The risk factors for youth T2DM are discussed under the following four broad categories: (1) genetics, (2) environment, (3) ethnicity, and (4) insulin resistance phenotype.
Genetics: family history of type 2 diabetes mellitus
The cause of T2DM is heterogeneous, including social, behavioral, and environmental risk factors in addition to a strong hereditary component [42,56]. Although few susceptibility genes have been identified thus far , the genetic component of T2DM is evidenced by the strong heritability of the disease . Studies in adult twins demonstrate a 50% to 76% concordance rate of T2DM in monozygotic twins, 37% in dizygotic twins, and a heritability estimate for T2DM of 26% and for abnormal glucose tolerance of 61% [58,59]. A 40% lifetime risk of developing T2DM has been reported in first-degree relatives of persons with T2DM .
A strong family history of T2DM is present in most pediatric patients regardless of ethnic background [2,32,33]. Markers of insulin resistance and beta-cell dysfunction are present in adult members of high-risk populations one to two decades before the diagnosis of the disease [56,61,62] and predict the progression to T2DM . In adults, insulin secretion adjusted for the degree of insulin sensitivity is a highly heritable trait, more familial than either insulin sensitivity or insulin secretion alone . Our studies demonstrate that family history of T2DM is associated with approximately 25% lower insulin sensitivity in prepubertal healthy African-American children compared with their peers without a family history of T2DM . Similarly, white children who do not have diabetes but have a positive family history for T2DM have lower insulin sensitivity with an inadequate compensation in insulin secretion, which results in a lower glucose disposition index compared with youth without a family history of diabetes . The superimposition of environmental factors, such as obesity and sedentary lifestyle, on this familial phenotype of an impaired balance between insulin secretion and insulin resistance may lead to T2DM over time.
Environment: behavior and lifestyle translate into a risk for obesity and altered body fat distribution
The increased prevalence of T2DM in childhood has been linked to the epidemic of childhood obesity in the United States and around the world [67,68]. The increasing prevalence of obesity  over a relatively short time span has been attributed to environmental factors that promote energy surplus [70,71] and sedentary lifestyle [72,73], rather than a change in the genetic pool
[74,75]. The effects of obesity on glucose metabolism are evident early in childhood. Percent body fat and BMI are proportional directly to fasting insulin levels (as a surrogate marker of insulin resistance) and inversely to glucose disposal in children and adolescents [76-78].
In a recent investigation of youth who do not have diabetes, our group demonstrated that obesity is associated with approximately 50% lower levels of the protective adipocytokine adiponectin in white adolescents . Hypoadipo-nectinemia was a strong and independent correlate of insulin resistance, beta-cell dysfunction, and increased abdominal adiposity . Adiponectin levels were approximately 50% lower in adolescents who had T2DM than obese non-diabetic controls, despite similar body composition and visceral adiposity . Weyer and associates  reported lower plasma adiponectin levels in adult Pima Indians with IGT and T2DM than in individuals with NGT.
Independent of total body adiposity and ethnicity, abdominal fat deposition (visceral adiposity) is considered a risk factor for insulin resistance in children [77,80,81] and T2DM in adults . Obese children with IGT were found to have peripheral insulin resistance without compensatory insulin secretion  and higher visceral and intramuscular fat .
Most pediatric patients with T2DM in the United States belong to minority ethnic populations, which encompass Native Americans, Pima Indians, Mexican Americans, and African Americans [1,84,85]. Among the Pima Indians, more than 5% of the 15- to 19-year old children are affected ; the pathogenesis of T2DM is attributed to a genetic predisposition to insulin resistance modified by lifestyle changes . Epidemiologic and clinical studies indicate that black children are more hyperinsulinemic and insulin resistant than their white peers [87-90]. A study that used genetic admixture analysis suggested a genetic and environmental basis to these differences . We recently showed that despite 30% lower visceral adiposity in black adolescents, insulin sensitivity was not better than that of their white peers . Black obese adolescents with high visceral fat manifested suboptimal compensatory increase in insulin secretion, which resulted in a lower glucose disposition index . The levels of the anti-diabetogenic hormone adiponectin are lower in African-American compared with white healthy children of similar body composition . These findings suggest racial differences in diabetogenic profile, with higher risk of progression to T2DM in blacks. Similarly, insulin sensitivity was found to be significantly lower in Hispanic compared with non-Hispanic white children .
