The emergence of type 2 diabetes in the pediatric population1,2 places many children and adolescents at risk for specific complications and comorbidities. Furthermore, even greater numbers of youth have prediabetes or metabolic syndrome, both of which carry specific risks as well. Pediatricians should be aware of recommended screening practices, preventive measures, and treatment options to lessen the risks incurred by these three conditions.
The definition of diabetes is based on the risk of developing specific vascular complications. It has long been known that a person's degree of hyperglycemia predicts risk of specific complications. Therein, diabetes mellitus is defined as hyperglycemia sufficiently elevated to predict future risk of microvascular diabetic complications (Table 1, see page 712), especially retinopathy. Other microvascular complications of diabetes include nephropathy and neuropathy.
Diabetes also predicts future risk of macrovascular complications, such as coronary artery disease, stroke, or peripheral vascular disease. However, macrovascular risk begins to accrue at a lower glycémie threshold, which means people with prediabetes (Table 1) are also at risk. In addition, people with prediabetes are at risk for progression to type 2 diabetes. In fact, the technical definition of prediabetes is based on glucose levels that predict risk of progression to diabetes. Metabolic syndrome is not defined by glycémie levels alone but rather is a constellation of pathophysiologic features that track with insulin resistance and predict future risk of cardiovascular disease and possible progression to diabetes.
Children and adolescents with type 2 diabetes, prediabetes, or metabolic syndrome often have comorbid conditions such as hypertension or dyslipidemia. These are not related to hyperglycemia per se but rather to the obesity and insulin resistance that almost invariably are present. All comorbidities must be recognized and treated.
Thus, a number of children and adolescents are at risk for complications and comorbidities of type 2 diabetes, prediabetes, or metabolic syndrome. These entities define levels of risk, with type 2 diabetes comprising the smallest group but the highest risk (Figure 1, see page 712). A larger number of children and adolescents have prediabetes and are at risk of macrovascular disease and progression to type 2 diabetes. Likewise, an even larger number of children and adolescents have multiple components of metabolic syndrome and are at risk of future cardiovascular disease, as well as for progression to prediabetes or type 2 diabetes.
Glycemic Thresholds Predicting Future Risk
LONG-TERM COMPLICATIONS OF DIABETES
The hyperglycemia and metabolic dysregulation of diabetes injure blood vessels, eventually leading to end-organ damage. People with diabetes of any etiology - whether type 1 or type 2 - are at risk for these vascular complications. These chronic complications of diabetes are classified into one of two categories, microvascular or macrovascular (Table 2, see page 713).
Figure I.GIycemia predicts vascular complications. Prediabetes predicts risk of macrovascular complications, whereas diabetes predicts not only risk for macrovascular but also for microvascular complications. Note that prediabetes is more common than type 2 diabetes. The dotted arrows represent the risk of progression over time from prediabetes to type 2 diabetes.
The microvascular complications of diabetes include damage to the retina, kidney, and peripheral nerves, termed diabetic retinopathy, nephropathy, and neuropathy respectively. These are accrued chronically, over years of hyperglycemia. However, because type 2 diabetes can present insidiously, with years of occult hyperglycemia proceeding diagnosis, diabetic complications may be present at the time of initial diagnosis. Thus, screening for complications should be initiated promptly after diagnosis of type 2 diabetes and should continue at regular intervals thereafter. Although most studies of complications in type 2 diabetes have been performed in the adult population, it is clear that people with youth-onset type 2 diabetes develop microvascular complications at nearly the same rate as their adult counterparts (Figure 2, see page 713).
Studies in adults with type 2 diabetes have strongly established two modifiable risk factors for the development of microvascular disease: hyperglycemia and hypertension. Furthermore, prospective randomized trials have shown that intensive blood glucose control and tight blood pressure control delay the progression of microvascular disease in adults with type 2 diabetes.3,4 Additional modifiable risk factors that likely contribute to microvascular disease include smoking and dyslipidemia.
Diabetes-associated retinopathy is a progressive disorder that affects the microvasculature of the retina and is the leading cause of acquired blindness among people of working age in the US. Nearly all patients with diabetes will develop the mildest stage, termed background retinopathy. This can progress to the intermediate pre-proliferative stage and, in many patients, will deteriorate to the proliferative stage, which carries high risk of visual loss due to hemorrhage or retinal detachment.
