'The Family Disease of the 21st Century'
Symposium on Adult Diseases in Children - February 2009
Tex Med . 2009;105(2):33-37.
By Stephen W. Ponder, MD, CDE
The emergence of type 2 diabetes in children and adolescents over the past two decades represents a seismic shift in pediatric chronic disease epidemiology. Yet it remains debatable whether the term "epidemic" is truly warranted in describing this phenomenon. 1 Type 2 diabetes can be found in any subset of the child and adolescent population in Texas. Still, the African-American and Hispanic communities remain primarily impacted by this condition. 2 Parity in incidence with type 1 diabetes is now being reported in some locations in South Texas (personal observation). Due to its high penetration within the family, type 2 diabetes is the family disease of the 21st century.
This monograph will emphasize the initial workup and medical management of type 2 diabetes in children and adolescents, including comorbidities. Basic principles of medical management have remained unchanged since the author's initial report almost one decade ago. 3 Special management challenges will be reviewed with suggestions to minimize their impact on delivery of care. Exceptions exist for some of the general statements regarding diagnosis and management and should be considered by the clinician.
Criteria for making the diagnosis of diabetes mellitus are well established. 4 Fasting plasma glucose levels greater than 125 mg/dL or random levels greater than 200 mg/dL on two separate occasions define the diagnosis, along with classic signs and symptoms (polyuria, polydipsia, and polyphagia). Clinically, most children with type 2 diabetes have nonexplosive clinical onsets. Signs and symptoms may be vague or subtle, at best. This is consistent with adult patients with type 2 diabetes, many of whom are believed to have had the disease for years before a formal diagnosis is made.
Diabetes may be discovered following an incidental laboratory study for another chief complaint, such as a urinalysis for nocturia, enuresis, or vaginitis. The presence of acanthosis nigricans (AN) may prompt either a fasting glucose measurement or a formal oral glucose tolerance test. However, the assignment of diabetes type can be challenging and may not be possible at initial presentation. An overweight or obese child discovered to have diabetes mellitus should not be assumed to have type 2 diabetes simply on the basis of size, ethnicity, presence of acanthosis nigricans, or even family history. 5
Insulin resistance is an independent variable in children with autoimmune-mediated type 1 diabetes. Its presence during adolescence is one reason metformin has been suggested as an adjunct to insulin management in teens with type 1 diabetes. 6 In type 2 diabetes, insulin resistance must be coupled with a second "defect" in pancreatic insulin production for sustained glucose intolerance to be expressed clinically. 7
One common clinical trap is to over-interpret results of serum insulin levels. Insulin levels are sometimes ordered fasting, along with a matched glucose level or even as part of an oral glucose tolerance test. A diagnosis of diabetes is not dependent on insulin levels, only by the laboratory-measured glucose levels collected fasting or as part of a formal carbohydrate challenge.
Astute clinicians will use all historical and physical examination data, combined with appropriate laboratory studies, to make the best diagnostic assessment. For children suspected of having type 2 diabetes, ruling out other common forms of diabetes, including type 1 diabetes and even monogenic forms such as maturity onset diabetes of youth (MODY), also known as monogenic diabetes, is critical. The sine qua non of type 1 diabetes is the presence of pancreatic autoimmunity. A panel of at least three of the four following assays should be performed: anti-IAA, autoantibodies to insulin; anti-GAD, autoantibodies to glutamic acid decarboxylase; anti-ICA, autoantibodies to islet cells; and anti-IA-2, autoantibodies to protein tyrosine phosphatase IA-2. Results are typically received within a few weeks.
In a recent report, 36 percent of 128 children with classic physical and historical features for type 2 diabetes were discovered to possess at least one positive antibody titer for pancreatic autoimmunity. 8 Such patients should be reconsidered as having type 1 diabetes complicated by insulin resistance.