Insulin resistance phenotype
Insulin resistance is a major feature of the conditions discussed in association with higher risk for type 2 diabetes.
Most youth who have T2DM present at a mean age of 13.5 years, around the time of puberty [56,85]. Puberty is associated with transient insulin resistance that manifests as hyperinsulinemia in response to an oral glucose tolerance test  and to intravenous glucose tolerance test . Measurement of in vivo insulin sensitivity using the hyperinsulinemic-euglycemic clamp technique demonstrated that insulin sensitivity is on average 30% lower in adolescents between Tanner stages II and IV of puberty, compared with prepubertal children and young adults [96-98]. In the presence of normally functioning pancreatic beta-cells, puberty-related insulin resistance is compensated by increased insulin secretion , which leads to peripheral hyperinsulinemia. The transient increase in growth hormone secretion during normal puberty, but not sex steroids, seems to be the most probable cause of the transient insulin resistance of puberty [89,100].
Insulin resistance and hyperinsulinemia are major components of polycystic ovary syndrome (PCOS) in obese and lean adult women and in adolescent girls [101,102]. PCOS affects 5% to 10% of women in the reproductive age group and is characterized by hyperandrogenism and amenorrhea or oligomenorrhea secondary to chronic anovulation . Thirty percent to 40% of women with PCOS have IGT, and 7.5% to 10% have T2DM by the fourth decade [103,104]. A recent study of screening PCOS adolescents with oral glucose tolerance test showed IGT in approximately 30% and diabetes in approximately 4% . Our studies revealed that insulin sensitivity is approximately 50% lower in obese adolescents who have PCOS versus matched controls . Adolescents who have PCOS and IGT have 40% lower first-phase insulin secretion and lower glucose disposition index compared with adolescents with NGT . The presence of this metabolic profile in the early course of PCOS significantly increases the risk of progression to T2DM.
Acanthosis nigricans is a diffuse hyperplasia of the spinous layer of the skin that manifests as a velvety, hyperkeratotic darkening of the skin. It involves the intertriginous regions, including the base of the neck, the axillae, the antecubital areas, and the beltline. It is associated with obesity, insulin resistance, and hyperinsulinemia. It is present in up to 90% of children and adolescents who have T2DM [1,85]. Its prevalence is 25-fold higher in African Americans compared with other populations . The prevalence of T2DM is six times higher in African-American individuals with acanthosis nigricans . A study in which subjects were preselected for the presence of acanthosis found that the prevalence of IGT was 24% in individuals with acanthosis nigricans . Adiposity, rather than acanthosis nigricans, is a better clinical predictor of insulin resistance in African-American, white, and Hispanic children [110,111]. Obese individuals without acanthosis nigricans should not be presumed to have normal insulin sensitivity.
Exposure to gestational diabetes or intrauterine growth retardation
Both extremes of overnutrition and undernutrition of a fetus during critical time of growth seem to have long-term effects on obesity and glucose tolerance [112,113]. Offspring of mothers with diabetes during pregnancy have a higher frequency of childhood obesity and earlier onset of diabetes [113,114]. A prospective study found that the prevalence of IGT in the offspring of mothers with a diabetic pregnancy increased with time from 1.2% at < 5 years of age to 19.3% at 10.6 years of age [115,116]. Conversely, low birth weight reflective of in utero growth deprivation has been linked to insulin resistance, which leads to adult-onset obesity, T2DM, and cardiovascular disease [112,117]. The intrauterine programming hypothesis has been supported by some clinical studies [118,119]; others have challenged it . Studies in young adults and in the pediatric age group have been few and conflicting, with some studies suggesting decreased insulin resistance in children born small for gestational age [121-123] and others suggesting that the major defect is in insulin secretion . Other studies suggest that obesity is a more powerful determinant of insulin resistance than size at birth [125,126]. In studies of Indian and British children, the highest levels of insulin resistance were in children of low birth weight but high BMI and fat mass in childhood [122,127]. A major deficiency in many of these studies is the absence of body composition and body fat topography evaluation, especially because a recent study showed a negative association between abdominal fat and birth weight .
