Lawrence M. Dolan

Increased incidence of non-insulin-dependent diabetes mellitus among adolescents

OBJECTIVE To determine whether a rise in the diagnosis of non-insulin- dependent diabetes mellitus (NIDDM) has accompanied the rise in obesity in the pediatric population, as it has among adults. STUDY DESIGN Medical records of 1027 consecutive patients from birth to age 19 years with a diagnosis of diabetes from 1982 to 1995 at a regional, university-affiliated pediatric diabetes referral center were reviewed and classified according to criteria of the National Diabetes Data Group. RESULTS The number of patients with a diagnosis of NIDDM rose from approximately 4% of new diagnoses of diabetes in patients from birth to age 19 years before 1992, to 16% in 1994. Among patients 10 to 19 years of age, NIDDM accounted for 33% of diagnoses of diabetes in 1994. The incidence of adolescent NIDDM in Greater Cincinnati increased tenfold, from 0.7/100,000 per year in 1982 to 7.2/100,000 per year in 1994. The mean (+/- SD) age and body mass index at presentation were 13.8 +/- 1.9 years and 37.7 +/- 9.6 kg/m2, respectively. The overall female/male ratio was 1.7:1, and female patients were seen 1 year earlier than male patients (p < 0.01). Male subjects had a higher body mass index than female subjects (p < 0.05). A first-degree relative with NIDDM was identified for 65% of patients. At presentation, 21% of the patients had had a diagnosis of at least one other condition associated with obesity. CONCLUSION There is an increasing incidence of NIDDM among adolescents in Greater Cincinnati, accompanying the national rise in adolescent obesity. Obesity and strong family histories of NIDDM are important risk factors. Because NIDDM leads to long-term morbidity, the prevention of obesity as well as early identification of overt disease, is critical.

The SEARCH for Diabetes in Youth study: rationale, findings, and future directions.

The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support from the National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U.S. and represents the largest, most diverse study of diabetes among U.S. youth. An active registry of youth diagnosed with diabetes at age <20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. Many youth with diabetes, particularly those from low-resourced racial/ethnic minority populations, are not meeting recommended guidelines for diabetes care. Markers of micro- and macrovascular complications are evident in youth with either diabetes type, highlighting the seriousness of diabetes in this contemporary cohort. This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions.

Instability in the Diagnosis of Metabolic Syndrome in Adolescents

Background— Factor analyses suggest that the structure underlying metabolic syndrome is similar in adolescents and adults. However, adolescence is a period of intense physiological change, and therefore stability of the underlying metabolic structure and clinical categorization based on metabolic risk is uncertain. Methods and Results— We analyzed data from 1098 participants in the Princeton School District Study, a school-based study begun in 2001–2002, who were followed up for 3 years. We performed factor analyses of 8 metabolic risks at baseline and follow-up to assess stability of factor patterns and clinical categorization of metabolic syndrome. Metabolic syndrome was defined using the current American Heart Association/National Heart, Lung, and Blood Institute definition for adults (AHA), a modified AHA definition used in prior pediatric metabolic syndrome studies (pediatric AHA), and the International Diabetes Federation (IDF) guidelines. We found that factor structures were essentially identical at both time points. However, clinical categorization was not stable. Approximately half of adolescents with baseline metabolic syndrome lost the diagnosis at follow-up regardless of the definitions used: pediatric AHA=56% (95% confidence interval [CI], 42% to 69%), AHA=49% (95% CI, 32% to 66%), IDF=53% (95% CI, 38% to 68%). In addition to loss of the diagnosis, new cases were identified. Cumulative incidence rates were as follows: pediatric AHA=3.8% (95% CI, 2.8% to 5.2%); AHA=4.4% (95% CI, 3.3% to 5.9%); IDF=5.2% (95% CI, 4.0% to 6.8%). Conclusions— During adolescence, metabolic risk factor clustering is consistent. However, marked instability exists in the categorical diagnosis of metabolic syndrome. This instability, which includes both gain and loss of the diagnosis, suggests that the syndrome has reduced clinical utility in adolescence and that metabolic syndrome–specific pharmacotherapy for youth may be premature.

