrome with an obese adolescent can be challenging and at times frustrating. A thorough explanation of this condition, with all its attendant risks, is needed if a child and family are to be expected to make the lifestyle changes. In the absence of overt diabetes, clinicians will have to identify other factors to motivate adolescents toward change. Based on individual assessment, this may include an appeal to improve athletic performance or academic scores (especially if OSA is present), or even for cosmetic reasons.

If a child does not have diabetes but has significant risk factors and is unwilling to make change despite all efforts to explain the risks, then it is unwise to compel the child to embark on a weight management program. In these cases, encourage routine follow-up to assess for glucose intolerance and suggest that the child or family return when they are willing to change.

Most successful weight management programs focus on behavior change and de-emphasize weight loss as an outcome. One should avoid using the term "diet" when discussing changes in food choices. Such a term implies a temporary solution and not a life-long change.43

Clinicians should start slowly, trying to focus on two or three behavior change goals to work on for each visit. If clinicians advocate a comprehensive change in an adolescent's eating behaviors, it only serves to discourage the teen and family, thus limiting adherence in other areas of self-management.

Most families will request a very detailed and structured diet, including a list of "yes" and "no" foods. Resist this temptation. Setting small, easily achievable goals for eating, including physical activity, lowering the contribution of calories from fat, limiting high-density carbohydrate foods and drinks, and using foods with higher fiber and water content should be a part of the nutrition education. A positive, "can-do" attitude, combined with regular follow-up visits can have a significant impact on slowing the rate of weight gain and can even facilitate weight loss.

The foundations of all treatments for obesity are a reduction of total daily caloric intake and enhanced caloric expenditure. In the case of insulin resistant teens, the emphasis should be to get children and families to see insulin resistance as a life-long process to manage through permanent lifestyle modification.

Use of appetite suppressants should be discouraged. Recent adverse outcomes with fenfluramine illustrate the potential problems with agents that affect appetite control. Furthermore, no class of anorectic agent is approved for use in children or adolescents.

Exercise Prescription
Most overweight children with type 2 diabetes have diminished exercise tolerance. A contributing factor is the lack of physical education in schools. Getting adolescents to engage in physical activity takes an understanding of what each child considers "acceptable." An overly ambitious exercise prescription can result in poor adherence and frustrate teens and their families.

For most inactive teens, walking is a good start. If there is an activity a child enjoys, such as dancing, skating, or a team sport, this can also be used. Keep in mind that one of the most common reasons given by teens for not exercising is not wanting to sweat. Work with each child, and come to a mutual agreement on the type and amount of activity.

Exercise must be started slowly (3 times a week) and for short periods of time (15–20 minutes) to build tolerance. The goal is to develop a healthy pattern of regular physical activity, not a competitive athlete. Parents or other family members should be encouraged to participate. This will help the entire family adopt a healthier lifestyle and improve adherence in most cases. The key to a successful exercise program for children, as for adults, is to engage in an enjoyable activity. As children develop greater exercise tolerance, encourage increasing the duration and intensity of their physician activity.

Pharmacological Management
Until recently, all pharmacological therapies for type 2 diabetes in children have formally gone untested. Consequently, pediatric endocrinologists have had to use many of these agents off-label to manage adolescents with type 2 diabetes. Clinical trials using all currently available pharmacological agents are needed to develop consistently effective treatment plans for these children. Furthermore, all new agents under consideration for Food and Drug Administration (FDA) approval should include evaluation of use in children with type 2 diabetes.

The guiding principles in choosing a pharmacological agent for managing type 2 diabetes in children and adolescents should be:

  • safety
  • effectiveness
  • ease of administration
  • cost

The only universally accepted pharmacological agent available for type 2 diabetes in children is insulin. Unfortunately, although optimal glycemic control can be obtained with insulin therapy, it often results in significant weight gain. At the time of diagnosis and depending on presentation, insulin therapy may be necessary, but with close medical follow-up it can often be reduced, substituted, or even discontinued within a few weeks, after glucose control is achieved.

The presence of DKA at diagnosis is not pathognomonic for type 1 diabetes in an overweight child. If the suspicion of type 2 diabetes is raised in this situation, treatment for type 1 diabetes should be continued until the diagnosis is confirmed by the constellation of physical features (e.g., obesity, acanthosis nigricans), clinical course, family history, and absence of appropriate serum autoimmune markers.

One effective therapy is to initiate insulin management and concomitant oral therapy with metformin once a patient is nonacidotic and well hydrated. The starting dose of metformin is usually 500 mg, twice daily with meals. Metformin is contraindicated if there is significant renal or liver impairment. Therefore, proper assessment of liver and renal function is essential before initiating therapy.