Clinical indicators of insulin resistance include hypertension  and dys-lipidemia [88,129,130]. Triglyceride levels and triglyceride/high density lipo-protein ratio are simple clinical markers that may help to identify overweight adolescents with insulin resistance. We have found that a triglyceride level > 130 mg/dL and triglyceride/high density lipoprotein > 3 predicts in vivo insulin resistance, as measured by hyperinsulinemic-euglycemic clamp, in white, overweight adolescents .
Clinical presentation and diagnosis of youth type 2 diabetes mellitus
The criteria for the diagnosis of diabetes, based on standard values of fasting blood glucose, random blood glucose, and the oral glucose tolerance test, are the same for adults and children (Table 2) . Normal fasting plasma glucose is less than 100 mg/dL subsequent to the 2003 revision by the ADA that lowered the threshold separating normal from elevated fasting plasma glucose from 110 mg/dL to 100 mg/dL . Based on revised criteria, patients with fasting
Criteria for the diagnosis of impaired glucose tolerance and diabetes
OGTT: 2 h PG Random
Abbreviations: IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; 2 h PG, plasma glucose at 2 hours after ingestion of glucose.
a Polyuria, polydipsia, weight loss. Data from American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus: follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26(11):3161.
plasma glucose levels between 100 and 125 mg/dL have impaired fasting glucose. Patients with fasting plasma glucose levels > 126 mg/dL have diabetes. A random or "casual" plasma glucose value > 200 mg/dL indicates diabetes if the patient has additional symptoms, such as polyuria and polydipsia. During an oral glucose tolerance test, a 2-hour plasma glucose value of < 140 mg/dL is considered normal, > 140 and < 200 mg/dL is considered IGT, and > 200 mg/dL indicates diabetes.
Screening of children and adolescents at risk for type 2 diabetes mellitus
T2DM in adults may be asymptomatic for years, yet findings of microangio-pathic damage in newly diagnosed patients with T2DM indicate that complications of diabetes often predate the diagnosis of clinical diabetes [133,134]. Aggressive treatment of diabetes has been shown to retard the development of vascular complications , thus early identification of children with T2DM may prevent or lessen the severity of comorbidities. Criteria for screening children and adolescents at risk for developing T2DM have been put forth by the ADA (Box 1) . BMI should be plotted by health care providers annually on the Centers for Disease Control and Prevention BMI growth charts, which are specific for age and sex. Screening for diabetes among children with a BMI at or above the eighty-fifth percentile for age and sex with two additional risk factors for T2DM should be part of routine pediatric care.
Screening should commence at 10 years of age or at onset of puberty, if it occurs at a younger age, and should be performed every 2 years. The ADA recommends fasting plasma glucose as a screening tool because of its lower cost and greater convenience . This recommendation is in contrast to the World Health Organization recommendation of an oral glucose tolerance test based on evidence from adult populations that shows that approximately 30% of all persons with undiagnosed diabetes have a nondiabetic fasting glucose  but are nevertheless at high cardiovascular risk . A study in obese children with IGT showed that the prevalence of impaired fasting glucose (based on the
Box 1. Screening guidelines for type 2 diabetes mellitus in children and adolescents
• BMI >eighty-fifth percentile for age and gender or
• Body weight for height > eighty-fifth percentile or
Plus any two of the following risk factors:
• Family history of type 2 diabetes in first- or second-degree relatives
• Race/ethnicity (American Indian, African American, Hispanic, Asian/Pacific Islander)
• Signs/symptoms of insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome)
When to screen: age 10 or at onset of puberty, if puberty occurs at a younger age
Frequency of screening: every 2 years
Screening test: fasting plasma glucosea
Clinical judgment should be used to test for diabetes in high-risk patients who do not meet these criteria. We agree with authorities who recommend a 2-hour postprandial glucose value as a more sensitive index of evolving diabetes mellitus. Fasting hyperglyce-mia is a late manifestation of failing glucose homeostasis.
a Fasting plasma glucose is the test recommended by the American Diabetes Association.
