Jill Hamilton

Hyperbolic Relationship Between Insulin Secretion and Sensitivity on Oral Glucose Tolerance Test

The utility of the disposition index as a measure of β‐cell compensatory capacity rests on the established hyperbolic relationship between its component insulin secretion and sensitivity measures as derived from the intravenous glucose tolerance test (IVGTT). If one is to derive an analogous measure of β‐cell compensation from the oral glucose tolerance test (OGTT), it is thus necessary to first establish the existence of this hyperbolic relationship between OGTT‐based measures of insulin secretion and insulin sensitivity. In this context, we tested five OGTT‐based measures of secretion (insulinogenic index, Stumvoll first phase, Stumvoll second phase, ratio of total area‐under‐the‐insulin‐curve to area‐under‐the‐glucose‐curve (AUCins/gluc), and incremental AUCins/gluc) with two measures of sensitivity (Matsuda index and 1/Homeostasis Model of Assessment for insulin resistance (HOMA‐IR)). Using a model of log(secretion measure) = constant + β × log(sensitivity measure), a hyperbolic relationship can be established if β is approximately equal to −1, with 95% confidence interval (CI) excluding 0. In 277 women with normal glucose tolerance (NGT), the pairing of total AUCins/gluc and Matsuda index was the only combination that satisfied these criteria (β = −0.99, 95% CI (−1.66, −0.33)). This pairing also satisfied hyperbolic criteria in 53 women with impaired glucose tolerance (IGT) (β = −1.02, (−1.72, −0.32)). In a separate data set, this pairing yielded distinct hyperbolae for NGT (n = 245) (β = −0.99, (−1.67, −0.32)), IGT (n = 116) (β = −1.18, (−1.84, −0.53)), and diabetes (n = 43) (β = −1.37, (−2.46, −0.29)). Moreover, the product of AUCins/gluc and Matsuda index progressively decreased from NGT (212) to IGT (193) to diabetes (104) (P < 0.001), consistent with declining β‐cell function. In summary, a hyperbolic relationship can be demonstrated between OGTT‐derived AUCins/gluc and Matsuda index across a range of glucose tolerance. Based on these findings, the product of these two indices emerges as a potential OGTT‐based measure of β‐cell function.

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer.

BACKGROUND Previous guidelines for the management of thyroid nodules and cancers were geared toward adults. Compared with thyroid neoplasms in adults, however, those in the pediatric population exhibit differences in pathophysiology, clinical presentation, and long-term outcomes. Furthermore, therapy that may be recommended for an adult may not be appropriate for a child who is at low risk for death but at higher risk for long-term harm from overly aggressive treatment. For these reasons, unique guidelines for children and adolescents with thyroid tumors are needed. METHODS A task force commissioned by the American Thyroid Association (ATA) developed a series of clinically relevant questions pertaining to the management of children with thyroid nodules and differentiated thyroid cancer (DTC). Using an extensive literature search, primarily focused on studies that included subjects ≤18 years of age, the task force identified and reviewed relevant articles through April 2014. Recommendations were made based upon scientific evidence and expert opinion and were graded using a modified schema from the United States Preventive Services Task Force. RESULTS These inaugural guidelines provide recommendations for the evaluation and management of thyroid nodules in children and adolescents, including the role and interpretation of ultrasound, fine-needle aspiration cytology, and the management of benign nodules. Recommendations for the evaluation, treatment, and follow-up of children and adolescents with DTC are outlined and include preoperative staging, surgical management, postoperative staging, the role of radioactive iodine therapy, and goals for thyrotropin suppression. Management algorithms are proposed and separate recommendations for papillary and follicular thyroid cancers are provided. CONCLUSIONS In response to our charge as an independent task force appointed by the ATA, we developed recommendations based on scientific evidence and expert opinion for the management of thyroid nodules and DTC in children and adolescents. In our opinion, these represent the current optimal care for children and adolescents with these conditions.

Type 2 Diabetes, Medication-Induced Diabetes, and Monogenic Diabetes in Canadian Children: A Prospective National Surveillance Study

OBJECTIVE To determine in Canadian children aged <18 years the 1) incidence of type 2 diabetes, medication-induced diabetes, and monogenic diabetes; 2) clinical features of type 2 diabetes; and 3) coexisting morbidity associated with type 2 diabetes at diagnosis. RESEARCH DESIGN AND METHODS This Canadian prospective national surveillance study involved a network of pediatricians, pediatric endocrinologists, family physicians, and adult endocrinologists. Incidence rates were calculated using Canadian Census population data. Descriptive statistics were used to illustrate demographic and clinical features. RESULTS From a population of 7.3 million children, 345 cases of non–type 1 diabetes were reported. The observed minimum incidence rates of type 2, medication-induced, and monogenic diabetes were 1.54, 0.4, and 0.2 cases per 100,000 children aged <18 years per year, respectively. On average, children with type 2 diabetes were aged 13.7 years and 8% (19 of 227) presented before 10 years. Ethnic minorities were overrepresented, but 25% (57 of 227) of children with type 2 diabetes were Caucasian. Of children with type 2 diabetes, 95% (206 of 216) were obese and 37% (43 of 115) had at least one comorbidity at diagnosis. CONCLUSIONS This is the first prospective national surveillance study in Canada to report the incidence of type 2 diabetes in children and also the first in the world to report the incidence of medication-induced and monogenic diabetes. Rates of type 2 diabetes were higher than expected with important regional variation. These results support recommendations that screening for comorbidity should occur at diagnosis of type 2 diabetes.