Often, teens with insulin resistance show mild elevations in hepatic transaminases (two times the upper limit of normal), which usually indicate the presence of fatty liver. This is not a contraindication for metformin use. However, since metformin is not approved for pediatric use, caution must be used and consultation with a gastroenterologist may be needed to eliminate the possibility of another reason for elevation in liver transaminases that would prohibit use of metformin (e.g., hepatitis). Caution should also be used if alcohol use, including binge drinking is suspected.

If a patient is only mildly hyperglycemic at diagnosis and is not acidotic or dehydrated, then metformin may be introduced as monotherapy along with diabetes self-management education and nutritional and exercise therapy. Close follow-up of metabolic control is needed to assure effectiveness.

Metformin may cause transient diarrhea or abdominal discomfort, which usually passes within a few days. If symptoms persist beyond a week, the medication should be discontinued and other therapy considered, or the dose should be lowered to once daily until side effects are tolerated, at which time the dose can then be increased. It is important that the medication be taken with meals to minimize the risk of abdominal discomfort. A typical effective regimen consists of between 500–1,000 mg taken orally twice a day.

One added benefit noted by many endocrinologists is the reduction in weight gain, and in fact weight loss with good glycemic control may occur. When asked, many teens on metformin report a diminished appetite for second portions not associated with abdominal discomfort or nausea.

Metformin acts to enhance the effect of endogenous insulin. The low risk of developing hypoglycemia in people taking metformin makes it highly desirable as a therapeutic agent. Its compatibility with all other oral agents, as well as insulin, is now well established.44 The risk of developing lactic acidosis, although exceedingly rare, makes it imperative to educate patients on the signs and symptoms of this particular complication, plus under what circumstances the medication should be withheld and replaced with insulin therapy (e.g., use of radiocontrast materials, severe dehydration, and renal impairment). Despite these potential problems, the risk-to-benefit ratio is clearly in favor of considering the use of metformin with proper monitoring of efficacy.

Repaglinide is a short-acting agent that enhances short-term glucose-stimulated insulin secretion. Designed to be taken with meals, it has been shown to be highly effective in adults, both as monotherapy and in combination with metformin. It can also be an effective agent in teens with type 2 diabetes, but adherence may be affected by the necessity to take medication with each meal. Our center has had success with repaglinide in combination with metformin, when metformin alone was ineffective in maintaining adequate glycemic control (unpublished observations). The lower formulation of 0.5 mg per dose is often sufficient to establish effective glycemic control, especially when combined with metformin.

Thiazolidinediones have been available for several years. Troglitazone [withdrawn from the U.S. market at press time] has been used successfully as monotherapy in adults. However, it is no longer indicated for such use by the FDA. Its cost is relatively high, but a major advantage is its option for once-daily dosing. Full effect may take up to 6 weeks to occur. Unfortunately, recent reports of idiosyncratic hepatic injury have tempered its use in adults and dramatically reduced interest in its use in children. Nevertheless, it still remains a highly effective agent, but requires regular monitoring of liver function during its use.

Newer thiazolidinediones have recently been introduced (rosiglitazone, pioglitazone), but their effectiveness in adolescents with type 2 diabetes has not yet been assessed. These agents are thought to possess less potential for hepatic injury, but regular assessments of liver functions are still recommended.

Acarbose and miglitol are both alpha-glucosidase inhibitors that antagonize the hydrolysis of complex carbohydrates, hence slowing the delivery of glucose into the portal circulation. Agents of this class have been utilized as effective monotherapy in adults. Their use in all age groups is affected by gastrointestinal side effects (bloating, flatulence), which understandably limits their effectiveness in an adolescent population. Aside from these side effects, they require a higher degree of adherence and do not address the issue of insulin resistance directly.

Oral hypoglycemic agents (sulfonylureas) act to increase insulin secretion. As a class, these agents have rapidly become second- or third-line therapies in the management of type 2 diabetes in adolescents. The risk of hypoglycemia is greater compared to the newer available drugs mentioned above. However, these drugs often have an advantage of being less expensive than the newer agents.

Use of first-generation sulfonylureas is increasing as a direct impact of managed care use of formularies for cost-cutting considerations. There is an increased risk of side effects with first-generation compared to second-generation sulfonylureas. Most pediatric diabetologists avoid using first-generation sulfonylureas.

Psychosocial Considerations
Adolescence is well known to be characterized by diminished adherence to medical regimens and increases in risk-taking behaviors. This problem is compounded by the focus on short-term rather than long-term goals typical of many adolescents.

Studies also show that children with type 2 diabetes are more likely to come from lower socioeconomic backgrounds.44 This leads to reduced access to health insurance and quality health care.

Cultural barriers to care may include use of nontraditional medicines or herbal therapies. Parents may be reluctant to comply with insulin therapy due to misconceptions about its connection with increased mortality. Proper education of the family is essential to maximizing adherence to the medical regimen.