Data from American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:381-9.
former threshold of > 110 mg/dL) was low (< 0.08%) . A report from our institution revealed that the new ADA criteria for impaired fasting glucose (100-125 mg/dL) not only yield a higher number of overweight children at risk for abnormalities of glucose metabolism but also suggest that even at a young age, youth with impaired fasting glucose have worse cardiovascular risk profiles than youth with normal fasting glucose . The prevalence of IGT and T2DM in children varies depending on the population studied. An obesity clinic-based study found 25% IGT in 4- to 10-year-old patients and 21% IGT in 11- to 18-year-old patients and approximately 4% T2DM . Other studies have found much lower rates of IGT that range from 4.1% to 4.5% in children recruited from the community [140,141].
Additional studies are needed to compare diabetes diagnostic categories in pediatric populations according to the ADA versus the World Health Organization diagnostic criteria before arriving at valid conclusions.
Presentation of type 2 diabetes mellitus and ketosis-prone diabetes
T2DM in children and adults may present in various ways that represent a spectrum of severity. On one end of the spectrum is asymptomatic presentation with diagnosis of glucosuria/incidental hyperglycemia on routine screening. In the Japanese experience, from among more than 7 million school children, 188 were detected by routine screening for glucosuria followed by an oral glucose tolerance test . Symptomatic patients may have candidal vulvovagi-nitis, polyuria, polydipsia, weight loss, headaches, or fatigue. The severe end of the spectrum harbors manifestations of insulin deficiency, however. As is in patients with T1DM, the relative deficiency of insulin in patients with T2DM can lead to diabetic ketosis/ketoacidosis (DKA). In its extreme form, DKA or hyperglycemic hyperosmolar nonketotic state/coma may be the initial presenting picture.
Approximately 5% to 25% of adolescents who are subsequently classified as having T2DM have ketoacidosis at presentation. These patients may have ketoacidosis without any associated stress, other illness, or infection . Pinhas-Hamiel and colleagues  reported that 42% of African-American adolescents with T2DM had ketonuria and 25% had DKA. On the contrary, none of the 12 American white adolescents diagnosed with T2DM within the same period had ketonuria. Another study reported that approximately 30% of Hispanic youth with T2DM may present with ketosis .
Genetic pancreatic beta-cell defects may predispose to the development of insulinopenia and ketosis, which lead to atypical diabetes in some populations, particularly African Americans [144-146]. Such patients are insulin resistant with acute, severe defects in insulin secretion that are not immune mediated [147,148]. After the institution of therapy, some endogenous insulin secretory capacity may be recovered , and normoglycemic remission may occur .
Pancreatic autoantibodies in youth type 2 diabetes mellitus
Once the diagnosis of diabetes is established, it is important to distinguish between T1DM and T2DM to optimize therapy. Given the heterogeneity of clinical presentation of T2DM in children, especially when DKA is present, classification into type 1 or type 2 diabetes cannot always be made reliably on the basis of clinical presentation. Additional testing has been proposed by the ADA Consensus Group using the obesity phenotype as the starting point . Clinical signs helpful in distinguishing T2DM from T1DM are obesity, signs of insulin resistance, and elevated C-peptide levels. It should be noted that the prevalence of obesity in children diagnosed with T1DM is increasing , which makes it more difficult to distinguish T2DM from T1DM.
Markers of the cellular-mediated immune destruction of the beta-cell, such as islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase-like protein autoantibodies, and insulin autoantibodies, are usually identifiable in individuals with or at risk for autoimmune T1DM. One or more of these autoantibodies are present in 85% to 90% of children with T1DM at initial diagnosis, compared with less than 5% of nondiabetic controls [152-154]. T2DM is not considered an autoimmune disease; however, as many as 10% to 15% of adults with apparent T2DM develop a clinical condition characterized by progression into insulin-dependent DM and autoimmune markers, referred to as latent autoimmune diabetes of adulthood [60,155,156]. Data from the UKPDS, which measured ICA and GADA at diagnosis of T2DM in 3672 patients of European background who were between 25 and 65 years of age, revealed that 12% of patients had either ICA or GADA, and 4% had both. At all ages, but more in the younger age group, the presence of these autoanti-bodies suggested an increased likelihood that insulin therapy would be required . Other studies suggest that the patients with evidence of autoimmunity have a lower BMI and present more commonly symptomatic with polyuria and poly-dipsia than patients who are antibody negative .
