In 1979 Savage and colleagues' description of type 2 diabetes in six obese Pima Indian children with strong family histories of type 2 diabetes was the first report of type 2 diabetes in children.1 Prior to the 1990s, it was rare to diagnose children or adolescents with type 2 diabetes. Any time a patient with presumed type 2 diabetes in childhood presented, all of the medical students and house staff would gather at the bedside to see this unusual case. By 1994, type 2 diabetes represented up to 16% of new cases of diabetes in children in urban areas.2 By 1999, that number had increased to 45% of all cases of diabetes in children in some geographic areas.3 In 2001, type 2 diabetes represented 76% of all cases of diabetes among American Indian populations.4
In the United States, an attempt has been made to quantify the numbers of patients diagnosed with diabetes. The SEARCH for Diabetes in Youth Study Group has reported on the largest surveillance effort of diabetes in youth conducted in the United States to date. Although the majority of cases of diabetes in young children (younger than age 10) have type 1 diabetes, type 2 diabetes is increasing in some ethnic populations: in American Indian populations, 13%are type 2, and in Asian/Pacific Islanders, 7% are type 2. The numbers are much more skewed towards type 2 diabetes in older children of certain ethnicities. Type 1 diabetes remains the leading type of diabetes in non-Hispanic white children 10 to 19, representing more than 90% of cases. However, the percentage of cases of diabetes in minority groups that are type 2 are much higher: 22% for Hispanic youths, 33% for black youths, 40% for young Asian/Pacific Islanders, and 76% for young American Indians.4 This phenomenon is being observed outside of the United States as well. As more societies adapt a Western diet and lifestyle, this epidemic is spreading to other countries, with increased incidences reported in Japanese and Canadian schoolchildren.5'6 In Japan, 80% of all new cases of diabetes in children and adolescents are type 2 diabetes.7
Type 2 diabetes also seems to have a gender effect In most ethnic groups, the ratio of females to males is 1.7:1; however, in American Indians, the ratio is as high as 6:1. The exact cause of the increased female incidence is not entirely understood, but estrogen may play a role.
There are a number of factors that have been proven to contribute to the risk of type 2 diabetes. Obesity is unquestionably the most important risk factor for insulin resistance. It remains a significant risk feetor and target for treatment when insulin resistance finally gives way to decompensation and progression to type 2 diabetes.8 Distribution of body fat also seems to be important Specifically, it is visceral fat rather than total body fat that correlates with the risk of developing type 2 diabetes. Many studies have demonstrated relative insulin resistance in puberty, which explains the sharp rise in diagnosis of type 2 diabetes at the age of puberty.9 It is most likely that the sex steroids produced at puberty are responsible for the significant rise in observed insulin resistance. There are also racial disparities in insulin resistance; black children are more insulin-resistant and therefore more predisposed to type 2 diabetes than are white childrea Typically, children and adolescents with type 2 diabetes have multiple family members with type 2 diabetes mellitus. A clearly related condition in girls called polycystic ovarian syndrome (PCOS) may have components of metabolic abnormalities that put those girls at greater risk than others for the development of type 2 diabetes. In fact, studies have shown that 15% of adolescent girls with PCOS have type 2 diabetes.
There may be reason to believe that our metabolic destiny is in some ways sealed even before we are born. There is a body of evidence supporting the existence of a U-shaped relationship between birth weight and risk for type 2 diabetes in children.10 Low birth weight and high birth weight children are at increased risk for type 2 diabetes. One theory is that maternal under-nutrition leads to reduced pancreatic cell mass and thus less insulin-producing capacity. Those with a high birth weight are also at a higher risk for diabetes, likely due to subsequent obesity and insulin resistance. These relationships were seen despite adjustment for other factors, such as the presence of gestational diabetes and family history of diabetes. However, new evidence has challenged the relationship between birth weight and subsequent risk for type 2 diabetes. Despite the lingering questions of uterine and maternal influences on subsequent risk for metabolic disease, maternal diabetes by itself is a risk factor for developing type 2 diabetes later in life.