Fortunately, vigilant screening allows detection of retinopathy at early stages, allowing sight-preserving treatment before vision is lost. Laser retinal photocoagulation therapy is very effective at preserving vision when sight-threatening retinopathy is present. Thus, annual screening (Table 3, see page 714) for retinal changes in patients with diabetes is essential and should be performed through dilated pupils by eye specialists trained and experienced in the detection and treatment of retinopathy.
Retinopathy can progress rapidly during pregnancy or when metabolic control changes drastically. Although frequent retinal screening is prudent in such situations, improving diabetes control remains paramount.
Diabetes-associated nephropathy is a progressive disorder of the microvasculature of the kidney and is the most common cause of end stage renal disease in Western countries. Mcroalbuminuria is the earliest nephropathy stage that is readily detectable and eventually occurs in 20% to 35% of patients with type 2 diabetes. Mcroalburmnuria is predictive of progression to the next clinical stage of nephropathy, termed overt albuminuria, which often is accompanied by systemic hypertension and impaired glomerular filtration. A portion of patients with overt albuminuria progress to end-stage renal disease.
Annual screeningfor microalbuminuria is advocated to detect incipient nephropathy (Table 3). Screening can be performed by measurement of the albumin to creatinine ratio in a urine specimen. The test should be specifically ordered for "microalbumin," not "albumin," as conventional urine albumin tests are of insufficient sensitivity. Timed collections can be more accurate, although less convenient, than spot samples. Upright posture or exercise can yield false positive results. Thus, frßt-morning-void urine samples have the advantage of higher specificity. It is recommended that microalbuminuria be confirmed in at least two of three collections before the diagnosis of mioroalbuminuria is considered. Once microalbummuria is present, the progression of nephropathy can be delayed by improvements in hemoglobin AlC, control of hypertension, and treatment with angiotensin-converting enzyme (ACE) inhibitors.
Complications of Diabetes
Early signs of diabetes-associated neuropathy include loss of ankle reflexes and decreased vibration sense or touch sensation. Annual screening should begin at puberty, examining for loss of touch sensation in the great toe to 5.07 nylon monofilament exam (Table 3).
The macrovascular complications of diabetes include coronary artery, peripheral vascular, and cerebral vascular diseases. Macrovascular events are the greatest overall cause of morbidity and mortality in people with type 2 diabetes. Comparison of people with onset of type 2 diabetes during early versus later adulthood shows that the relative risk of macrovascular events is much higher in those who develop type 2 diabetes at a younger age (Figure 3, see page 714). Data examining the relative risks of macrovascular events in people with youth-onset type 2 diabetes have not been published, but the possibility that the age-dependent risk trend among adults extends into the pediatric age range is alarming.
Figure 2. Microvascular complications stratified by age of type 2 diabetes onset. These data show that individuals with youth-onset type 2 diabetes have no age-related protection against nephropathy and only a slight lag in the onset of retinopathy.
Studies in adults with type 2 diabetes have strongly established hypertension and dyslipidemia as modifiable risk factors contributing to macrovascular risk. Moreover, randomized intervention trials consistently have shown significantly reduced macrovascular risk when hypertension or dyslipidemia are managed aggressively. Management guidelines for the control of these factors in children and adolescents are described in subsequent sections of this article. Smoking cessation likewise is an important aspect of macrovascular risk reduction among children and adolescents with type 2 diabetes (Sidebar 1, see page 715).
Screening for Microvascular Complications
Existing data are insufficient to establish whether intensive glycémie control reduces the risk of macrovascular events in adults with type 2 diabetes. It is generally agreed, based on existing data, that intensive management of blood glucose levels in type 2 diabetes has no detrimental effect on macrovascular risk. However, subgroup analysis of obese adults with type 2 diabetes suggests that improvement of blood sugar levels with the insulin-sensitizing agent metformin leads to decreased macrovascular risk, compared with treatment with insulin or sulfonylureas.4 For this reason, metformin is considered by many to be the agent of first choice for the treatment of type 2 diabetes in people whose hyperglycemia can be managed with a single oral agent and when there are no contraindications to its use.
Figure 3. Myocardial infarction relative-risk stratified by age of onset of type 2 diabetes. These data show that onset of type 2 diabetes earlier in life confers greater relative risk of myocardial infarction compared to controls. It is possible that if this trend continues, individuals with youth-onset type 2 diabetes have even higher relative risk.
