Phil Zeitler

Type 2 diabetes in children and adolescents

Arlen L. Rosenblooma, Janet H. Silversteinb, Shin Amemiyac, Phil Zeitlerd and Georgeanna J Klingensmithe abDivision of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; cDivision of Endocrinology, Department of Pediatrics, Saitama Medical University, Saitama, Japan; dDivision of Endocrinology, Department of Pediatrics, The Children’s Hospital, University of Colorado Denver, Aurora, CO, USA; eDepartment of Pediatrics, The Children’s Hospital and Barbara Davis Center, University of Colorado Denver, Aurora, CO, USA. Corresponding author: Professor Emeritus Arlen L Rosenbloom Division of Endocrinology Department of Pediatrics, University of Florida College of Medicine, 1701 SW 16th Avenue Gainesville, FL 32608 USA. e-mail: rosenal@peds.ufl.edu

Insulin Resistance in Adolescents with Type 1 Diabetes and Its Relationship to Cardiovascular Function

CONTEXT Cardiovascular disease is the major cause of death in adults with diabetes, yet little is specifically known about the effects of type 1 diabetes (T1D) on cardiovascular outcomes in youth. Although insulin resistance (IR) likely contributes to exercise and cardiovascular dysfunction in T2D, IR is not typically considered a contributor in T1D. OBJECTIVE We hypothesized that cardiopulmonary fitness would be reduced in T1D youth in association with IR and cardiovascular dysfunction. DESIGN AND PARTICIPANTS This cross-sectional study at an academic hospital included 12 T1D adolescents compared with 12 nondiabetic controls, similar in age, pubertal stage, activity level, and body mass index. OUTCOME MEASURES Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, intramyocellular lipid by magnetic resonance spectroscopy, and body composition by dual-energy x-ray absorptiometry. RESULTS T1D adolescents had significantly decreased VO(2)peak, peak work rate, and insulin sensitivity compared with nondiabetic adolescents. T1D youth also had reduced vascular reactivity and evidence of diastolic dysfunction and left ventricular hypertrophy. Despite their IR and reduced cardiovascular fitness, T1D youth had paradoxically normal intramyocellular lipid, waist to hip ratio, and serum lipids and high adiponectin levels. In multivariate analysis, IR primarily, and forearm blood flow secondarily, independently predicted VO(2)peak. CONCLUSIONS T1D youth demonstrated IR, impaired functional exercise capacity and cardiovascular dysfunction. The phenotype of IR in T1D youth was unique, suggesting a pathophysiology that is different from T2D, yet may adversely affect long-term cardiovascular outcomes.

Rapid rise in hypertension and nephropathy in youth with type 2 diabetes: The TODAY clinical trial

OBJECTIVE Among adolescents with type 2 diabetes, there is limited information regarding incidence and progression of hypertension and microalbuminuria. Hypertension and microalbuminuria assessments made during the TODAY clinical trial were analyzed for effect of treatment, glycemic control, sex, and race/ethnicity. RESEARCH DESIGN AND METHODS A cohort of 699 adolescents, 10–17 years of age, <2 years duration of type 2 diabetes, BMI ≥85%, HbA1c ≤8% on metformin therapy, controlled blood pressure (BP), and calculated creatinine clearance >70 mL/min, were randomized to metformin, metformin plus rosiglitazone, or metformin plus intensive lifestyle intervention. Primary study outcome was loss of glycemic control for 6 months or sustained metabolic decompensation requiring insulin. Hypertension and microalbuminuria were managed aggressively with standardized therapy to maintain BP <130/80 or <95th percentile for age, sex, and height and microalbuminuria <30 μg/mg. RESULTS In this cohort, 319 (45.6%) reached primary study outcome, and 11.6% were hypertensive at baseline and 33.8% by end of study (average follow-up 3.9 years). Male sex and higher BMI significantly increased the risk for hypertension. Microalbuminuria was found in 6.3% at baseline and rose to 16.6% by end of study. Diagnosis of microalbuminuria was not significantly different between treatment arms, sex, or race/ethnicity, but higher levels of HbA1c were significantly related to risk of developing microalbuminuria. CONCLUSIONS Prevalence of hypertension and microalbuminuria increased over time among adolescents with type 2 diabetes regardless of diabetes treatment. The greatest risk for hypertension was male sex and higher BMI. The risk for microalbuminuria was more closely related to glycemic control.

Addition of Metformin to a Lifestyle Modification Program in Adolescents with Insulin Resistance

OBJECTIVE To evaluate whether metformin, when added to a program of personal goal setting, improves weight loss and clinical status in obese adolescents. STUDY DESIGN In a randomized double-blind placebo controlled trial, 85 adolescents with insulin resistance were randomized to receive metformin (70%) or placebo (30%), along with monthly goal setting for diet and exercise modification. Anthropometric measures, fasting blood analysis, and glucose tolerance tests were performed at baseline and 6 months. RESULTS Mean age was 15.7 years. Mean body mass index (BMI) was 39.7 kg/m(2). 71% were female, 58% were Hispanic, and 34% were African-American. 76% of participants completed the study. Goal setting alone did not result in significant weight loss. In addition, there were no group differences between metformin and placebo in weight loss or measures of glucose metabolism. However, among females taking metformin, there was a significant decrease in BMI not seen in the placebo group. Furthermore, metformin adherence, when accompanied by lifestyle change, was a predictor of BMI decrease of 5% or more. 60% of 10 subjects who adhered to metformin and decreased portion size decreased BMI by >5%. CONCLUSIONS In this group of predominately minority adolescents, monthly goal setting alone did not lead to weight loss. Although the addition of metformin had no effect on weight loss overall, the agent did significantly increase weight loss among females and weight loss was predicted by degree of metformin adherence. However, weight loss was only found in those participants also reporting lifestyle change, particularly a decrease in portion sizes. These results suggest that metformin may be a useful agent to promote short-term weight loss among girls making modest lifestyle changes.