The diagnosis of diabetes in children and adolescents is made using the same American Diabetes Association criteria as those established for adults.11 In children with symptoms of diabetes, such as polyuria and polydipsia, the diagnosis can be made by finding a fasting blood sugar greater than or equal to 126 mg/dL. It also can be diagnosed by performing an oral glucose tolerance test and finding a two-hour blood sugar level 200 mg/ dL. However, in asymptomatic children, these abnormal levels should be repeated and confirmed on another day to confirm the diagnosis of diabetes. A commonly ordered test, the glycosylated hemoglobin, is not part of the diagnostic criteria. (See Sidebar 1, page 111.)
A Consensus Panel of the American Diabetes Association has issued recommendations for screening youngsters at risk for type 2 diabetes. A consensus statement was necessary not only to establish uniformity but also to justify the need for screening for this disease at all. Approximately 50% of adults who have diabetes are unaware that they do so. This disease fits all of the standard requirements to justify a screening program; it is common, serious and presents asymptomatically, screening is sensitive and specific, and treatments are available. Early diagnosis by screening allows for early treatment and the prevention of complications.
Any person who is overweight (defined as BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal body weight) and has any two of the other risk factors should be screened for diabetes. The risk factors are family history of type 2 diabetes in first- or second-degree relative; race/ethnicity (American Indian, African-American, Hispanic, or Asian/ Pacific Islander); and signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, and PCOS). Screening should begin by age 10 or onset of puberty if puberty occurs at a younger age (see Sidebar 2, page 112). The recommendation for frequency of screening by primary care providers is every two years. 12 (It is important to note that the two-year rather than yearly criterion was instituted because the American Academy of Pediatrics guidelines call for well-visit pediatrie visits every other year in this age group.) Current guidelines call for screening with a fasting plasma glucose. However, research is needed to provide more information on the usefulness of a random glucose measurement, 2-hour postprandial glucose, and hemoglobin AIc (HbA 1c) in screening for diabetes in children.
At the time of diagnosis of new-onset diabetes, it is important to try to differentiate between type 1 and type 2 diabetes. Type 1 diabetes is usually due to the lack of insulin production by the pancreas as a result of autoimmune destruction of the pancreatic beta cells, whereas type 2 diabetes is primarily a disease of insulin resistance associated with obesity. Therefore, although there is some overlap in treatments, the pathophysiological mechanisms are different and dictate different approaches. The obese patient with type 2 diabetes may need a low-caloric diet, whereas a patient with type 1 diabetes may have no such restriction. This distinction can be made with the assistance of historical, physical, and laboratory data. From a historical perspective, those with type 2 diabetes are usually obese and tend to have a much more insidious progression of elevated blood sugars than those with type 1 diabetes. With the growing obesity epidemic, however, some children with type 1 diabetes are overweight; 85% of patients with type 2 diabetes are overweight.
Acanthosis nigricans - a skin condition characterized by dark, thickened, velvety patches especially in the folds of skin, the axilla (armpit), the groin, and the back of the neck - is a marker of insulin resistance. It is found in 60% to 90% of adolescents with type 2 diabetes, but is extremely uncommon in those with type 1 diabetes. Many youngsters with type 2 diabetes have a host of other comorbidities, including sleep apnea, hyperlipidemia, hypertension, and, in girls, amenorrhea (absence of menstrual periods), and hirsutism (excessive sexual hair growth on the body). However, these are usually not found in youngsters with type 1 diabetes.