Currently, absence of diabetes autoimmune markers is a prerequisite for the diagnosis of T2DM in children and adolescents . Some contradictory data exist in the literature, however. Observations of First Nation youth of Manitoba with T2DM revealed positive ICA titers in 4 of 14 children who have not required insulin during 10 years of follow-up . A study from Loma Linda, California analyzed 48 children and adolescents with T2DM and 39 with T1DM for the presence of ICA, GADA, and insulin antibodies at diagnosis . The group with T2DM had positive ICA in 8.1%, positive GADA in 30.3%, and positive insulin autoantibodies in 34.8%, in comparison to 71.1%, 75.7%, and 76.5%, respectively, in the T1DM group. One additional study from New York also demonstrated that as evidenced by fasting and 90-minute standard liquid meal stimulated serum C-peptide levels of > 0.2 and >0.5 nmol/L, respectively, 11 of 37 patients (29.7%) with T2DM tested positive for at least one autoantibody (8.1%, 8.1%, and 27% for GADA, tyrosine phosphatase-like protein autoantibodies, and insulin autoantibodies, respectively). It should be mentioned, however, that nine of ten patients who tested positive for insulin autoantibodies were on insulin treatment at time of testing, which influenced the result. Therefore, 10.8% were considered truly positive (for either GADA or tyrosine phosphatase-like protein autoantibodies or both) .
The clinical significance of the presence of autoantibodies in some youth with what seems to be T2DM is uncertain. It is also important to note that currently, pancreatic autoantibody testing methodology is not standardized among commercial and research laboratories. In our research experience we have encountered inconsistencies in pancreatic autoantibodies reported on the same serum sample by various laboratories (S. Arslanian, N. Gungor, unpublished observations) and these issues need clarification. These observations may be in terpreted as a reflection of the broad spectrum of T2DM of youth as a nonuniform disease. Longer prospective studies are needed for definitive conclusions.
Comorbidities and complications of youth type 2 diabetes mellitus
The medical literature on complications of childhood-onset T2DM is scanty. Data that pertain to early morbidities indicate that T2DM of youth is not a benign entity, however. In some series, 17% to 34% of the youth who had T2DM had hypertension [32,33], and 4% to 32% had high triglyceride concentrations at diagnosis [32,162]. Pima Indian children who had diabetes were found to have a high prevalence of cardiovascular risk factors, including hyper-cholesterolemia (7%), hypertension (18%), and microalbuminuria (22%) at diagnosis . Further follow-up of these children between 20 and 29 years of age revealed poor diabetes control (median glycated HbA1c, 12%), with progression of renal impairment, microalbuminuria in 60%, and macroalbuminuria in 17%. In the Northland New Zealand Maori population, microalbuminuria was present at diagnosis in 14% of patients with T2DM diagnosed before the age of 30 years
. In Hong Kong Chinese patients with T2DM diagnosed before age 35, hypertension was present in 18% and abnormal albuminuria was present in 27%
. Similarly there is a high risk for early nephropathy among Japanese persons who develop T2DM before age 30 . Japanese patients with early-onset T2DM developed severe diabetic vascular complications in their thirties, such as blindness or end-stage renal failure . In Manitoba and Northwestern Ontario, follow-up data in youth diagnosed with T2DM before age 17 revealed alarming observations of high mortality rate (9%), morbidity (eg, dialysis, blindness, amputation), pregnancy loss (38%), and poor glycemic control .
