Mitchell E. Geffner

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

CONTEXT The 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. OBJECTIVE The objective of the study was to describe the baseline characteristics of participants in the TODAY randomized clinical trial. DESIGN Participants 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. SETTING The study was conducted at pediatric diabetes care clinics and practices. PARTICIPANTS Eligible 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. INTERVENTIONS After 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. MAIN OUTCOME MEASURES Baseline data presented include demographics, clinical/medical history, biochemical measurements, and clinical and biochemical abnormalities. RESULTS At 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

Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion.

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. CONCLUSIONS The 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.

Aortic dilation, dissection, and rupture in patients with turner syndrome

Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05). As an indicator of insulin sensitivity, in vitro proliferation of erythrocyte progenitor cells of PCOD subjects exposed to physiologic concentrations of insulin was significantly blunted (P less than 0.001). Monocyte insulin receptor binding was not impaired in the PCOD subjects. Three of the PCOD patients were treated with a long-acting gonadotropin-releasing hormone agonist for 6 months, which resulted in marked suppression of ovarian androgen secretion but no demonstrable changes in in vivo or in vitro indicators of insulin resistance. Thus insulin resistance in PCOD subjects appears to be unrelated to ovarian hyperandrogenism (or acanthosis or obesity). Although certain tissues are insulin-resistant in PCOD patients, the ovary may remain sensitive and overproduce androgens in response to high circulating insulin levels.

Improvement in Risk Factors for Metabolic Syndrome and Insulin Resistance in Overweight Youth Who Are Treated With Lifestyle Intervention

We report two patients with Turner syndrome who had aortic dissection and rupture, one with prior repair of coarctation. We also note the high incidence (8.8%) of unrecognized aortic root dilation in a group of 57 patients with Turner syndrome whom we prospectively evaluated by echocardiography. Our analysis and review of previously reported cases suggests that multiple risk factors may exist for aortic dissection, including coarctation, bicuspid aortic valve, and systemic hypertension, but that these need not be present. Aortic root dilation may be an additional finding that suggests the patient with Turner syndrome is also at risk. When it is present, magnetic resonance imaging visualizes the entire aorta and allows quantification of the site and degree of dilation. In patients with dissection, the aorta often exhibits pathologic evidence of cystic medial necrosis similar to the finding in patients with Marfan syndrome. Therapeutic methods to decrease risk, such as those directed toward prevention of bacterial endocarditis, blood pressure control, and perhaps prophylactic beta blockade or surgical reconstruction, may need to be considered. Patients with Turner syndrome, their families, and the physicians who care for them should be aware of the significance of unexplained chest pain, dyspnea, or hypotension as potential manifestations of aortic dissection or rupture.

Increased aggression and activity level in 3- to 11-year-old girls with congenital adrenal hyperplasia (CAH).

OBJECTIVE. To evaluate the prevalence of risk factors that are associated with the metabolic syndrome and insulin resistance in overweight youth and to determine the effect of a short-term, family-centered, lifestyle intervention on various associated anthropometric and metabolic measures. METHODS. Overweight youth who were between 8 and 16 years of age participated in a 12-week, family-centered, lifestyle intervention program. Anthropometric and metabolic measures were assessed before the program in all participants (n = 109) and after the program in a subset of the participants (n = 43). RESULTS. At baseline, 49.5% of youth had multiple risk factors associated with the metabolic syndrome, based on a modified definition of the National Cholesterol Education Program, and 10% had impaired fasting glucose and/or impaired glucose tolerance. Measures of insulin resistance correlated significantly with the risk factors of the metabolic syndrome. Forty-three youth had pre- and postintervention evaluations that showed statistically significant improvements in body mass index, systolic blood pressure, lipids (total, low-density lipoprotein cholesterol, and triglycerides), postprandial glucose, and leptin levels. CONCLUSION. Overweight youth have multiple risk factors associated with the metabolic syndrome. A 12-week lifestyle program may have a positive effect on reducing risk factors for the metabolic syndrome and insulin resistance in overweight youth.

The growth without growth hormone syndrome

Experimental research in a wide range of mammals has documented powerful influences of androgen during early development on brain systems and behaviors that show sex differences. Clinical research in humans suggests similar influences of early androgen concentrations on some behaviors, including childhood play behavior and adult sexual orientation. However, findings have been inconsistent for some other behaviors that show sex differences, including aggression and activity level in children. This inconsistency may reflect small sample sizes and assessment limitations. In the present study, we assessed aggression and activity level in 3- to 11-year-old children with CAH (38 girls, 29 boys) and in their unaffected siblings (25 girls, 21 boys) using a questionnaire that mothers completed to indicate current aggressive behavior and activity level in their children. Data supported the hypotheses that: (1) unaffected boys are more aggressive and active than unaffected girls; (2) girls with CAH are more aggressive and active than their unaffected sisters; and (3) boys with and without CAH are similar to one another in aggression and activity level. These data suggest that early androgens have a masculinizing effect on both aggressive behavior and activity level in girls.