Type 2 diabetes mellitus in the child and adolescent

Division of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; Division of Endocrinology, Department of Pediatrics, Saitama Medical University, Saitama, Japan; Division of Endocrinology, Department of Pediatrics, The Children’s Hospital, University of Colorado Denver, Aurora, CO, USA; and Department of Pediatrics, The Children’s Hospital and Barbara Davis Center, University of Colorado Denver, Aurora, CO, USA

Clinical presentation and treatment of type 2 diabetes in children

Abstract:  Type 2 diabetes mellitus (T2DM) has dramatically increased throughout the world in many ethnic groups and among people with diverse social and economic backgrounds. This increase has also affected the young such that over the past decade, the increase in the number of children and youth with T2DM has been labeled an ‘epidemic’. Before the 1990s, it was rare for most pediatric centers to have significant numbers of patients with T2DM. However, by 1994, T2DM patients represented up to 16% of new cases of diabetes in children in urban areas and by 1999, depending on geographic location, the range of percentage of new cases because of T2DM was 8–45% and disproportionately represented among minority populations. Although the diagnosis was initially regarded with skepticism, T2DM is now a serious diagnostic consideration in all young people who present with signs and symptoms of diabetes in the USA.

Hyperglycemic hyperosmolar syndrome in children: Pathophysiological considerations and suggested guidelines for treatment

A.H. received support from the Alberta Diabetes Institute and the Women & Children’s Health Research Institute at University of Alberta. These Clinical Practice Guideline are endorsed by the Lawson Wilkins Pediatric Endocrine Society. They were developed to be of assistance to endocrinologists by providing guidance and yperglycemic hyperosmolar syndrome (HHS), characterized by extreme elevations in serum glucose concentrations andhyperosmolalitywithout significant ketosis, has historically been infrequent in children. However, recent case reports and series describing HHS in children suggests that the incidence of this disorder may be increasing. The epidemiology of HHS in children and adolescents has been reviewed recently. HHS has a high mortality rate, and an understanding of the unique pathophysiology (Figure 1) of this condition is important to guide clinical decision-making. However, although treatment of diabetic ketoacidosis (DKA) in children is familiar to most clinicians, the management of HHS in youth presents a unique set of clinical challenges for which little guidance is currently available. The aim of this review is to discuss the pathophysiology of HHS and to provide broad treatment recommendations on the basis of the available literature and known physiological principles. Criteria for the diagnosis of HHS are listed in Table I. Although HHS is distinct from DKA (Table II; available at www.jpeds.com), patients may present with features of both conditions. HHS occurs less frequently in children than DKA, and some children with DKA can have severe hyperosmolality, complicating the recognition of HHS as a distinct entity. As a result, children with HHS are often treated with DKA protocols. However, the pathophysiology of HHS differs from DKA, and these differences should be considered in planning a rational therapeutic approach. Unlike the usual symptoms of DKA (hyperventilation, vomiting, and abdominal pain), which typically bring children to medical attention, the gradually increasing polyuria and polydipsia of HHS may go unrecognized. As a result, both dehydration and electrolyte loss are profound in HHS; in adults, fluid losses in HHS have been estimated to be twice those of DKA. Furthermore, obesity and hyperosmolality can make the clinical assessment of dehydration unreliable. It has been suggested on the basis of information from small case series that intake of copious quantities of carbonated sugar-enriched drinks before presentation may be a common feature of patients presenting with severe hyperglycemia. Because these case series lack control data, however, it is unclear whether this finding is specific to these patients.

HbA1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Type 2 Diabetes

OBJECTIVE To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy. RESEARCH DESIGN AND METHODS TODAY was a randomized clinical trial of adolescents with type 2 diabetes. Two groups, including participants from all three treatments, were defined for analysis: 1) those who remained in glycemic control for at least 48 months of follow-up and 2) those who lost glycemic control before 48 months. Outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics (age, sex, race/ethnicity, socioeconomic status, BMI, waist circumference, Tanner stage, disease duration, depressive symptoms) and biochemical measures (HbA1c, C-peptide, lean and fat body mass, insulin inverse, insulinogenic index). Receiver operating characteristic curves were used to analyze HbA1c cut points. RESULTS In multivariate models including factors significant in univariate analysis, only HbA1c and insulinogenic index at randomization remained significant (P < 0.0001 and P = 0.0002, respectively). An HbA1c cutoff of 6.3% (45 mmol/mol) (positive likelihood ratio [PLR] 3.7) was identified that optimally distinguished the groups; sex-specific cutoffs were 6.3% (45 mmol/mol) for females (PLR 4.4) and 5.6% (38 mmol/mol) for males (PLR 2.1). CONCLUSIONS Identifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy. HbA1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy. Adolescents with type 2 diabetes unable to attain a non–diabetes range HbA1c on metformin are at increased risk for rapid loss of glycemic control.

Health-related quality of life in adolescents with comorbidities related to obesity.

INTRODUCTION Psychosocial correlates of medically complex obesity are poorly understood in adolescents. METHODS Health-related quality of life was examined among 111 obese adolescents with medical comorbidities. RESULTS AND CONCLUSION A higher body mass index and greater number of comorbidities were associated with diminished health-related quality of life, thus underscoring the relevance of psychosocial functioning in obese youth.

Use of glycosylated hemoglobin increases diabetes screening for at-risk adolescents in primary care settings.

To examine rates of diabetes screening in obese adolescents in an ethnically diverse primary care health care system before and after an internal recommendation to use HbA1c‐based screening.