Youth with T2DM may present with DKA or hyperglycemic hyperosmolar state (HHS), which are associated with high morbidity and mortality . DKA and HHS may be the presentation of new-onset T2DM or may develop as a complication of inadequate control. Acute decompensation with DKA has been recognized to occur at the time of diagnosis in as many as 25% of children with T2DM . HHS was previously considered a complication in elderly patients with T2DM . Two recent case series, however, brought this condition to attention as an uncommon presentation in T2DM in pediatric patients that can lead to multisystemic organ failure or death [169,170]. The criteria for HHS include plasma glucose concentration > 600 mg/dL, serum carbon dioxide concentration > 15 mmol/L, small ketonuria, absent to low ketonemia, effective serum osmolality > 320 mOsm/kg, and stupor or coma . HHS may not always present with its typical diagnostic criteria, however, and there may be considerable overlap with DKA. Cerebral edema and rhabdomyolysis may accompany HHS or DKA. (See the article by Glaser elsewhere in this issue). The ADA guidelines for fluid rehydration of hyperglycemic crises in patients who have diabetes prescribe a slower fluid resuscitation (48 hours) for patients younger than 20 years with DKA or HHS . Timely diagnosis and prompt and appropriate treatment are the keys for recovery [169,170].
Pediatric patients who have T2DM occasionally may present with the skin manifestation of necrobiosis lipoidica diabeticorum, the incidence of which is 0.3% to 1.2% in patients who have diabetes . Necrobiosis lipoidica dia-beticorum lesions start as painless, reddish brown papules that slowly enlarge to waxy yellow plaques with a depressed central area and elevated purple peripheral ring . Necrobiosis lipoidica diabeticorum lesions may predate the diagnosis of diabetes. The pathogenesis is believed to be unrelated to the adequacy of metabolic control. Recurrent necrobiosis lipoidica diabeticorum that required extensive medical and surgical treatment was reported recently in a 16-year-old morbidly obese girl with poorly controlled T2DM . Despite its rare occurrence, clinicians should be aware of this skin condition and its possible association with T2DM of youth.
Atherosclerotic cardiovascular disease is the major cause of mortality and morbidity in adults who have T2DM . The origin of atherosclerosis is early in childhood with progression toward clinically significant lesions in young adulthood [174,175]. Carotid artery intima media thickness and aortic pulse wave velocity, a measure of arterial stiffness, are noninvasive measures of subclini-cal atherosclerosis that have been used as surrogate measures of cardiovascular events in various adult studies [176-178]. Data regarding intima media thickness and arterial stiffness in children are limited despite the increasing tide of obesity and T2DM. We recently demonstrated significantly higher aortic pulse wave velocity measurements in adolescents with T2DM compared with obese and normal weight controls, with no differences in intima media thickness among the three groups .The elevated aortic pulse wave velocity in our T2DM youth, which reflects increased arterial stiffness, was comparable to values reported in 41- to 59-year-old obese adults  and in approximately 40-year-old men in the Baltimore Longitudinal Study of Aging . Such an observation would be consistent with the premature aging of the cardiovascular system in youth who have T2DM. These findings may reflect early functional changes in the vascu-lature in the absence of ultrasonographically detectable structural changes. With increasing age and duration of diabetes, these functional changes may progress to structural changes if left without intervention. This and similar observations would lend further support to the American Heart Association guidelines of primary prevention of atherosclerotic cardiovascular disease beginning in childhood .
Management of type 2 diabetes mellitus in children
Ideally, the care of a child with T2DM is shared among a physician, diabetes nurse educator, nutritionist, physical activity leader, and behavioral specialist . Conscientious involvement by family members also is necessary for children to reach therapeutic goals. Components of the comprehensive diabetes evaluation are updated annually by the ADA . The goals of treatment of T2DM are to reverse acute metabolic abnormalities, achieve and maintain near-normoglycemic states (fasting blood glucose < 126 mg/dL, HbA1c 7% or less), eliminate symptoms of hyperglycemia, improve insulin sensitivity and secretion, promote achievement of a healthy body weight, screen for and treat comorbidi-ties, and prevent complications of DM [2,19]. The ultimate goal is to decrease the acute and chronic complications associated with DM. The UKPDS and the Kumamoto Study demonstrated that intensive treatment of adults with T2DM improved metabolic control and decreased the risk of microvascular disease [183,184]. In the UKPDS study, for each 1% reduction in mean HbA1c, a 21% reduction in risk for any end point related to diabetes (ie, 21% for deaths, 14% for myocardial infarction, and 37% for microvascular complications) was seen .