Deteriorating diabetes control during adolescence: physiological or psychosocial?

Metabolic control often worsens during the pubertal years in individuals with type diabetes mellitus (DM). This may be due in part to the developmental transition from dependency on parents to a more autonomous lifestyle. Adolescence is also marked by challenging of authority figures and previous ways of thinking, experimentation, and, in some female teenagers, emergence of disordered eating attitudes and behaviors. The insulin resistance of puberty may be particularly maladaptive for the teenager with type 1 DM and is likely under-recognized. In this review, we examine the impact of physiological and psychosocial changes during puberty in type 1 DM, highlight treatment strategies aimed at modifying these factors, and suggest further interventions that warrant evaluation.

Diiodothyropropionic Acid (DITPA) in the Treatment of MCT8 Deficiency

CONTEXT Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. MCT8 deficiency causes severe psychomotor retardation and abnormal thyroid tests. The great majority of affected children cannot walk or talk, and all have elevated serum T(3) levels, causing peripheral tissue hypermetabolism and inability to maintain weight. Treatment with thyroid hormone is ineffective. In Mct8-deficient mice, the thyroid hormone analog, diiodothyropropionic acid (DITPA), does not require MCT8 to enter tissues and could be an effective alternative to thyroid hormone treatment in humans. OBJECTIVE The objective of the study was to evaluate the effect and efficacy of DITPA in children with MCT8 deficiency. METHODS This was a multicenter report of four affected children given DITPA on compassionate grounds for 26-40 months. Treatment was initiated at ages 8.5-25 months, beginning with a small dose of 1.8 mg, increasing to a maximal 30 mg/d (2.1-2.4 mg/kg · d), given in three divided doses. RESULTS DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The following significant changes were also observed: decline in SHBG (in all subjects), heart rate (in three of four), and ferritin (in one of four). Cholesterol increased in two subjects. There was no weight loss and weight gain occurred in two. None of the treated children required a gastric feeding tube or developed seizures. No adverse effects were observed. CONCLUSION DITPA (1-2 mg/kg · d) almost completely normalizes thyroid tests and reduces the hypermetabolism and the tendency for weight loss. The effects of earlier commencement and long-term therapy remain to be determined.

Childhood Obesity: Causes, Consequences, and Management

One-third of North American children are overweight or obese. Pathologic obesity accounts for only a small percentage of these cases. The vast majority are the result of a complex interaction of genetic and hormonal, nutritional, physical activity, and physical and social environmental factors. Obesity increases the risk for various cardiometabolic, pulmonary, and psychosocial complications for children, which often continues into adulthood. Multidisciplinary care, focusing on family-centered behavior change, is an evidence-based, essential part of the treatment, along with pharmacologic and surgical options for more complex cases. Prevention and early intervention strategies are key to reversing the obesity epidemic.

Weight gain in craniopharyngioma--a model for hypothalamic obesity.

OBJECTIVES To evaluate (1) the pattern of post-operative weight gain and (2) the risk factors associated with the development of post-operative weight gain and obesity in children treated for craniopharyngioma. STUDY DESIGN The records of 43 children who had primary craniopharyngioma resection were reviewed. Neurological, endocrine, anthropometric and radiological risk factors for the development of obesity and for post-operative increase in BMI SDS were analyzed. RESULTS Twenty-five patients (58%) became obese post-operatively. Obesity was significantly associated with higher BMI SDS at presentation and pre-operative hydrocephalus (p < 0.05). Increased BMI SDS from 0-12 months was significantly associated with post-operative MRI evidenced hypothalamic damage and higher BMI at presentation (p < 0.05). CONCLUSIONS Children who developed hypothalamic obesity had a significant, rapid BMI increase over the first 6 months, followed by stabilization, with no regression of BMI SDS.