Presence of Diabetic Ketoacidosis at Diagnosis of Diabetes Mellitus in Youth: The Search for Diabetes in Youth Study

OBJECTIVE. The purpose of this work was to determine the prevalence and predictors of diabetic ketoacidosis at the diagnosis of diabetes in a large sample of youth from the US population. PATIENTS AND METHODS. The Search for Diabetes in Youth Study, a multicenter, population-based registry of diabetes with diagnosis before 20 years of age, identified 3666 patients with new onset of diabetes in the study areas in 2002–2004. Medical charts were reviewed in 2824 (77%) of the patients in a standard manner to abstract the results of laboratory tests and to ascertain diabetic ketoacidosis at the time of diagnosis. Diabetic ketoacidosis was defined by blood bicarbonate <15 mmol/L and/or venous pH < 7.25 (arterial/capillary pH < 7.30), International Classification of Diseases, Ninth Revision, code 250.1, or listing of diabetic ketoacidosis in the medical chart. RESULTS. More than half (54%) of the patients were hospitalized at diagnosis, including 93% of those with diabetic ketoacidosis and 41% without diabetic ketoacidosis. The prevalence of diabetic ketoacidosis at the diagnosis was 25.5%. The prevalence decreased with age from 37.3% in children aged 0 to 4 years to 14.7% in those aged 15 to 19 years. Diabetic ketoacidosis prevalence was significantly higher in patients with type 1 (29.4%) rather than in those with type 2 diabetes (9.7%). After adjusting for the effects of center, age, gender, race or ethnicity, diabetes type, and family history of diabetes, diabetic ketoacidosis at diagnosis was associated with lower family income, less desirable health insurance coverage, and lower parental education. CONCLUSION. At the time of diagnosis, 1 in 4 youth presents with diabetic ketoacidosis. Those with diabetic ketoacidosis were more likely to be hospitalized. Diabetic ketoacidosis was a presenting feature of <10% of youth with type 2. Young and poor children are disproportionately affected.

Factor Analysis of Clustered Cardiovascular Risks in Adolescence Obesity Is the Predominant Correlate of Risk Among Youth

Background—Clustering of cardiovascular (CV) risks begins in childhood, yet studies of the factor structure underlying this clustering have focused on adults. The increasing rates of obesity and type 2 diabetes and the growing importance of metabolic syndrome among adolescents make assessment of CV risk clustering even more urgent in this age group. Methods and Results—Exploratory factor analysis (principal components analysis) was performed with data from 1578 healthy seventh to 12th graders from the Princeton School District Study, a school-based study in Cincinnati, Ohio. Measured CV risks included cholesterol, triglycerides, fasting insulin and glucose, body mass index (BMI), waist circumference, fibrinogen, and blood pressure. Factor analysis yielded 4 uncorrelated factors (adiposity [BMI, waist, fibrinogen, insulin], cholesterol [LDL and total cholesterol], carbohydrate-metabolic [glucose, insulin, HDL cholesterol, triglycerides], and blood pressure [systolic and diastolic blood pressure]). These factors explained approximately 67% of the total variance. A summary cumulative risk scale was derived from factor scores, and high risk was defined as scoring in the top 5%. Although insulin loaded onto both the adiposity and carbohydrate-metabolic factors, obesity was a much stronger correlate of high cumulative risk (odds ratio=19.2; 95% CI, 7.6 to 48.5) than hyperinsulinemia (odds ratio=3.5; 95% CI, 1.8 to 6.8). A sizable proportion (18.5%; n=12) of those who were at high cumulative risk were not at high risk for any of the individual factors. Conclusions—The patterning of CV risk clustering seen among adults is present in healthy adolescents. Among youth, obesity is the predominant correlate of cumulative risk.

