The Changing Nature of Diabetes
from Practice Update, Winter 2005
Orit Pinhas-Hamiel, MD, Director, Juvenile Diabetes Center, Maccabi Healthcare Services and the Pediatric Endocrinology and Diabetes Unit, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel.
Philip S. Zeitler, MD, PhD, Associate Professor, Division of Endocrinology and the Barbara Davis Center for Childhood Diabetes, Department of Pediatrics, University of Colorado Health Sciences Center and The Children’s Hospital, Denver.
This article is an excerpt from “Patient Care.”
Until the mid-1990s, children and adolescents with new-onset diabetes were routinely diagnosed with type 1 diabetes mellitus (T1DM). Type 2 diabetes mellitus (T2DM) has historically been associated with aging and obesity. In recent years, however, T2DM has become increasingly common among children and adolescents.1 While prior to 1990, T2DM accounted for up to 3 percent of all new cases of diabetes between ages 10 and 19, more recent data indicate that this percentage has risen to about 40 percent.2 This change in the epidemiology of T2DM among adolescents is now reported in Europe and the Asia-Pacific regions, as well as in the United States.3
Furthermore, the prevalence of T2DM in the pediatric population may be underestimated. First, patients may be not classified correctly. A recent study from Chicago of 814 insulin-treated African American and Hispanic children with onset of diabetes before age 18 years reported that 195 subjects (24 percent) treated with insulin may actually have had early T2DM.4 In addition, data from the National Health and Nutrition Examination Survey III (NHANES III) suggest that up to one third of adults with T2DM are undiagnosed.5 If the same is true for children and adolescents, T2DM may be more common in this age-group than current data indicate. Indeed, in a recent study of obese children, silent T2DM was identified in four percent of obese adolescents at screening.6
To help primary care physicians deal with this growing health problem, we will review current knowledge regarding the epidemiology, risk factors, diagnosis, and treatment of T2DM in children and adolescents. The American Diabetes Association (ADA) has held a consensus conference on T2DM in children, the report of which is available for readers seeking greater detail.7
Risk factors: When Should We Get Suspicious?
Who are the children at risk of developing T2DM? Factors that should raise suspicion include obesity, certain clinical factors, ethnic group, age and gender, and family history.
Obesity
The most prominent clinical risk factor for T2DM in children and adolescents is severe obesity. The average body mass index (BMI) of patients with T2DM in published reports ranges from 35 to 39 kg/m2. A BMI in this range reflects severe obesity in adults and is extremely remarkable in children. About one third of children with T2DM have a BMI greater than 40 kg/m2, indicating morbid obesity, and 17 percent have a BMI greater than 45 kg/m2. Measurement of the waist-to-hip ratio in a representative subgroup of adolescent patients with type 2 disease indicates that obesity in such patients is central (the “apple” shape).8
Despite the strong association between obesity and T2DM, it is important to note that obese children and adolescents have the same risk for T1DM as other children. Since starting insulin treatment in patients with T1DM is critical, the diagnosis of T2DM should be made with caution and only when other supporting clinical, historical, and laboratory information is present.
Clinical Factors
A number of clinical factors should alert the physician to further investigate type of diabetes in a morbidly obese adolescent. Acanthosis nigricans — hyperpigmentation and thickening of the skin into velvety irregular folds in the neck and flexural areas — reflects chronic hyperinsulinemia. It is rare in patients with T1DM but occurs in 60 to 90 percent of adolescents with T2DM. Acanthosis in an obese child with diabetes should therefore prompt consideration of type 2 disease. Obese children and adolescents who have acanthosis but not overt diabetes should be evaluated to exclude the possibility of undiagnosed hyperglycemia.
Hypertension is rare in patients with T1DM at presentation but may occur in 20 to 30 percent of patients with T2DM. The presence of both hypertension and acanthosis strongly suggests hyperinsulinemia. Obese adolescents with hypertension should be checked for symptoms of hyperglycemia and also asked about any family history of T2DM. Consider obtaining fasting glucose and insulin levels or evaluating glucose tolerance in such patients to exclude either undiagnosed diabetes or impaired glucose tolerance.