Physically, most children with type 2 diabetes are overweight or obese. Specifically, they often possess significant abdominal obesity and are most likely to be non-Caucasian. While some children aged 6 years or younger with type 2 diabetes have been reported in the literature, most are older than 8 years and the majority are adolescents. The family history is strongly positive for diabetes, especially in the parents. In fact, a parent may have undiagnosed type 2 diabetes when the child or teen is diagnosed. AN, a dermatologic marker suggestive for insulin resistance, may be present on the neck or in other flexural areas. The presence of AN confers only a risk for diabetes, not a diagnosis. Reports from the school-based Texas AN screening program reveal that less than 1 percent of children referred for AN evaluation have been diagnosed with type 2 diabetes at the time of referral (Doreen Garza, personal communication). AN remains a risk factor for future development of diabetes.
The hemoglobin A1c is not intended to be a diagnostic tool. Untreated children with newly diagnosed type 2 diabetes often have values lower than 10 percent when their diabetes is discovered. Higher A1c values suggest stronger consideration of type 1 diabetes. Ketosis and frank diabetic ketoacidosis at presentation are uncommon and, if present, suggest the need for further workup to rule out type 1 diabetes.
If autoimmunity studies are negative for type 1 diabetes and there is a strong family history of noninsulin-dependent diabetes in at least three successive generations (i.e., an autosomal dominant pattern of inheritance), the diagnosis of any of several monogenic forms of diabetes, also known as MODY, should be considered. 9 Some have argued that the number of patients with MODY forms of diabetes collectively rival the total number of patients with known type 1 diabetes. 10 The specific test for MODY is offered only by a single reference laboratory (www.athenadiagnostics.com) and the cost is relatively expensive. However, if present, the management of MODY forms of diabetes diverges significantly from that of type 2 diabetes in its early stages. The evaluation and management of MODY forms of diabetes is best made by referral to a pediatric endocrinologist.
Most children with type 2 diabetes are expected to have considerable pancreatic beta cell reserve. In adults, pancreatic insulin production capacity is reduced by half at the time of diagnosis. 11 Furthermore, loss of the residual insulin secretory capacity in the following years is considered progressive. 12 Given the younger age at onset, insulin dependency will likely occur in the patient's young adult life, if not earlier.
Medical management should aim to lower the insulin resistance. This is best accomplished in several ways, some nonpharmacologic. As in adults with type 2 diabetes, increasing physical activity will enhance insulin sensitivity. But like many adults, getting children and teens to engage in regular physical activity, especially those who may have been sedentary for years, can be a tremendous challenge. Being very specific about an exercise or activity prescription is important. Basic principles still apply: Choose an activity the child or teen likes. Also, start slowly and increase tolerance over time. Keep a record of what is done and for how long. The clinician should set specific and achievable goals for the patient and family. A target of 60 to 90 minutes a day (or more) of physical activity should be a minimal target to aim for over time, as well as a reduction in screen time (including use of televisions, video game systems, and computers) to less than 60 minutes. 13 Most important, the family should play an active role in the activity prescription. However, because many parents of children with type 2 diabetes may be quite sedentary themselves, this can be a major management hurdle to overcome. Still, the practitioner should strongly encourage family involvement in the activity prescription.
Proper meal planning, the other major arm of nonpharmacologic management, is the most challenging therapy to implement. Most children with type 2 diabetes have poor nutritional habits and often are members of families with reduced nutritional knowledge. A single educational encounter with the diabetes dietitian rarely makes a lasting impact. Nutritional education should be an ongoing effort. Many teens with type 2 diabetes have a history of consuming processed foods high in calories, fat, and refined sugars. Even after a thorough session of medical nutrition therapy, many of these teens will continue to imbibe high-calorie liquids or fail to restrict portion sizes. Furthermore, if the family does not understand or support these changes, adherence to the meal plan is certain to fail. The definition of success needs to be reconsidered. For example, reducing regular cola intake from 2 liters a day to half a liter a day might be considered a very positive step. Incremental changes in food behavior should be encouraged by the clinician, even though such changes may seem minimal. If patients don't have access to a dietitian, the success of nutritional management recommendations will be limited. The practitioner should constantly emphasize the value of proper meal planning in the overall management of this disease.
Pharmacologic management of type 2 diabetes in children and adolescents has two fundamental options: metformin and insulin. Metformin is approved for use in children over age 10 years and comes in a variety of dosing options, including b.i.d. and t.i.d. dosing, extended release for once-daily dosing, and even a liquid preparation (Riomet) for children unable to swallow pills. Insulin dosing is available in an array of combinations, including two insulin premixtures (75/25 and 70/30). Whether using metformin or insulin, or both, optimal adherence always comes with the least frequent dosing regimen.