Reversal of Type 2 Diabetes Mellitus and Improvements in Cardiovascular Risk Factors After Surgical Weight Loss in Adolescents

OBJECTIVES. Type 2 diabetes mellitus is associated with obesity, dyslipidemia, and hypertension, all well-known risk factors for cardiovascular disease. Surgical weight loss has resulted in a marked reduction of these risk factors in adults. We hypothesized that gastric bypass would improve parameters of metabolic dysfunction and cardiovascular risk in adolescents with type 2 diabetes mellitus. PATIENTS AND METHODS. Eleven adolescents who underwent Roux-en-Y gastric bypass at 5 centers were included. Anthropometric, hemodynamic, and biochemical measures and surgical complications were analyzed. Similar measures from 67 adolescents with type 2 diabetes mellitus who were treated medically for 1 year were also analyzed. RESULTS. Adolescents who underwent Roux-en-Y gastric bypass were extremely obese (mean BMI of 50 ± 5.9 kg/m2) with numerous cardiovascular risk factors. After surgery there was evidence of remission of type 2 diabetes mellitus in all but 1 patient. Significant improvements in BMI (−34%), fasting blood glucose (−41%), fasting insulin concentrations (−81%), hemoglobin A1c levels (7.3%–5.6%), and insulin sensitivity were also seen. There were significant improvements in serum lipid levels and blood pressure. In comparison, adolescents with type 2 diabetes mellitus who were followed during 1 year of medical treatment demonstrated stable body weight (baseline BMI: 35 ± 7.3 kg/m2; 1-year BMI: 34.9 ± 7.2 kg/m2) and no significant change in blood pressure or in diabetic medication use. Medically managed patients had significantly improved hemoglobin A1c levels over 1 year (baseline: 7.85% ± 2.3%; 1 year: 7.1% ± 2%). CONCLUSIONS. Extremely obese diabetic adolescents experience significant weight loss and remission of type 2 diabetes mellitus after Roux-en-Y gastric bypass. Improvements in insulin resistance, β-cell function, and cardiovascular risk factors support Roux-en-Y gastric bypass as an intervention that improves the health of these adolescents. Although the long-term efficacy of Roux-en-Y gastric bypass is not known, these findings suggest that Roux-en-Y gastric bypass is an effective option for the treatment of extremely obese adolescents with type 2 diabetes mellitus.

Increased Arterial Stiffness is Found in Adolescents with Obesity or Obesity-Related Type 2 Diabetes Mellitus

Objective Adults with obesity or obesity-related type 2 diabetes (T2DM) are at higher risk for cardiovascular disease possibly due to increased arterial stiffness. We sought to determine if arterial stiffness is increased in youth with obesity or T2DM as compared with lean controls. Methods Youth age 10–24 years (N = 670, 62% non-Caucasian, 35% male) were examined. They were stratified by the 85th% of BMI as lean (L=241), obese (O=234) or obese with T2DM (T2DM=195). Questionnaire, anthropometric, BP, laboratory (fasting glucose, insulin, HbA1c, lipids, CRP), physical activity, and DXA were collected. Brachial artery distensibility (BrachD), pulse wave velocity (PWV) and augmentation index (AIx) were measured. Group differences were evaluated by ANOVA. General linear multivariate models were constructed to elucidate independent determinates of arterial stiffness. Results CV risk profile deteriorated from L to O to T2DM group. There was a progressive increase in AIx and PWV-trunk with progressive decline in BrachD from L to O to T2DM individuals (all P < 0.05). Group (status as L, O or T2DM) was an independent predictor of arterial stiffness even after adjusting for CV risk factors. Conclusion Arterial stiffness is increased in young individuals with obesity and obesity-related T2DM even after correction for risk factors.

Youth With Obesity and Obesity-Related Type 2 Diabetes Mellitus Demonstrate Abnormalities in Carotid Structure and Function

Background— Adults with obesity or type 2 diabetes mellitus (T2DM) are at higher risk for stroke and myocardial infarction. Increased carotid intima-media thickness (cIMT) and stiffness are associated with these adverse outcomes. We compared carotid arteries in youth who were lean, were obese, or had T2DM. Methods and Results— Carotid ultrasound for cIMT measurement was performed, the Young elastic modulus and beta stiffness index were calculated, and anthropometric and laboratory values and blood pressure were measured in 182 lean, 136 obese, and 128 T2DM youth (aged 10 to 24 years). Mean differences were evaluated by ANOVA. Independent determinants of cIMT, Young elastic modulus, and beta stiffness index were determined with general linear models. Cardiovascular risk factors worsened from lean to obese to T2DM groups. T2DM subjects had greater cIMT than that in lean and obese subjects for the common carotid artery and bulb. For the internal carotid artery, cIMT measurements in both obese and T2DM groups were thicker than in the lean group. The carotid arteries were stiffer in obese and T2DM groups than in the lean group. Determinants of cIMT were group, group×age interaction, sex, and systolic blood pressure for the common carotid artery (r2=0.17); age, race, and systolic blood pressure for the bulb (r2=0.16); and age, race, sex, systolic blood pressure, and total cholesterol for the internal carotid artery (r2=0.21). Age, systolic blood pressure, and diastolic blood pressure were determinants of all measures of carotid stiffness, with sex adding to the Young elastic modulus (r2=0.23), and body mass index Z score, group, and group×age interaction contributing to the beta stiffness index (r2=0.31; all P<0.0001). Conclusions— Youth with obesity and T2DM have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors. These vascular changes should alert healthcare practitioners to address cardiovascular risk factors early to prevent an increase in the incidence of stroke and myocardial infarction.

Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012.

BACKGROUND Diagnoses of type 1 and type 2 diabetes in youths present a substantial clinical and public health burden. The prevalence of these diseases increased in the 2001–2009 period, but data on recent incidence trends are lacking. METHODS We ascertained cases of type 1 and type 2 diabetes mellitus at five study centers in the United States. Denominators (4.9 million youths annually) were obtained from the U.S. Census or health‐plan member counts. After the calculation of annual incidence rates for the 2002–2012 period, we analyzed trends using generalized autoregressive moving‐average models with 2‐year moving averages. RESULTS A total of 11,245 youths with type 1 diabetes (0 to 19 years of age) and 2846 with type 2 diabetes (10 to 19 years of age) were identified. Overall unadjusted estimated incidence rates of type 1 diabetes increased by 1.4% annually (from 19.5 cases per 100,000 youths per year in 2002–2003 to 21.7 cases per 100,000 youths per year in 2011–2012, P=0.03). In adjusted pairwise comparisons, the annual rate of increase was greater among Hispanics than among non‐Hispanic whites (4.2% vs. 1.2%, P<0.001). Overall unadjusted incidence rates of type 2 diabetes increased by 7.1% annually (from 9.0 cases per 100,000 youths per year in 2002–2003 to 12.5 cases per 100,000 youths per year in 2011–2012, P<0.001 for trend across race or ethnic group, sex, and age subgroups). Adjusted pairwise comparisons showed that the relative annual increase in the incidence of type 2 diabetes among non‐Hispanic whites (0.6%) was lower than that among non‐Hispanic blacks, Asians or Pacific Islanders, and Native Americans (P<0.05 for all comparisons) and that the annual rate of increase among Hispanics differed significantly from that among Native Americans (3.1% vs. 8.9%, P=0.01). After adjustment for age, sex, and race or ethnic group, the relative annual increase in the incidence of type 1 diabetes was 1.8% (P<0.001) and that of type 2 diabetes was 4.8% (P<0.001). CONCLUSIONS The incidences of both type 1 and type 2 diabetes among youths increased significantly in the 2002–2012 period, particularly among youths of minority racial and ethnic groups. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Centers for Disease Control and Prevention.)

Cardiac and Vascular Consequences of Pre‐Hypertension in Youth

Hypertension is associated with increased left ventricular mass (LVM) and carotid intima‐media thickness (cIMT), which predict cardiovascular (CV) events in adults. Whether target organ damage is found in pre‐hypertensive youth is not known. The authors measured body mass index, blood pressure, fasting glucose, insulin, lipids and C‐reactive protein, LVM/height2.7 (LVM index), diastolic function, cIMT, carotid stiffness, augmentation index, brachial artery distensibility, and pulse wave velocity (PWV) in 723 patients aged 10 to 23 years (29% with type 2 diabetes mellitus). Patients were stratified by blood pressure level (normotensive: 531, pre‐hypertensive: 65, hypertensive: 127). Adiposity and CV risk factors worsened across blood pressure group. There was a graded increase in cIMT, arterial stiffness, and LVM index and decrease in diastolic function from normotension to pre‐hypertension to hypertension. In multivariable models adjusted for CV risk factors, status as pre‐hypertension or hypertension remained an independent determinant of target organ damage for LVM, diastolic function, internal cIMT, and carotid and arterial stiffness. Pre‐hypertension is associated with cardiovascular target organ damage in adolescents and young adults.