A family history of diabetes in a firstor second-degree relative is found in close to 100% of those presenting with type 2 diabetes compared with 5% in those with type 1 diabetes. The presence of ketosis or diabetic ketoacidosis, a sign of insulin deficiency as would occur in type 1 diabetes, does not exclude type 2 diabetes as the diagnosis but, if present, is usually less severe. Laboratory testing can help differentiate between these two disorders. One or more antibodies to islet-derived antigens (antiglutamic acid decarboxylase antibodies, islet cell antibodies, and insulin autoantibodies) are present in 85% of patients with type 1 diabetes. Some patients with type 2 diabetes may have positive antibodies, but it is less frequent and patients will not typically have more than one antibody positive. The levels of insulin and C-peptide (a byproduct of pancreatic insulin production) are universally low in patients with type 1 diabetes but are not necessarily low in patients with type 2 diabetes. However, this test may be misleading because the levels may be temporarily low, even in type 2 diabetes, as a result of the transient toxic effect of the high blood sugar levels on the pancreatic insuUn-producing cells (glucotoxicity).13
There are many complications typically found in people with long standing diabetes, such as microalbuminuria, hypertension, and lipid abnormalities. Fortunately most children do not develop these complication while still in the pediatrie age group. In general, children with type 2 diabetes are more likely to have complications than those with type 1. Microalbuminuria and hypertension are significantly more common in children with type 2 than type 1 diabetes. Despite a short duration of diabetes (less than one and half years), microalbuminuria was present in more than 25% of patients with type 2 diabetes, compared with only 6% of patients with type 1 diabetes. Lipid abnormalities were also more frequent in type 2 diabetes, with hypercholesterolemia found in one-third and hypertriglyceridemia in more than one-half. Although rates of peripheral and autonomie neuropathy were similar in both groups, only retinopathy was less common in type 2 diabetes.
HYPEROSMOLAR HYPERGLYCEMIC STATE
Hyperosmolar hyperglycemic state (HHS) is the most serious acute metabolic complication of diabetes mellitus and is life threatening. It is by far much more common in patients with type 2 diabetes compared with type 1 diabetes. This syndrome, first described in 1957, has been referred to by many terms, including hyperosmolar nonketotic state, hyperosmolar coma, hyperglycemic hyperosmolar syndrome, or nonketotic hyperosmolar syndrome. The new term recommended by the American Diabetes Association, hyperosmolar hyperglycemic state, emphasizes that varying alterations in sensorium less severe than coma are usually present and that HHS may occur with some degree of ketosis and acidosis.
Diagnostic features of HHS include the following: plasma glucose level of 600 mg/dL or greater, effective serum osmolality of 320 mOsm/kg or greater, and profound dehydration. Typically, there may be a small degree of ketonuria, but absent or low ketonemia. Bicarbonate is greater than 15 mEq/L, and patients usually have some alteration in level of consciousness.
The hyperosmolar hyperglycémie state occurs primarily in patients with type 2 diabetes, although they may have not known that they had diabetes at the time that they presented with HHS. In 30% to 40% of cases, HHS is the initial presentation of a patient's diabetes.14
As is the case with many treatment choices in pediatrie endocrine disorders, most therapies approved for type 2 diabetes in adults are not approved for use in children. Although pharmaceutical companies are offered lucrative incentives to conduct pivotal trials with their drugs in the pediatrie population, such as extension of patent protection for 6 months, most have opted not to do so given the significant and burdensome cost to perform such trials in pediatrics. Thus, the use of most drugs discussed in this section will be under the general heading of "off-label" use. However, despite the obstacles present in prescribing these drugs, most patients are satisfactorily treated with insulin alone in the initial phases of their disease, because most patients will present with significant insulinopenia and ketosis with glycosylated hemoglobin values above 9%.
Methods and Goals
The mainstay of type 2 diabetes treatments remains lifestyle change accomplished through multi-disciplinary methods of behavior modification. Our group and other authors in this issue of Pediatrie Annals have pioneered successful lifestyle change programs, such as "The Kids Weight Down Program" and "The Healthy Life Program," whose main goals are to increase physical activity, reduce caloric intake, improve food choices through nutritional guidance, and maintenance of these changes through behavioral change over the long term. In individuals who are successful, primary prevention of type 2 diabetes can be accomplished, and improvement if not normalization of glycemic control can be achieved. For those who cannot or will not engage in lifestyle management, and for those who have failed lifestyle change, the use of pharmacotherapy should be considered. The patient should strive to achieve as normal a glycosylated hemoglobin as possible, with the ideal being a level of 6.4% or below. Additional goals would include weight loss, maintenance of normal blood pressure and lipid levels.