Two recent randomized, controlled clinical trials on the prevention of diabetes among adults have demonstrated the benefits of lifestyle intervention on the prevention of progression from IGT to T2DM [186,187]. The impact of such interventions on prevention and treatment of T2DM in children is underway in a national, multicenter, clinical trial. Currently, aggressive lifestyle modification is widely recommended for all children who have risk factors for T2DM, have IGT, or have been diagnosed with T2DM. Lifestyle modification should encompass medical nutrition therapy and increased activity habits.
Patients who present with severe hyperglycemia (> 200 mg/dL), HbA1c more than 8.5%, or severe manifestations of insulin deficiency (eg, ketosis/DKA) should be treated initially with insulin to achieve metabolic control rapidly. Once a child recovers from ketosis after hydration and treatment with insulin, met-formin should be started and insulin may be gradually weaned if normoglycemia is maintained. Deterioration in pancreatic beta-cell function occurs with increasing duration in individuals with T2DM, which necessitates the introduction of insulin to achieve metabolic control [19,52,55]. Evidence in adult patients suggests that the early introduction of insulin therapy may reverse some of the damage imparted by hyperglycemia on pancreatic beta-cells and insulin-sensitive tissues and facilitate glucose control in the long-term . Short-term insulin therapy (< 4 months) with premixed insulin (70/30) in adolescents who have early T2DM (duration 8.7 ± 4.3 weeks) has been shown to improve glycemic control . It is possible that T2DM is more aggressive in certain populations, including children or persons with islet cell autoantibodies, and serious consideration should be given to starting insulin early [19,55].
New insulin analogs allow for enhanced, more flexible dosing. Ultra-short-acting analogs (eg, insulin lispro, insulin aspart) allow for immediate insulin action and relatively rapid clearance from the blood stream. The ultra-long-acting analog (eg, insulin glargine) is systemically absorbed from the subcutaneous tissues slowly, has a relatively smooth blood concentration profile, and has a prolonged duration of action (approximately 24 hours), which makes it useful as a once-a-day basal insulin . Clinical trials in adults with T2DM have shown insulin glargine to promote optimal glycemic control effectively . Clinical therapeutic studies are needed to examine the optimal combinations of oral agents or insulin preparations for treatment of T2DM in pediatric populations. (See the article by Jacobson-Dickman and Levitsky elsewhere in this issue).
Children and adolescents who present with mild hyperglycemia (fasting plasma glucose, 126-199 mg/dL) and HbAlc less than 8.5% can be treated initially with therapeutic lifestyle change in combination with metformin, which has been shown to be safe and effective for use in pediatric patients . Metformin, a biguanide, decreases hepatic glucose production and increases insulin-mediated glucose uptake in peripheral tissues, primarily muscle tissue [67,193], and is the only drug approved by the US Food and Drug Administration for pediatric patients who have T2DM. Metformin is prescribed to non-ketotic patients at a low dose (500 mg twice a day or 850 mg once a day, given with meals) and increased as tolerated (in increments of 500 mg or 850 mg every 2 weeks, up to a total of 2000 mg/d). Side effects associated with metformin include gastrointestinal discomfort and, on rare occasion, lactic acidosis [67,193]. Metformin should not be given to a child who has T2DM and ketosis, renal impairment, abnormal liver enzymes, cardiopulmonary insufficiency, or is undergoing evaluation with radiographic contrast materials, because it may precipitate lactic acidosis. Therapy should be intensified whenever glucose control is not achieved after 3 to 6 months. Fig. 4 provides a working algorithm for the management of youth who have T2DM, based on our current knowledge and approved therapies (Fig. 4) .
Sulfonylureas (eg, glimepiride, glyburide, glipizide) and meglitinides (eg, re-paglinide, nateglinide) are insulin secretagogues that exert their effect in the presence of glucose . Unlike metformin, sulfonylureas are associated with hypoglycemia and weight gain , which can be particularly troublesome for children and adolescents. Thiazolidinediones (eg, rosiglitazone, pioglitazone) reduce hepatic glucose production, increase glucose uptake by muscle, and inhibit lipolysis in adipose tissue . Edema, weight gain, anemia, and liver damage may occur with thiazolidinediones . Clinical trials are under way with thia-zolidinediones and sulfonylureas in pediatric patients who have T2DM. Clinical trials in adult patients who have T2DM demonstrate that all four classes of oral glucose-lowering agents improve HbA1c similarly (reduction of 1%-2%) .