Thyroid Cancer in Childhood: A Retrospective Review of Childhood Course

BACKGROUND Thyroid cancer (TC) is an uncommon childhood malignancy, but the incidence may be increasing. Recent American Thyroid Association guidelines focus primarily on adult data. Natural history studies of TC in childhood are important to determine outcomes. The objectives of this study were to describe the demographics and outcomes in children with TC treated at The Hospital for Sick Children, Toronto, from 1983 to 2006. We hypothesized that childhood TC was increasing at our institution. METHODS Cases of papillary TC (PTC) (including follicular variant PTC) and follicular TC (FTC) were identified from pathology databases. Chart review was performed, and data were extracted on clinical, treatment, and outcome variables. RESULTS Sixty-one cases were identified, and complete data were available in 54, including 36 girls and 18 boys. There was no statistical change in numbers of cases diagnosed yearly during the study period. Younger children were more likely to have metastases at presentation or during follow-up. Pathological TC diagnosis included 40 PTC, 1 diffuse-sclerosing papillary, 7 follicular variant PTC, and 6 FTC. There was no difference in pathology findings between children less than or greater than 10 years old. Five patients had a history of previous malignancy, and five had a history of previous thyroid conditions. Three patients were born in areas of high TC endemnicity. Twenty-three patients had thyroiditis on pathology examination. All patients underwent total thyroidectomy, and 53/54 patients received therapeutic radioactive iodine ablation. Twenty-seven patients had metastases at presentation (19 lymph nodes only, 2 lung only, and 6 lymph node and distant) and 6 developed distant metastases during follow-up (3 lung, 2 thymus, and 1 paraspinal). Male sex was associated with development of metastases during follow-up. On multiple regression, tumor size was predicted positively by PTC but not by age, sex, or metastases at presentation or during follow-up. CONCLUSION We did not find evidence of increasing numbers of cases of TC diagnosed yearly during the study period, or difference in tumor aggressiveness, or between outcomes in children aged less than or greater than 10 years. Children with metastases at presentation or during follow-up were likely to be younger than children without metastases. There is a need for prospective, collaborative multicenter studies of TC.

Effect of maternal weight, adipokines, glucose intolerance and lipids on infant birth weight among women without gestational diabetes mellitus

Background: The delivery of excess maternal nutrients to the fetus is known to increase the risk of macrosomia, even among infants of women without gestational diabetes mellitus. With the current obesity epidemic, maternal adiposity and its associated effects on circulating adipokines and inflammatory proteins may now have a greater impact on fetal growth. We sought to evaluate the independent effects of maternal glycemia, lipids, obesity, adipokines and inflammation on infant birth weight. Methods: We included 472 women who underwent an oral glucose tolerance test in late pregnancy and were found not to have gestational diabetes; 104 (22.0%) had gestational impaired glucose tolerance. We also measured fasting levels of insulin, low-and high-density lipoprotein cholesterol, triglycerides, leptin, adiponectin and C-reactive protein. Obstetric outcomes were assessed at delivery. Results: The mean birth weight was 3481 g (standard deviation 493 g); 68 of the infants were large for gestational age. On multiple linear regression analysis, positive determinants of birth weight were length of gestation, male infant, weight gain during pregnancy up to the time of the oral glucose tolerance test, body mass index (BMI) before pregnancy and impaired glucose tolerance in pregnancy. Leptin, adiponectin and C-reactive protein levels were each negatively associated with birth weight. On logistic regression analysis, the significant metabolic predictors of having a large-for-gestational-age infant were BMI before pregnancy (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05–1.27, per 1 kg/m2 increase), weight gain during pregnancy up to the time of the oral glucose tolerance test (OR 1.12, 95% CI 1.05–1.19, per 1 kg increase) and leptin level (OR 0.50, 95% CI 0.30–0.82, per 1 standard deviation change). Interpretation: Among women without gestational diabetes, maternal adiposity and leptin levels were the strongest metabolic determinants of having a large-for-gestational-age infant rather than glucose intolerance and lipid levels.

Skeletal muscle metabolic dysfunction in obesity and metabolic syndrome.

Obesity and the related metabolic syndrome have become a worldwide epidemic. Inactivity appears to be a primary causative factor in the pathogenesis of this obesity and metabolic syndrome. There are two possible, perhaps not mutually exclusive, events that may lead to intramyocellular lipid accumulation and mitochondrial dysfunction in patients with obesity. First, obesity, with high intake-associated lipid accumulation in muscle may interfere with cellular mitochondrial function through generation of reactive oxygen species leading to lipid membrane peroxidative injury and disruption of mitochondrial membrane-dependent enzymes. This in turn leads to impaired oxidative metabolism. Secondly, a primary defect in mitochondrial oxidative metabolism may be responsible for a reduction in fatty acid oxidation leading to intramyocellular lipid accumulation as a secondary event. Non-invasive techniques such as proton (1H) and phosphorus (31P) magnetic resonance spectroscopy, coupled with specific magnetic resonance imaging techniques, may facilitate the investigation of the effects of various ergometric interventions on the pathophysiology of obesity and the metabolic syndrome. Exercise has positive effects on glucose metabolism, aerobic metabolism, mitochondrial density, and respiratory chain proteins in patients with metabolic syndrome, and we propose that this may be due to the exercise effects on AMP kinase, and a prospective physiological mechanism for this benefit is presented. A physiological model of the effect of intramyocellular lipid accumulation on oxidative metabolism and insulin mediated glucose uptake is proposed.