Ethnic Group
T2DM is more prevalent in certain ethnic groups, including Pima Indians and other Native Americans, First Nation children of Canada, and African Americans, as well as Mexican American and other Hispanics. Nonetheless, ethnicity is not a useful predictive factor in individual cases, since in areas of large Caucasian predominance, most patients will be Caucasian despite their lower specific risk.
Age and Gender
The mean age of adolescents with T2DM ranges from 13-14 years. Rare cases of T2DM among children as young as age five have been reported. Generally, age is not helpful in differentiating between T1DM and T2DM in adolescents. Because of the shape of the two prevalence curves, however, the younger the child, the more likely it is that he has T1DM.
In our series, all patients with T2DM were in puberty (Tanner stage III or greater), though some studies have reported prepubertal cases.2 The age of onset of puberty among obese children is usually earlier than it is among their peers. Since puberty is characterized by relative insulin resistance, it may be an aggravating factor in the appearance of overt T2DM in obese adolescents.
Girls appear to be more susceptible to type 2 disease than boys, with an overall female-to-male ratio of 1.7/1 regardless of race. Since the ratio is based on studies from diabetes centers and not from population screening, however, the gender discrepancy may result from a higher proportion of undiagnosed cases among boys caused by the known lower frequency of medical visits among adolescent males compared to females.
Family History
Adolescents with T2DM generally come from families in which the parents are also obese and tend to have insulin resistance or overt T2DM. In published series, 60 to 80 percent of patients have had a family history of type 2 disease in one first-degree relative. Moreover, otherwise healthy siblings of patients with T2DM have been found to have elevated levels of C peptide and proinsulin, both of which are associated with a high risk of developing T2DM, and first-degree family members have turned out to have “undiagnosed diabetes” on subsequent evaluation.
Once a young proband has been identified, other family members should be screened for insulin resistance or overt diabetes. Families with T2DM should be differentiated, however, from families with maturity-onset diabetes of the young, which is an autosomal disorder associated with relatively mild hyperglycemia, but not necessarily obesity.
History Of Diabetes During Pregnancy
Recent reports indicate that being born to a mother with diabetes, irrespective of diabetes type and including gestational diabetes, is a significant risk factor for the development of early-onset diabetes in adolescence. Indeed, among Pima Indians, being the product of a pregnancy complicated by diabetes was the strongest risk factor for development of T2DM in offspring9 Similar results are now appearing in other populations and will likely prove to be generally true.10 The mechanism behind this effect has not been elucidated.
Presentation: What Does T2DM Look Like?
Because there is significant overlap in the initial presentation of T1DM and T2DM in children and adolescents, presenting symptoms are not diagnostically reliable. Considering the presentation can provide some insight into the likely etiology, however.
In general, patients with T2DM present with signs of chronic hyperglycemia, while patients with T1DM are more likely to present with acute metabolic decompensation. About 20 percent of adolescents with T2DM have polyuria, polydipsia, and weight loss as their presenting complaints, clinical signs common to both type 1 and type 2 disease. About one third of patients with T2DM, however, are diagnosed by routine laboratory screening (usually urinalysis) as part of a school physical, rather than as a result of specific complaints. Such “accidental” diagnosis is rare in patients with T1DM.
Similarly, 25 percent of girls with T2DM have a vaginal monilial infection as their chief complaint at presentation. While this is a typical complaint among adult females with T2DM and indicates long-standing glycosuria, it is exceedingly rare as a presenting symptom in patients with T1DM. The remaining patients with T2DM present with a variety of other complaints including severe infection (osteomyelitis, pharyngitis), obesity, dysuria and enuresis.
Diabetic Ketoacidosis
Some adolescents, particularly African Americans, who are eventually diagnosed with T2DM may present with diabetic ketoacidosis (DKA), traditionally considered the hallmark of T1DM. In our series, 42 percent of black patients with T2DM presented with ketonuria and 25 percent with DKA.11 In another study, about a third of Hispanic adolescents with type 2 disease presented with ketonuria.12 This phenomenon has been demonstrated among obese black adult patients who present with ketosis and DKA but follow a subsequent clinical course typical of T2DM.