Approval of these drugs for use in children will greatly expand the armament of treatment options for T2DM in the pediatric population.
Children who have T2DM and their families, regardless of whether they are receiving insulin treatment, should receive intensive diabetes education, including education regarding routine self-monitoring of blood glucose. Glucose levels should be monitored frequently, especially when medications are being adjusted, when symptoms of diabetes are present, and during acute illness. As with individuals who have T1DM, patients who have T2DM should check urinary ketones with a dipstick at such times. Routine glucose self-monitoring should include fasting and postprandial measurements. Diabetes therapy should be prescribed and titrated to maintain fasting glucose levels between 70 and 126 mg/dL. We recommend the same follow-up regimen for individuals who have T2DM as for persons with T1DM: clinical follow-up every 3 months with measurement of HbA1c and monitoring of complications as outlined later. The ADA recommends a goal HbA1c of less than 7% , whereas the American College of Endocrinology recommends a more stringent goal of < 6.5%, based on evidence that shows that there is no minimum level of HbA1c at which complications of diabetes and mortality do not occur .
Management of complications
Acute complications of T2DM, including DKA and hyperosmolar coma (ie, hyperglycemia, hyperosmolarity, and an absence of significant ketosis), can be life threatening. The clinical features of DKA and hyperosmolar coma overlap and often are observed simultaneously. Patients who present with either of these complications should be managed in an inpatient setting by a medical team with expertise in the appropriate fluid replacement, insulin therapy, correction and replacement of electrolytes, neurologic/mental status evaluation, and airway management for youth who have DKA [2,169,170].
Blood pressure should be monitored regularly. Height- and age-specific population-based blood pressure percentiles for boys and girls are available . A systolic and diastolic blood pressure less than the ninetieth percentile, adjusted for age, sex, and height, is normal. Prehypertension is defined as either systolic or diastolic blood pressure between the ninetieth and ninety-fifth per-centile for age, sex, and height. Stage 1 hypertension is either systolic or diastolic blood pressure more than or equal to the ninety-fifth percentile for age, sex, and height. Stage 2 hypertension is present if either the systolic or diastolic blood pressure is more than the ninety-ninth percentile plus 5 mm Hg.
Lifestyle modifications in the form of weight loss, dietary changes, and increased physical activity form the foundation of initial therapy for children with hypertension. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and diuretics have been used to treat children who have hypertension who do not respond to lifestyle modification. We recommend that all children who have stage 2 hypertension undergo additional renal evaluation, and our preference for medical therapy is initiation of angiotensin-converting enzyme inhibitors.
Fasting lipid profile should be obtained upon diagnosis, after glucose control has been established, and annually thereafter. Target lipid levels and treatment recommendations for youth who have diabetes have been established by the ADA consensus for the treatment of diabetes in youth (Table 3) . Separate and somewhat different target levels for children were recommended recently by the American Heart Association . Recommended lipid levels were as follows: total cholesterol < 170 mg/dL (170-200 mg/dL borderline), low density lipoprotein (LDL) < 130 mg/dL (110-130 mg/dL borderline), triglycerides < 150 mg/dL, and high density lipoprotein >35 mg/dL . Because diabetes is a major risk factor for cardiovascular disease, the more stringent ADA guidelines seem appropriate for youth who have T2DM.
Therapeutic dietary changes and increased physical activity are the first-line treatment for dyslipidemia in children. Lipid-lowering medications can be considered if lipids remain elevated after 6 months of lifestyle modification [199,201]. HMG-CoA reductase inhibitors (statins) are the most commonly used lipid-lowering agents in pediatric patients. Statins (eg, atorvastatin, lovastatin, pravastatin) are currently indicated for use after an adequate trial of lifestyle
Management of dyslipidemia in youth with type 2 diabetes mellitus
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