Other Chronic Complications of Diabetes
Limited joint mobility manifests as inability to extend the fingers or wrist to a normal extent, occurring due to skin inelasticity or thickening or tendinous contraction. The presence of limited joint mobility is associated with increased risk of microvascular complications.
Necrobiosis lipoidica diabeticorum is a rare complication involving chronic granulomatous skin disease, most commonly in the pretibial area. Satisfactory treatment often is elusive, although intralesional injection of corticosteroids is commonly used to provide some relief.
COMORBIDITIES OF TYPE 2 DIABETES
Children and adolescents with type 2 diabetes are also at risk for a number of comorbid conditions, including hypertension, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). These comorbidities may be present before type 2 diabetes develops and are thought likely related to the obesity and insulin resistance that are strongly associated with pediatric type 2 diabetes, rather than to hyperglycemia per se. Along these lines, children and adolescents with prediabetes or metabolic syndrome are at risk for these comorbidities as well,5 whereas people with type 1 diabetes are not routinely at primary risk for these comorbidities.
Primary (ie, essential) hypertension once was considered rare in the pediatric population. However, with the increasing prevalence of obesity, secondary hypertension, such as that resulting from renal disease, has become less common than primary hypertension in youth.6
Timely diagnosis is essential, as hypertension is an independent risk factor for the development of nephropathy, retinopathy, and cardiovascular disease in type 2 diabetes. Thus, blood pressure should be measured in all children and adolescents with type 2 diabetes during each routine health care visit.7 Blood pressure should be taken with the patient resting in the sitting position, recording the first and fifth Korotkoff sounds as systolic and diastolic pressure. If an elevated reading is obtained, it should be repeated later in the visit to minimize the "white coat effect" - increased blood pressure caused by the anxiety of the office visit. Use of an appropriate blood pressure cuff length and width for the upper arm of the small obese patient may be challenging. Ideally, an appropriate cuff size should have a bladder width that is approximately 40% of the arm circumference midway between the olecranon and the acromion processes.8
Hypertension is currently defined as average systolic or diastolic blood pressure at the 95th percentile or higher for gender, age, and height on at least three occasions. Prehypertension in children is defined as average systolic or diastolic blood pressure levels that are greater than or equal to the 90th percentile but less than the 95th percentile. Updated population-based percentiles for blood pressure values in children, adjusted for age, gender, and height, are available readily.8
The preferred therapies for primary hypertension are diet, exercise, and weight reduction. Indeed, weight loss among overweight adolescents clearly is associated with a decrease in blood pressure;9,10 reduction of body mass index by approximately 10% has been shown to diminish blood pressure by 8 to 12 mmHg.
When hypertension does not respond to lifestyle modifications, antihypertensive therapy with a single agent is indicated. Angiotensin-Converting enzyme (ACE) inhibitors or angiotensin-receptor blockers are the agents of choice because of their cardiovascular and renal benefits in type 2 diabetes.8,11 Therapy should be initiated at the lowest recommended dose, titrating upwards until the blood pressure goal is achieved. Serum creatinine and potassium should be checked monthly during the first 2 to 3 months of treatment.
ACE inhibitors are teratogenic (Pregnancy Category D) in the second and third trimesters, and alternative agents should be considered for girls at risk for pregnancy. If ACE inhibition is not discontinued with pregnancy planning, it is important to identify pregnancy early so that that alternative therapy can be instituted. Anti-hypertensive options in such cases might include diltiazem extended release (Category C) or the beta-blockers acebutolol, labetalol, or metoprolol (Categories B-C). The beta-blocker atenolol (Category D) must be avoided in pregnancy. Beta-blockers can impair hypoglycemia awareness and thus may be less than ideal in individuals taking insulin or oral agents with risk of hypoglycemia, such as the sulfonylureas.
The term dyslipidemia refers to an atherogenic serum lipid profile that may consist of increased low-density lipoprotein (LDL) cholesterol, decreased high-density lipoprotein (HDL) cholesterol, or increased serum triglycerides. It is well established, based on large, prospective, randomized clinical trials that included adults with type 2 diabetes, that pharmacologic therapy aimed at lowering LDL in people with dyslipidemia results in significant reduction of cardiovascular events.