Because metformin has the capacity to reduce food intake and to potentially slow down further weight gain or facilitate weight loss, it's often a mainstay therapy. It has a well-known side-effect profile, but has been generally safe for use in children and teens. The most common side effects are gastrointestinal upset or diarrhea or both. It's important to instruct the child or teen taking metformin not to chew the tablets, as doing so increases the risk of gastrointestinal complaints. If given once daily, metformin should be taken with the largest meal. Minimal side effects are associated with starting the smallest unit dose (500 mg regular metformin or 500 mg extended-release metformin), then increasing the dose as tolerated at weekly intervals based on blood sugar patterns. Maximum daily dose is considered 2550 mg for regular metformin and 2000 mg for the extended-release product. Patients should be advised to avoid taking metformin when dehydrated or when receiving radiocontrast dye.
Insulin therapy for type 2 diabetes in children and adolescents is typically delivered during one of two clinical windows. If the patient has been chronically hyperglycemic, as reflected by sustained blood sugars >200 mg/dL or hemoglobin A1c higher than 7 percent, insulin therapy at diagnosis is indicated. The starting dose ranges between 0.8 and 1.0 units/kg/day. Insulin therapy will lower blood sugar levels and reverse the effect of chronic hyperglycemia on reducing insulin secretion and insulin action at the tissue level ("glucose toxicity"). 14 Combined with frequent blood glucose monitoring, the combination of metformin and insulin can quickly normalize blood sugar levels in most cases. As the metformin dose is increased to mid-range (around 1000 daily), insulin may be tapered rapidly (first by 50 percent, then discontinued altogether if glucose levels remain within the target range).
The second opportunity to apply insulin therapy is when glycemic control is deteriorating, e.g., when A1c levels are rising (typically 7 percent or higher) in a patient who is on a maximum prescribed metformin dose. A low total daily dose (0.5 units/kg/day) is a reasonable starting point and should be increased on the basis of response. The use of long-acting insulin analogs (glargine or detemir) versus intermediate and rapid-acting insulin premixtures (75/25 or 70/30) delivered b.i.d. should be based on A1c levels. Premixed insulin delivers a basal component for between-meal glycemic control and a rapid-acting component for meal coverage, whereas long-acting analogs provide basal insulin coverage only. Satisfactory glycemic control (<7 percent) obtained with basal insulin only is preferred. However, if the A1c continues to rise and remains >7 percent, or if the blood glucose patterns fail to show satisfactory control, then a more conventional split-mixed regimen, preferably with premixed insulin (70/30 or 75/25), should be considered. Even if the A1c increases, metformin remains helpful in minimizing the total supplemental insulin dose.
Obesity is the most common comorbid problem with type 2 diabetes. (See "Childhood Obesity: The Scope of the Problem.") It is usually long-standing and may be present from early childhood. Being overweight or obese at ages 3 to 5 years and having a parent with type 2 diabetes are strong risk factors. Aggressive weight management at an early age is indicated in this situation.
At diagnosis, the clinician should look for several conditions. Some of these are interconnected with the underlying insulin resistance and so-called "cardiometabolic risk" that often accompanies type 2 diabetes. Hypertension and dyslipidemia are core elements of cardiovascular disease associated with early plaque formation and must be aggressively comanaged with the diabetes. Effective management of diabetes is a primary therapeutic strategy, along with pharmacologic and medical nutrition therapy.
Other problems not to miss include ovarian hyperandrogenism and polycystic ovary syndrome, which relate to the preexisting hyperinsulinemic state. Use of metformin may be sufficient to reestablish monthly ovulatory cycles in many adolescents, but this increase in fertility poses another problem - the risk for teen pregnancy. Use of contraceptive agents with low androgenic profiles is recommended and has the added benefit of reducing ovarian androgen output directly. Consultation with a gynecologist is recommended.