The mechanism behind ketosis in patients with T2DM is unclear. It is generally believed that insulin resistance combined with the deleterious effect of chronic hyperglycemia on insulin secretion and action (“glucose toxicity”) results in relative insulin deficiency. When the deficiency becomes severe (because of long-standing hyperglycemia with decompensation or intercurrent illness), it leads to enhanced lipolysis and increased levels of free fatty acids, ketonemia, and ketonuria, characteristically seen in patients with T1DM. Why this phenomenon is more common in black and Hispanic patients with T2DM is unknown, though evidence indicates that basal insulin sensitivity in these groups is lower than it is in their Caucasian peers, possibly increasing their susceptibility to developing relative insulin deficiency.
Are Diet and Lifestyle Relevant To Diagnosis?
Adolescents with T2DM report a high-fat, low-fiber diet. An increase in fat intake has been associated with the rising incidence of T2DM in children in Japan.13 In our series, two of 11 adolescent patients with type 2 disease, met criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) for binge eating disorder (BED), while six had significant characteristics of BED but did not meet strict criteria.8 BED is marked by eating larger amounts of food than most people would eat in a discrete time period accompanied by a sense of lack of control. It occurs in an estimated 20 to 50 percent of individuals who seek specialized obesity treatment. Unfortunately, our data do not indicate whether the patients in our study engaged in binge eating at the time of diagnosis or developed it as a result of rigid standards of dietary restraint.
As a group, children with T2DM lead a sedentary lifestyle and do not participate in structured or routine exercise programs.8 In adults, low physical activity and high caloric intake are known risk factors for obesity and T2DM.
The Current Criteria For the Diagnosis Of Diabetes and Pre-Diabetes Are:
Diabetes:
1. Symptoms of diabetes (include polyuria, polydipsia, and unexplained weight loss) plus random plasma glucose concentration > 200 mg/dl (11.1 mmol/l).
2. Fasting plasma glucose above 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.
3. 2-h PG above 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 75-g anhydrous glucose dissolved in water.
Pre-diabetes
The ADA now defines pre-diabetes as
- Impaired fasting glucose: fasting plasma glucose between 100 and 126 mg/dl.
- Imparied glucose tolerance: 2-h PG between 140 and 200 mg/dl during an OGTT.22
How Helpful Are Laboratory Tests?
Are laboratory tests helpful in distinguishing between type 1 and type 2 disease in a patient with new-onset diabetes? The answer is not always clear-cut.
Insulin and C Peptide Levels
In patients with T2DM, both plasma insulin and C peptide concentrations are usually high, reflecting underlying insulin resistance.14 Chronic hyperglycemia, however, can cause transient insulin deficiency with a low initial plasma insulin concentration despite insulin resistance. Insulin and C peptide levels therefore may be deceptively low in the presence of acute metabolic deterioration at the time of presentation. Conversely, “insulin reserve” can persist in patients with T1DM for up to two years. Thus, although measurement of insulin and C peptide can be helpful in making the distinction between T1DM and T2DM — particularly when levels are elevated — a significant degree of overlap exists.
Autoantibody Levels
Autoantibodies to the islet cell (ICAs), insulin (IAA), glutamic acid decarboxylase (GAD), and tyrosine phosphatase (ICA-512), employed individually or in combination, may be helpful diagnostic tools. Autoantibodies have been identified in up to 90 percent of patients with T1DM at the time of presentation. Conversely, the presence of autoantibodies in adults with clinically suspected T2DM is associated with a high risk of eventual development of insulin dependence, a condition termed latent autoimmune diabetes. Thus the absence of antibodies, in the right clinical context, suggests T2DM, while their presence suggests T1DM. Assessment of all patients with new-onset diabetes for the presence of autoantibodies is not necessary, but the information may be significant when other clinical signs, such as obesity, acanthosis, or family history, make T2DM a diagnostic consideration.