Analogous trials in the pediatric age range have not been reported. Nonetheless, the genesis of coronary atherosclerosis often occurs by late adolescence, and it is generally thought that children and adolescents with type 2 diabetes, prediabetes, or metabolic syndrome are at increased risk for coronary events early in adulthood. For these reasons, the American Diabetes Association (ADA) has published consensus-based guidelines for the treatment of dyslipidemia in youth with diabetes,12 developed primarily by extrapolation of guidelines for adults with type 2 diabetes.
According to these guidelines, all children and adolescents with type 2 diabetes should be screened, preferably in the fasting state, for dyslipidemia with a lipid profile to include total cholesterol, LDL, HDL, and triglycerides. The initial screening should be performed once metabolic stabilization is achieved. If normal lipid values are obtained, lipid screening should be repeated every 2 years.
Many laboratories measure LDL indirectly based on the total cholesterol, HDL, and triglycerides levels, using Friedewald's equation: LDL = total cholesterol - HDL - triglycerides/5. When triglycerides are elevated above 200 mg/dL, the indirect approach loses accuracy, and direct measurement of LDL is preferred.13 When the calculated LDL is borderline, the greater accuracy of direct LDL measurement may be beneficial. Optimal lipid levels for children and adolescents with diabetes have been suggested as LDL below 100 mg/dL, HDL above 35 mg/dL, and triglycerides below 150 mg/dL. "Elevated" levels are greater than 200mg/dL for total cholesterol and greater than 130 mg/dL for LDL cholesterol.
When lipid levels are not optimal, the initial recommended intervention is dietary, specifically the American Heart Association (AHA) step 2 diet, with a goal dietary cholesterol of less than 200 mg/day and saturated fat making up less than 7% of total calories.14 Follow-up fasting lipid profiles should be performed at 3 months and again at 6 months. If treatment goals are achieved, the lipid profile should be repeated yearly.
Figure 4. Progression from prediabetes to type 2 diabetes was slowed significantly by intensive lifestyle modification, which included goals of 7% weight loss, 1 50 minutes of weekly exercise,and intensive nutritional modification. Metformin also diminished progression risk, although to a lesser degree. These data were collected in adults.
If, after 6 months of dietary therapy and tight glucose control, LDL remains above 160 mg/dL, pharmacologic therapy is recommended in children older than 10. Pharmacologic treatments options include resins (bile acid séquestrants) such as cholestyramine and colestipol hydrochloride. These typically are recommended as the first-line treatment option for dyslipidemia in children and adolescents. However, compliance rates with this class of medications often are so low, owing to frequency of dosing and adverse gastrointestinal effects, that therapeutic efficacy is lacking.
Therefore, HMG-CoA (3-hydroxy3-methylglutaryl coenzymeA) reductase inhibitors (statins) should be considered. Recent studies indicate excellent efficacy and safety of statins in adolescents.15 Initially, the lowest recommended statin dose should be used. The dose can be increased gradually as dictated by the LDL level and the occurrence of side effects. Liver function tests should be monitored periodically, and the statin should be discontinued if test results are three times the upper limit of normal.
Rhabdomyolysis is a rare adverse effect of statin therapy. Obtaining a baseline creatinine Phosphokinase (CPK) level should be considered in patients receiving insulin therapy before beginning statin treatment because, on occasion, inadvertent intramuscular administration of insulin can result in an elevated CPK level. Therefore, documenting the level before statin therapy can be useful. If persistent muscle pain or soreness occurs during therapy, the statin should be stopped and a repeat CPK level checked.
Statins are thought to be teratogenic and are not approved for use during pregnancy. Their risks and benefits in sexually active adolescent females must be weighed carefully.
The term NAFLD refers to pathologic lipid overload of the liver of varying types and severity. The primary risk factors for NAFLD in childhood are thought to be obesity and insulin resistance. Therefore, as the prevalence of obesity in youth increases, fatty liver is being recognized with increased frequency.
The pathologic finding in NAFLD is macrovesicular steatosis, an accumulation of large lipid droplets that displace and condense the nuclei of hepatocytes. This is associated with varying degrees of hepatic inflammation and fibrosis.16 Without inflammation or fibrosis, steatosis has an indolent, often benign clinical course. However, if inflammation is present, the condition is termed nonalcoholic steatohepatitis (NASH), which may progress to chronic liver disease with fibrosis and cirrhosis.
NAFLD and NASH are asymptomatic in the large majority of patients, and laboratory findings are often nonspecific. Typically, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are twofold to fivefold elevated, and the AST to ALT ratio is less than 1. Occasionally, alkaline phosphatase levels are abnormal. Bilirubin is not elevated, and albumin and prothrombin time values are normal until the latest stages of disease.