Occult comorbidities include hepatic steatosis and microalbuminuria. Elevations in hepatic transaminases characterize nonalcoholic steatohepatitis. Progressive hepatic fibrosis is possible. Metformin has been found to be beneficial, but factors predicting progression to hepatic failure are still unknown. Annual measures of liver function studies are indicated. Microalbuminuria has been reported to be twice as prevalent in children with type 2 diabetes compared with those with type 1 diabetes. 15 This is a strong risk factor for future development of renal insufficiency. Yearly screening for microalbumin in spot or timed urine samples is indicated from the time of diagnosis.
Obesity is associated with obstructive sleep apnea (OSA). Morbidly obese individuals are at extremely high risk for sleep-disordered breathing. If OSA remains undiagnosed or untreated, the risk for further metabolic deterioration and further weight gain is guaranteed. For this reason, OSA may be the most serious comorbidity for an overweight or obese child or teen with type 2 diabetes to manage acutely. (See " Obstructive Sleep Apnea in Children .") Referral to a sleep specialist or pulmonologist is a management imperative.
Primary hypothyroidism is a common endocrine problem in the general population and is often cited as a reason for weight gain, although it rarely contributes significantly to morbid obesity. It is reasonable to screen the child or adolescent with type 2 diabetes at diagnosis with a serum thyrotropin (TSH) measurement and serum thyroxine (T4) level.
Finally, bone and joint problems are common in morbidly obese children and teens. The weight burden on the skeleton often is dramatic and increases the risk for back, hip, knee, and ankle injury, requiring orthopedic intervention. These injuries limit mobility and endurance, aggravating the primary obesity problem with which most of these patients already struggle.
Management of the child with type 2 diabetes poses special considerations and challenges. Many patients come from families highly penetrated with type 2 diabetes and with less-than-optimal outcomes in some cases. In fact, many parents of children or teens with type 2 diabetes may be poor role models for self-care or may suffer themselves from debilitating long-term complications of the disease. The family may likely be uninsured or enrolled in state health insurance programs. Median family income is lower than the national average, and single-parent households are commonplace. Health literacy is generally low, which allows more myths and misconceptions to exist about the disease and its proper management. Overall, diabetes appears to be taken less seriously in these families than in families of children with type 1 diabetes. A general sense of fatalism may persist that acts to disempower the patient and family, making lasting behavior change difficult to achieve.
Outpatient follow-up visits often are less frequent than with patients with type 1 diabetes, as no-show rates are higher. Transportation costs can be limiting, and single parents may be unable to take time off from their jobs to make doctor visits and attend important educational visits. Language can also be a significant management barrier, as well, as some families may be primarily Spanish speaking.
A thorough social history is the best strategy to address many of these long-term care issues. Provider awareness of the psychosocioeconomic barriers to care can minimize or even eliminate many adherence problems later on. One common problem many families on state insurance programs deal with is loss of coverage due to paperwork barriers. Easy access to an experienced social worker with good knowledge of these barriers is the best defense against disruption of care or loss of coverage for diabetes medications and supplies.
Type 2 diabetes is now a commonplace medical occurrence in 21st century Texas children and adolescents. Making a careful and proper diagnosis is important, remembering that assigning diabetes type may not be possible at the time of initial presentation. Significant overlap exists with other common forms of diabetes in children, including type 1 diabetes and MODY, which impacts medical management. In contrast to children with type 1 diabetes, the child or teen with type 2 diabetes may possess numerous comorbidities at the time of diagnosis and in the ensuing years. Psychosocioeconomic issues drive the management agenda for most children and families. Metformin is a mainstay of pharmacologic management, along with medical nutrition therapy and exercise, which are challenging to implement. Insulin strategies are best kept simple and may be required initially to address the problem of glucose toxicity until metformin can treat the insulin resistance and facilitate weight loss efforts. Insulin therapy should be reintroduced when glycemic control is deteriorating with maximum doses of insulin sensitizers and concomitant nonpharmacologic management.
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- Brosnan PG, Slover R, Willi S, et al. Prevalence of microalbuminuria (MA) in children and adolescents with diabetes mellitus (DM) and rate of spontaneous remission. Poster presented at: 2006 Pediatric Academic Societies' Annual Meeting; April 28-May 2, 2006; San Francisco, CA.
Dr. Ponder is professor of pediatrics and director of the Children's Diabetes and Endocrine Center of South Texas at Driscoll Children's Hospital in Corpus Christi.
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