Philip Zeitler

A clinical trial to maintain glycemic control in youth with type 2 diabetes.

BACKGROUNDnDespite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes.nnnMETHODSnEligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin.nnnRESULTSnOf the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P=0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants.nnnCONCLUSIONSnMonotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328.).

Acute and chronic complications of type 2 diabetes mellitus in children and adolescents

With the increase in prevalence of type 2 diabetes mellitus in adolescents, a rise in incidence of secondary comorbidities--including hypertension, hyperlipidaemia, nephropathy, and retinopathy--is anticipated. Furthermore, findings of studies in young adults have suggested that the development and progression of clinical complications might be especially rapid when the onset of type 2 diabetes is early, raising the possibility of a serious public-health challenge in the next few decades. To date, reports of the epidemiology and natural history of secondary complications specifically in adolescents with type 2 diabetes have been scarce. Yet, we must begin to understand the extent of the coming challenge. To this end, we have reviewed reports on acute and long-term comorbidities associated with type 2 diabetes in young people and have looked at mounting evidence that this group could be at increased risk for development of early complications.

Characteristics of Adolescents and Youth with Recent-Onset Type 2 Diabetes: The TODAY Cohort at Baseline

CONTEXTnThe Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort represents the largest and best-characterized national sample of American youth with recent-onset type 2 diabetes.nnnOBJECTIVEnThe objective of the study was to describe the baseline characteristics of participants in the TODAY randomized clinical trial.nnnDESIGNnParticipants were recruited over 4 yr at 15 clinical centers in the United States (n = 704) and enrolled, randomized, treated, and followed up 2-6 yr.nnnSETTINGnThe study was conducted at pediatric diabetes care clinics and practices.nnnPARTICIPANTSnEligible participants were aged 10-17 yr inclusive, diagnosed with type 2 diabetes for less than 2 yr and had a body mass index at the 85th percentile or greater.nnnINTERVENTIONSnAfter baseline data collection, participants were randomized to one of the following groups: 1) metformin alone, 2) metformin plus rosiglitazone, or 3) metformin plus a lifestyle program of weight management.nnnMAIN OUTCOME MEASURESnBaseline data presented include demographics, clinical/medical history, biochemical measurements, and clinical and biochemical abnormalities.nnnRESULTSnAt baseline the cohort included the following: 64.9% were female; mean age was 14.0 yr; mean diabetes duration was 7.8 months; mean body mass index Z-score was 2.15; 89.4% had a family history of diabetes; 41.1% were Hispanic, 31.5% were non-Hispanic black; 38.8% were living with both biological parents; 41.5% had a household annual income of less than

Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 Pediatric Official Positions.

25,000; 26.3% had a highest education level of parent/guardian less than a high school degree; 26.3% had a blood pressure at the 90th percentile or greater; 13.6% had a blood pressure at the 95th percentile or greater; 13.0% had microalbuminuria; 79.8% had a low high-density lipoprotein level; and 10.2% had high triglycerides.nnnCONCLUSIONSnThe TODAY cohort is predominantly from racial/ethnic minority groups, with low socioeconomic status and a family history of diabetes. Clinical and biochemical abnormalities and comorbidities are prevalent within 2 yr of diagnosis. These findings contribute greatly to our understanding of American youth with type 2 diabetes.

Diabetic Ketoacidosis Among Obese African-American Adolescents With NIDDM

Osteoporosis in adults has been defined on the basis of densitometric criteria, but at present the term osteoporosis does not have a widely recognized definition in pediatrics. Consequently, the International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference reviewed the literature describing the relationship between bone densitometric studies and fractures in apparently healthy children and adolescents, and prepared Official Positions regarding the definition of osteoporosis in children and adolescents. The ISCD Official Positions with respect to the above issues, as well as the rationale and evidence used to derive these positions, are presented here.

48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome

OBJECTIVE To determine whether ketosis at the time of presentation occurs among African-American adolescents with NIDDM. RESEARCH DESIGN AND METHODS We reviewed the charts of all islet cell antibody (ICA) negative patients diagnosed with NIDDM at Childrens Hospital Medical Center (CHMC) between 1982 and 1995. RESULTS Between 1982 and 1985, 70 adolescents were diagnosed with NIDDM. Of these, ICA determinations were available and negative on 42 subjects (28 African-American, 12 white). Twelve of 28 (42%) African-American patients presented with ketonuria, and seven of 28 (25%) presented with DKA. In comparison, none of the 12 white adolescents with NIDDM had ketonuria at presentation or during their subsequent course. Mean follow-up time for patients with ketosis at presentation was 24 months. There was no difference between the age, BMI, or sex distribution of patients with and without ketosis. Previously diagnosed hypertension was present in 42% of patients presenting with ketosis, compared with 17% of the general NIDDM population at CHMC. CONCLUSIONS We conclude that ketosis may occur among African-American adolescents with NIDDM, as has been previously reported among African-American adults with NIDDM. Therefore, ketosis in obese young African-American patients with new-onset diabetes does not necessarily imply the presence of IDDM and insulin dependence.

Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents.

Sex chromosome tetrasomy and pentasomy conditions occur in 1:18u2003000–1:100u2003000 male births. While often compared with 47,XXY/Klinefelter syndrome because of shared features including tall stature and hypergonadotropic hypogonadism, 48,XXYY, 48,XXXY and 49,XXXXY syndromes are associated with additional physical findings, congenital malformations, medical problems and psychological features. While the spectrum of cognitive abilities extends much higher than originally described, developmental delays, cognitive impairments and behavioural disorders are common and require strong treatment plans. Future research should focus on genotype–phenotype relationships and the development of evidence‐based treatments.

Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities

Abstract:u2002 The presence of fatty liver per ultrasound and liver‐associated enzymes were measured in a select cohort of youth with both obesity and insulin resistance, and the effect of metformin on these parameters evaluated. Fifty obese, multiethnic, insulin‐resistant adolescents (mean age 15.1u2003yr, mean body mass index 39.8u2003kg/m2) were randomized to receive lifestyle recommendations plus either twice per day doses of 850u2003mg of metformin or placebo. Fasting and post‐glucose challenge biochemistries and liver ultrasounds were compared at baseline and 6u2003months. The prevalence of fatty liver was 74%, elevated alanine aminotransferase (ALT) 14%, aspartate aminotransferase (AST) 14%, and gamma‐glutamyl transferase (GGT) 17%. Fatty liver was mild in 23%, moderate in 31%, and severe in 46%. Fatty liver was more common in male and Hispanic subjects and elevated ALT more common in Hispanic subjects. Subjects with fatty liver appeared more insulin resistant (higher fasting insulin and triglycerides, lower high‐density lipoprotein cholesterol) and had higher ALT and AST. At 6u2003months, mean ALT, GGT, and fasting insulin improved significantly in all subjects. Fatty liver prevalence (pu2003<u20030.04), severity (pu2003<u20030.04), and fasting insulin (pu2003<u20030.025) improved significantly with metformin compared to placebo. Non‐alcoholic fatty liver disease (NAFLD) occurs with a high prevalence and severity in obese, insulin‐resistant adolescents. While metformin plus lifestyle intervention appears promising, defining NAFLD therapies capable of preventing fibrosis and cirrhosis requires further study.

Cardiovascular Risk Factors Among Youth With and Without Type 2 Diabetes: Differences and possible mechanisms

Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments.

Rhinocerebral mucormycosis complicated by internal carotid artery thrombosis in a pediatric patient with type 1 diabetes mellitus: a case report and review of the literature

OBJECTIVE—To compare cardiovascular disease (CVD) risk factors among recently diagnosed youth with type 2 diabetes and nondiabetic youth and investigate whether demographic, behavioral, or metabolic factors might account for observed differences. RESEARCH DESIGN AND METHODS—Data from 106 type 2 diabetic and 189 nondiabetic multiethnic youth, aged 10–22 years, were analyzed. Prevalence of CVD risk factors were age and race/ethnicity adjusted using direct standardization. Multiple linear regression models were sequentially adjusted for demographic, behavioral (dietary saturated fat intake and physical activity), and metabolic (body adiposity and glycemia) factors to explore possible mechanisms associated with differences in CVD risk factors between the case and control groups. RESULTS—Compared with control subjects, youth with type 2 diabetes had a higher prevalence of elevated blood pressure, obesity, large waist circumference, low HDL cholesterol, high triglycerides, and high albumin-to-creatinine ratio (P < 0.05 for each risk factor). Type 2 diabetic youth also had higher levels of apolipoprotein B, fibrinogen, interleukin (IL)-6, C-reactive protein, and leptin; lower adiponectin levels; and denser LDL particles (P < 0.05 for each risk factor). Adjustment for BMI, waist circumference, and A1C substantially attenuated differences in the CVD risk factors between the case/control groups, except for fibrinogen and IL-6, which remained significantly higher in type 2 diabetic youth. CONCLUSIONS—Compared with control youth, type 2 diabetic youth have a less favorable CVD risk factor profile. Adiposity and glycemia are important contributors to differences in CVD risk profiles among type 2 diabetic and control youth. Inflammatory and prothrombotic factors may also play an important role.