The prevalence of NAFLD in children and adolescents is not known. However, the Third National Health and Nutrition Examination Survey (NHANES HI)17 found abnormal ALT values in 1.5%, 5.0%, and 9.5% of normal weight, overweight, and obese adolescents, respectively.18
Routine care of children and adolescents with type 2 diabetes should include physical examination for hepatomegaly and monitoring of serum aminotransferase values as screening for liver disease. Those patients found to have persistent abnormalities should undergo diagnostic testing to exclude other causes of liver disease (eg, hepatitis C virus infection, Wilson's disease, autoimmune hepatitis, alcoholic liver disease). If no other cause is found, NAFLD may be the likely diagnosis, and a trial of gradual weight reduction is recommended. If the hepatic abnormalities fail to resolve, or if evidence of advanced liver disease is present, gastroenterologist consultation, abdominal imaging, and liver biopsy should be considered.
No large therapeutic trials for NAFLD in type 2 diabetes have been reported. Treatment is aimed at gradually reducing obesity and improving insulin resistance while maintaining glycémie control. Overzealous dieting with rapid weight loss can exacerbate hepatic fibrosis. Alcohol consumption should be avoided.
The Food and Drug Administration warns against use of metformin in patients with liver disease, due to the risk of exacerbating lactic acidosis. However, metformin has not been implicated in causing hepatic damage. Furthermore, metformin has been studied for the treatment of NAFLD in several small trials, with no reported toxicity.19"21 Because of the small numbers and nonrandomized nature of these trials, no specific recommendations for use of metformin for treatment of NAFLD can be made. However, because metformin is often the agent of first choice for the treatment of type 2 diabetes, it may be reasonable to proceed with metformin therapy in children and adolescents with type 2 diabetes in the setting of a mildly elevated ALT as long as transaminase values are followed closely and consultation obtained if the elevations worsen or fail to resolve.
Prediabetes refers to an intermediate level of hyperglycemia that is sufficient to predict risk of progression to diabetes as well as risk of future macrovascular complications.22 Whether these cutoffs are representative in children and adolescents of diabetes risk and macrovascular risk remains to be determined.
Prediabetes may be diagnosed (Table 1) either by elevated fasting plasma glucose, termed impaired fasting glucose (IFG), or by an elevated oral glucose tolerance test (OGTT) response, termed impaired glucose tolerance (IGT). Among adults, the presence of IGT may be more predictive of future cardiovascular disease than IFG. Prediabetes may be prevalent in children and adolescents with pronounced obesity, with measured rates approaching 25% when determined by OGTT.2 It is reported23,24 that IFG alone is uncommon in children and adolescents, such that an OGTT may be a much more sensitive test to determine the presence of prediabetes in this population.
Studies aimed at reducing the rate of progression from prediabetes to type 2 diabetes have been performed in adults with important, encouraging results.25 Intensive lifestyle modification, with goals of 7% weight loss coupled with 150 minutes per week of moderate-intensity exercise and a low-calorie diet, led to a 58% reduction in the progression to type 2 diabetes during the ensuing 4 years when compared with standard advice (Figure 4, see page 716). Metformin, an insulin sensitizer, likewise was efficacious in delaying progression to type 2 diabetes, although the effect was more modest at 3 1 %. Thus, the diagnosis of prediabetes in an adolescent or child represents an opportunity to begin lifestyle intervention that will significantly delay progression to type 2 diabetes.
Metabolic syndrome represents the association among several common metabolic, anthropomorphic, and vascular abnormalities that cluster with insulin resistance and increased risk of atherosclerotic disease.26 The syndrome has various names, including Syndrome X, insulin resistance syndrome, and dysmetabolic syndrome.
Although there is no universally accepted definition of metabolic syndrome, most guidelines require several of the following factors: obesity, hyperglycemia (prediabetes or type 2 diabetes), high triglycerides, low HDL, or hypertension (Sidebar 2). While many of the individual components of metabolic syndrome are associated with atherosclerotic processes early in adulthood,27"29 the collective effect of multiple childhood components of metabolic syndrome on clinical endpoints remains to be determined.