Is It Important To Differentiate Between T1DM and T2DM?
Since the clinical course, treatment options, and comorbidities associated with type 1 and type 2 disease are quite different, it is important not to just treat the hyperglycemia, but to try to determine the exact diagnosis. While patients with T1DM are at risk for development of other autoimmune disorders such as thyroiditis, Addison’s, and celiac disease, patients with T2DM are at risk for development of hyperlipidemia, hypertension, cardiovascular disease (CVD), and, in females, polycystic ovary disease.
What Is the Clinical Course?
The diagnosis of T2DM in a child or adolescent with new-onset diabetes is indeed difficult. The ability to distinguish definitively between T1DM and T2DM at onset is often limited, particularly if the patient presents following an acute deterioration. Whenever there is a doubt, and until proven otherwise, patients should be treated with insulin as if they have T1DM.
Clinical reassessment should be done at each visit in patients with suspected T2DM. Patients with type 2 disease who are treated with insulin may have recurrent hypoglycemic episodes, insulin requirements per weight that are unusually low (after overcoming initial insulin resistance) or high, and long periods off insulin without decompensation.
What Is the Best Approach To Treatment?
Primary efforts should focus on treating the underlying causes of the disorder, namely obesity, poor diet, and sedentary lifestyle, particularly in patients who are asymptomatic at presentation. The majority of children with T2DM are adolescents and present challenges to healthcare providers attempting to promote behavior and lifestyle changes. Moreover, adolescents with T2DM often come from families whose members are sedentary, unrestrained eaters. Treating these patients can be frustrating, and although occasional individuals manage to lose weight and regain metabolic control, a considerable number either drop out of treatment or stay overweight with poor diabetes control. These facts must be taken into account when planning treatment strategies. Unlike adults with T2DM, adolescents generally require an intensive, multidisciplinary approach if treatment is to succeed.
Screening For T2DM In Obese Adolescents
The incidence of undiagnosed T2DM in the adult population strongly suggests that the problem of undiagnosed T2DM among children may be significant. However, as in adults, the best approach to screening for glucose tolerance abnormalities remains unresolved. The easiest approach is to obtain a fasting glucose level using the same criteria for diagnosis of impaired fasting glucose (levels of 100-126 mg/dL) and diabetes (levels greater than 126 mg/dL) as in adults. However, it can be difficult to ensure fasting in adolescents, and abnormal results should be confirmed on a separate day after careful discussion with the patient of the implications of a second abnormal test.
Furthermore, fasting laboratory evaluation significantly underestimates the incidence of diabetes and impaired glucose tolerance in adolescents. In a recent study, impaired glucose tolerance was present in 21 percent of obese adolescents, and diabetes in 4 percent, following glucose tolerance testing. However, none of these children had an abnormal fasting glucose concentration.20 Thus, a clinician who relies on fasting glucose measurements alone will miss a significant number of children with T2DM and all children with impaired glucose tolerance. Fasting insulin and C-peptide levels did not improve the ability to predict glucose intolerance.
On the other hand, performing oral glucose tolerance testing is expensive, burdensome, and inefficient, since these same studies indicate that most obese children will not demonstrate glucose intolerance. Further studies will need to be undertaken to determine whether there are specific clinical or biochemical features that would identify a subgroup of obese children in whom glucose tolerance testing would be expected to be most informative.
Until that time, we recommend that fasting glucose, insulin, and C-peptide levels be obtained on obese patients under evaluation. This will provide information on fasting glucose control, as well as insight into the presence and degree of insulin resistance. In prepubertal patients, no additional evaluation is recommended in the absence of specific symptomatology, since overt T2DM is highly unusual prior to puberty. In the pubertal patient with additional signs of significant insulin resistance (hypertension, dyslipidemia, polycystic ovary syndrome, severe acanthosis nigricans) or a history of being the offspring of a diabetic pregnancy, formal oral glucose tolerance testing should be considered and repeated annually.