There is little evidence-based medicine on the efficacy of dietary interventions in the treatment of type 2 diabetes in children. In particular, there is a scarcity of trials designed to distinguish between low-carbohydrate and highcarbohydrate diets popularized during the Atkins era in adults. One short-term study conducted in children with obesity and insulin resistance subjected patients to a short-term diet very low in carbohydrates and restrictive enough to generate ketones. Results found improvement in BMI and in indices of insulin resistance.15 Compliance with these diets and with lifestyle change in general is clearly problematic for most patients, and therefore it is not surprising that less than 10% of adolescent patients with type 2 diabetes can comply.16 Clearly prospective randomized trials are needed to address the safety and efficacy of a variety of dietary approaches in this population, as have been performed in adults.
Pharmacotherapeutic options for type 2 diabetes have increased over the past 5 years. In addition to insulin secretagogues and, more recently, insulin sensitizing agents, newer novel agents that influence insulin sensitivity by modulating a new class of hormones that originate primarily in the gut - the "incretins" - have made it to market in adult type 2 diabetes. However, none of these drugs has been approved for use in children with type 2 diabetes mellitus except for a biguanide drug called metformin. Metformin works to decrease insulin resistance primarily by decreasing hepatic glucose output, which is responsible for nearly 50% of serum glucose values. A number of studies have demonstrated the safety and efficacy of metformin in the management of type 2 diabetes in children.17 Much experience has been gained in recent years due to the relatively widespread use of metformin in the treatment of PCOS and the prediabetes state. Clinically, a main limiting factor in the use of metformin is the gastrointestinal distress seen early in the treatment that tends to abate within a few weeks. A useful strategy is initiating treatment with one500-mg pill nightly and then titrating up to a maximum of 2,000 to 2,500 mg daily when tolerated.
Despite metformin's usefulness as monotherapy at diagnosis, most type 2 diabetes patients with glycosylated hemoglobin levels greater than 9% will require insulin as well as metformin. The insulin can be weaned when better glycemic control is attained and the beta cell recovers from the acute glucose toxic effect This fits in well with the pathophysiology that many patients with type 2 diabetes present with ketones, a sign of absolute insulin deficiency. Insulin can be administered by multiple injections or continuous subcutaneous insulin administration via an insulin pump.
Most patients ultimately require more than one drug to achieve normal blood sugars. This phenomenon is due to ongoing, progressive beta-cell failure. Other drugs that may be used when polypharmacy is inevitably necessary include the thiazolidenediones, a class of drugs that works primarily by increasing skeletal muscle uptake of glucose and thus decreasing insulin resistance. Other drugs that work primarily through increasing insulin secretion include the sulfonylureas and meglitinides. Alpha-glucosidase inhibitors block carbohydrate absorption and thus decrease glucose load and serum blood glucose. Most recently, drugs that either mimic the incretin hormone glucagon-like peptide, a known sensitizer of insulin action, or those that decrease the enzymatic degradation of glucagon-like peptide have also received approval for use in adults with type 2 diabetes.
COMORBIDITIES: DYSLIPIDEMIA AND HYPERTENSION
In 2003, the American Diabetes Association published guidelines for the treatment of dyslipidemia in children with diabetes.18 Their guidelines permitted LDL-cholesterol target levels measured biannually as high as 160 mg/dL; however, the authors have adopted tighter LDL target levels of 130 mg/dL or lower. Initial management should be dietary intervention, but if it is unsuccessful, ezetimibe can be used in children age 10 and older. Statins are not approved for use in children, and cholestyramine is not well tolerated because of gastrointestinal symptoms.