The prevalence of metabolic syndrome among children and adolescents has been estimated at 4% to 30%, depending upon the criteria used and population studied. Currently, there is no specific therapy for metabolic syndrome other than lifestyle intervention aimed at sustained reduction of obesity. Individual components of metabolic syndrome should be screened for and treated when indicated. This is especially true in children and adolescents who have multiple components, because they likely are at high risk for ensuant atherosclerosis.
A number of children and adolescents are at risk for complications and comorbidities of type 2 diabetes, prediabetes, or metabolic syndrome. These complications and comorbidities are likely to present significant personal burdens and societal costs. The pediatrician should be aware of screening and interventions to lessen the effect of these risks on their patients. Societal-wide lifestyle changes are needed desperately to reduce the prevalence of these largely preventable diseases.
1. Pinhas-Hamiel O, Dolan LM, Daniels SR, et al. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. / Pediatr. 1996;128(5 Pt 1):608-615.
2. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346(11): 802-810.
3. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998; 317(7160):703-713.
4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-865.
5. Vaccaio O, Imperatore G, Iovino V, et al. Does impaired glucose tolerance predict hypertension? A prospective analysis. Diabetologia. 1996;39(l):70-76.
6. Sorof J, Daniels S. Obesity hypertension in children: a problem of epidemic proportions. Hypertension. 2002;40(4):441447.
7. Alberti G, Zirrtmet P, Shaw J, et al.; Consensus Workshop Group. Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. Diabetes Care. 2004;27(7): 1798-1 811.
8. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004; 1 14(2 Suppl 4th Report):555-576.
9. Rocchini AP, Key J, Bondie D, et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med. 1989;321(9):580-585.
10. Rocchini AP, Katch V, Anderson J, et al. Blood pressure in obese adolescents: effect of weight loss. Pediatrics. 1988;82(1): 16-23.
11. Miller K. Pharmacological management of hypertension in paediatric patients. A comprehensive review of the efficacy, safety and dosage guidelines of the available agents. Drugs. 1994;48(6):868-887.
12. American Diabetes Association. Management of dyslipidemia in children and adolescents with diabetes. Diabetes Care. 2003; 26(7):2194-2197.
13. Branchi A, Rovellini A, Torri A, Sommariva D. Accuracy of calculated serum low -density lipoprotein cholesterol for the assessment of coronary heart disease risk in NTDDM patients. Diabetes Care. 1998;21(9):1397-1402.
14. Kavey RE, Daniels SR, Lauer RM, et al.; American Heart Association. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003; 107(11): 1562-1566.
15. de Jongh S, Ose L, Szamosi T, et al.; Simvastatin in Children Study Group. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, doubleblind, placebo-controlled trial with simvastatin. Circulation. 2002; 106(17):223 1-2237.
16. Jonas MM. Nonalcoholic fatty liver disease. Adolesc Med CHn. 2004;15(1): 159-173, xi.
17. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med. 2003;157(8):821-827.
18. Strauss RS, Barlow SE, Dietz WH. Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. / Pediatr. 2000;136(6):727-733.
19. Nair S, Diehl AM, Wiseman M, Fair GH, Perrillo RP Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20(l):23-28.
20. Duseja A, Murlidharan R, Bhansali A, et al. Assessment of insulin resistance and effect of metformin in nonalcoholic steatohepatitis - a preliminary report. Indian J Gastroenterol. 2004;23(1):12-15.
21. Marchesini G, Brizi M, Bianchi G, et al. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358(9285):893-894.
22. Genuth S, Alberti KG, Bennett P, et al.; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26(11):3 160-3167.
23. Wiegand S, Maikowski U, Blankenstein O, et al. Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity - a problem that is no longer restricted to minority groups. Eur J Endocrinol. 2004;151(2):199-206.
24. Reinehr T, Andler W, Kapellen T, et al. Clinical characteristics of type 2 diabetes mellitus in overweight European Caucasian adolescents. Exp Clin Endocrinol Diabetes. 2005;113(3):167-170.
25. Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393403.
26. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595-1607.
27. Bao W, Srinivasan SR, Berenson GS. Persistent elevation of plasma insulin levels is associated with increased cardiovascular risk in children and young adults. The Bogalusa Heart Study. Circulation. 1996;93(l):54-59.
28. Weiss R, Dziura J, Bürgert T, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350(23):2362-2374.
29. Raitakari OT, Juonala M, Kanonen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA. 2003;290(17):2277-2283.
Glycemic Thresholds Predicting Future Risk
Complications of Diabetes
Screening for Microvascular Complications