Complications
Hypoglycemia, DKA, and hyperosmolar hyperglycemic non-ketotic coma are possible acute complications of type 2 diabetes. Complications from insulin resistance may be present at the time of diagnosis (i.e., hypertension, dyslipidemia) and should be managed aggressively. Regular yearly dilated eye exams are recommended as is annual screening for microalbuminuria. The first screening should occur within the first year of diagnosis, in contrast to recommendations for people with type 1 diabetes (i.e., after 5 years). Proper foot care is a health habit to be promoted early even though the immediate risk to extremities is low. There are no data to indicate that adolescents with type 2 diabetes develop significant peripheral vascular disease during their teen years, but peripheral neuropathy is possible in this group.

Prevention
The Diabetes Prevention Program (DPP) is currently in progress and should be completed in a few years. This study asks the question: can type 2 diabetes be prevented? It is investigating the role of nonpharmacological (lifestyle modification only) and pharmacological intervention (metformin) on the rate of development of type 2 diabetes in adults considered at imminent risk. Until the results of this study are available, no prospective data will be available to validate diabetes prevention efforts.

Unfortunately, children and adolescents were not included as part of this study. Nevertheless, the basic premise of the study (weight reduction and improvement of insulin sensitivity to reduce the rate of development of type 2 diabetes) should be considered a desirable goal for all at-risk teens and younger children. Further investigation will be required to develop effective protocols in at-risk youth.

Summary
Unfortunately, adolescence is now a time when virtually any major clinical type of diabetes can occur. Clinicians must be astute regarding the possibility that an overweight teenager who develops weight loss, polydipsia, and polyuria could have either classic type 1 diabetes or insulin resistant type 2 diabetes.

Type 2 diabetes presenting in adolescence underscores an ominous consequence of the epidemic of childhood obesity in developed countries. With no evidence to indicate a reduction in the incidence of obesity in children, the number of adolescents developing type 2 diabetes will undoubtedly increase in the foreseeable future.

Type 2 diabetes in adolescents and MODY need not be confused. Both have clinical characteristics that should make them easy to separate. Furthermore, MODY is far more uncommon. Judicious use of autoimmune markers for type 1 diabetes aids greatly in differentiating between MODY and the other forms of diabetes that can occur in the first two decades of life.

Evaluation of teens with type 2 diabetes involves a thorough evaluation for co-morbid problems that are a direct consequence of chronic hyperinsulinemia (hypertension, dyslipidemia, menstrual irregularities), or those secondary to obesity (orthopedic problems, obstructive sleep apnea, depression). Treatment of these related problems can significantly improve the quality of management of the diabetes.

The basic tenets of management of type 2 diabetes in teens are similar to those for adults, with a few exceptions. DKA can occur at presentation of type 2 diabetes and mimic type 1 diabetes. However, the clinical and family history combined with physical exam may suggest that type 2 diabetes should be considered. Treatment with insulin may only be needed to manage glucose toxicity at time of diagnosis. Use of a suitable oral agent that enhances insulin response (such as metformin) may be employed.

By consensus and until new research is available, the only effective method to prevent type 2 diabetes in adolescents is to prevent obesity. Given the currently dismal level of accomplishment in obesity prevention in the United States, we are sure to see a continued rise in the diabetes prevalence in teens. Unfortunately, experimental protocols to prevent type 2 diabetes in children and adolescents are nonexistent.


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Stephen W. Ponder MD, CDE, is a profesor of pediatrics and director of the Division of Pediatric Endocrinology, Susan Sullivan RN, CDE, is a pediatric diabetes nurse educator, and Grete McBath RD, LD, CDE, is a pediatric diabetes nutritionist at Driscoll Children's Hospital in Corpus Christi, Tex.


Note of disclosure: Dr. Ponder is a co-investigator in two pharmacological studies funded by Bristol Myers Squib Corporation. The studies involve a drug that is being evaluated as a treatment for type 2 diabetes mellitus in pediatric patients.


Guest Editor

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Jane K. Kadohiro, DrPH, APRN, CDE, is an assistant professor of nursing at the University of Hawaii at Manoa School of Nursing in Honolulu, where her research is in diabetes among adolescents. Dr. Kadohiro served in several capacities for the Hawaii State Department of Health, from public health nurse to chief of the chronic disease and preventive health services branches, before beginning her faculty position in 1991.

In Hawaii, Dr. Kadohiro has been a founding member, past president, or director, and continues to be an active volunteer for the American Diabetes Association (ADA), the Hawaii State Diabetes Control Program, and the Hawaii Association of Diabetes Educators. For the past 18 years, she has been the director for He Ola Ke Keiki, Hawaii's camp for children and teens with diabetes. She has worked closely with colleagues from Asia and the Pacific to develop international camping and other programs for teens with diabetes.

Dr. Kadohiro has been involved in national committees and task forces of the ADA and is currently President, Health Care and Education, for its Pacific Northwest Region. She is a member of the national board of directors of the American Association of Diabetes Educators and is chair of that organization's continuing education committee.


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