Echocardiography reveals a high incidence of bicuspid aortic valve in Turner syndrome

The phenomenon of growth without GH has been recognized for over a quarter of a century in various physiologic or near-physiologic situations, including the fetal state and obesity, and in various obviously pathologic states, including postsurgical resection of suprasellar/hypothalamic tumors, most notably craniopharyngiomas, and in acromegaloidism. The mechanism or mechanisms responsible for this fascinating clinical syndrome are unknown. The available data implicate, at least in some of these subjects, a role for hypothalamic injury leading to obesity and insulin resistance which, in turn, leads to elevated circulating concentrations of insulin to which the body retains mitogenic sensitivity. Alternatively, in other subjects with this syndrome, evidence exists to support the presence of a circulating as yet incompletely characterized potent growth-promoting factor which appears in the serum. Further studies of this syndrome should help to enhance our knowledge of the mechanisms governing both normal and abnormal human growth.

Selective Insulin Action on Skin, Ovary, and Heart in Insulin-Resistant States

The most common cardiac defect in Turner syndrome has been described previously as coarctation of the aorta. We have evaluated 35 consecutive patients with Turner syndrome by clinical examination and by M-mode and two-dimensional echocardiography. Twelve patients (34%) had isolated, nonstenotic bicuspid aortic valve. A high correlation (82%) existed between the presence of a systolic ejection click and echocardiographic evidence of a bicuspid aortic valve. These data indicate that bicuspid aortic valve may be the most common cardiac anomaly in Turner syndrome.

An arginine to histidine mutation in codon 311 of the C-erbA beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype.

States of hyperinsulinemia with resistance to insulin action on glucose disposal are frequently associated with proliferative tissue abnormalities of the skin (acanthosis nigricans), ovary, and heart. That insulin may be involved in the pathogenesis of these growth-related abnormalities despite resistance to its metabolic effects mediated through the insulin receptor issuggested by the known ability of high concentrations of insulin to stimulate DNA synthesis and cell proliferation in vitro through the insulin-like growth factor I (IGF-I) receptor. IGF-I receptors are present in skin keratinocytes, some ovarian tissue compartments, and in the heart. Furthermore, ovarian tissue from hyperinsulinemic insulin-resistant women responds to supraphysiologic insulin concentrations in vitro by enhanced steroidogenesis. Cultured, transformed T-lymphocytes from an infant with leprechaunism fail to augment basalcolony formation in response to physiologic insulin concentrations in vitro (compared to a doubling seen in normal subjects), but respond normally to supraphysiologic insulin concentrations, the effect of which is competitively inhibited by a monoclonal antibody to the IGF-I receptor. Thus, insulin action mediated through the IGF-I receptor may initiate growth-promoting tissue effects in the face of limited insulin effect on glucose metabolism. Such spillover actions may add to the morbidity associated with states of clinical insulin resistance.

Neuroradiographic, Endocrinologic, and Ophthalmic Correlates of Adverse Developmental Outcomes in Children With Optic Nerve Hypoplasia: A Prospective Study

We have examined the c-erbA beta thyroid hormone receptor gene in a kindred, G.H., with a member, patient G.H., who had a severe form of selective pituitary resistance to thyroid hormones (PRTH). This patient manifested inappropriately normal thyrotropin-stimulating hormone, markedly elevated serum free thyroxine (T4) and total triiodothyronine (T3), and clinical hyperthyroidism. The complete c-erbA beta 1 coding sequence was examined by a combination of genomic and cDNA cloning for patient G.H. and her unaffected father. A single mutation, a guanine to adenine transition at nucleotide 1,232, was found in one allele of both these members, altering codon 311 from arginine to histidine. In addition, a half-sister of patient G.H. also harbored this mutant allele and, like the father, was clinically normal. The G.H. receptor, synthesized with reticulocyte lysate, had significantly defective T3-binding activity with a Ka of approximately 5 x 10(8) M-1. RNA phenotyping using leukocytes and fibroblasts demonstrated an equal level of expression of wild-type and mutant alleles in patient G.H. and her unaffected father. Finally, the G.H. receptor had no detectable dominant negative activity in a transfection assay. Thus, in contrast to the many other beta-receptor mutants responsible for the generalized form of thyroid hormone resistance, the G.H. receptor appeared unable to antagonize normal receptor function. These results suggest that the arginine at codon 311 in c-erbA beta is crucial for the structural integrity required for dominant negative function. The ARG-311-HIS mutation may contribute to PRTH in patient G.H. by inactivating a beta-receptor allele, but it cannot be the sole cause of the disease.