Hypertension is a known risk factor for both atherosclerosis and nephropathy and should be aggressively treated. Blood pressure should be monitored at each visit, and treatment should be initiated if it is above the 95th percentile for age and sex on at least two occasions. Initial therapy is lifestyle modifications (Step 1 diet), followed by medical therapy with angiotensin-converting enzyme inhibitors if these lifestyle modifications are unsuccessful.
Large, ongoing, multi-center trials are being conducted on different treatment and prevention regimens sponsored by the National Institutes of Diabetes, Digestive and Kidney Diseases (Studies to Treat or Prevent Pediatrie Type 2 Diabetes [STOPP-T2D]). The treatment arm of this initiative is called the TODAY trial (Treatment Options for type 2 Diabetes in Adolescents and Youth). Patients are randomized into one of three treatment arms: metformin alone, metformin and a thiazolidenedione, or metformin and an intensive lifestyle program. Results of these trials are still to come. Regardless of the outcome of the TODAY trial, primary prevention of obesity, a critical link in the worldwide epidemic of obesity, must be addressed if we are to deal effectively with pediatrie type 2 diabetes.
1. Savage PJ, Bennett PH, SenterRG, Miller M. High prevalence of diabetes in young Pima Indians: evidence of phenotypic variation in a genetically isolated population. Diabetes. 1979;28(10):937-942.
2. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr. May 1996; 128(5 Pt l):608-6 15.
3. Silverstein JH, Rosenbloom AL. Type 2 diabetes in children. Curr Diab Rep. 2001;1(1):19-27.
4. SEARCH for Diabetes in Youth Study Group, Liese AD, D'Agostino RB, et al. The Burden of Diabetes Mellitus Among US Youth: Prevalence Estimates From the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510-1518.
5. Kitagawa T, Owada M, Urakami T, Yamauchi K. Increased incidence of non-insulin dependent diabetes mellitus among Japanese schoolchildren correlates with an increased intake of animal protein and fat. Clin Pediatr (Phila). 1998;37(2):111-115.
6. Dean H NIDDM-Y in First Nation children in Canada. CKn Pediatr (Phila). 1998;37(2):89-96.
7. Cockram CS. The epidemiology of diabetes mellitus in the Asia-Pacific region. Hong Kong Med J. 2000;6(1):43-52.
8. Caprio S, Tamborlane WV. Metabolic impact of obesity in childhood. Endocrinol Metab Clin North Am. 1999;28(4):731-747.
9. Caprio S, Plewe G, Diamond MP, et al. Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity. J Pediatr. 1989;114(6):963-967.
10. Wei JN, Sung FC, Li CY, et al. Low birth weight and high birth weight infants are both at an increased risk to have type 2 diabetes among schoolchildren in Taiwan. Diabetes Care. 2003;26 (2): 343-348.
11. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(Suppl 1):S5-S20.
12. Type 2 diabetes in children and adolescents. American Diabetes Association. Diabetes Care. 2000;23(3):38 1-389.
13. Kaufman FR. Type 2 diabetes in children and youth. Endocrinol Metab Clin North Am. Sep 2005;34(3):659-676, ix-x.
14. Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am. 2005;23(3):629-648, vii.
15. Ebbeling CB, Leidig MM, Sinclair KB, Hangen JP, Ludwig DS. A reduced-glycemic load diet in the treatment of adolescent obesity. Arch Pediatr Adolesc Med. 2003; 157(8):773-779.
16. Kaufman FR. Type 2 diabetes mellitus in children and youth: a new epidemic. J Pediatr Endocrinol Metab. 2002;15(Suppl 2):737-744.
17. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2002;25(1):89-94.
18. American Diabetes A. Management of dyslipidemia in children and adolescents with diabetes. Diabetes Care. 2003;26(7):2194-2197.