Objectives. The prevalence of type 2 diabetes in American adolescents has increased markedly during the past generation. Although the factors that contribute to the development of type 2 diabetes are complex and not wholly elucidated, the triad of severe obesity, hyperinsulinemia, and a family history of type 2 diabetes places a child at an increased risk for development of the disease. Current approaches to the prevention of type 2 diabetes, including dietary counseling and exercise, have had limited success. We reasoned that drugs that increase glucose tolerance in diabetic patients might prove useful in preventing the progression to glucose intolerance in high-risk patients. To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index (BMI), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Methods. The study population consisted of 29 white and black adolescents aged 12 to 19 years. All had BMIs exceeding 30 kg/m². Criteria for enrollment included: 1) a fasting insulin concentration exceeding 15 μU/mL; and 2) at least 1 first- or second-degree relative with type 2 diabetes. All patients had fasting plasma glucose concentrations <110 mg% and hemoglobin A1c concentrations ≤6.0%. All had normal linear growth and sexual development for age, with no marked hirsutism, severe acne, or menstrual irregularities characteristic of polycystic ovary syndrome. Eight participants had acanthosis nigricans. After baseline laboratory studies including a rapidly sampled intravenous glucose tolerance test, patients were randomized to receive metformin (500 mg twice daily) or a placebo for a total of 6 months. The effects of metformin on BMI standard deviation score, serum leptin, glucose tolerance, and serum lipids were analyzed. The study was double-blinded and included no specific dietary restrictions. Results. Metformin caused a decline of 0.12 standard deviation in BMI in study participants (−1.3% from baseline), and a 5.5% reduction in serum leptin in girls. In contrast, BMI and serum leptin rose 0.23 standard deviation (2.3%) and 16.2%, respectively, in the placebo group during the treatment period. Metformin caused a progressive decline in fasting blood glucose (from a mean of 84.9 to 75.1 mg%) and a reduction in fasting insulin levels (from 31.3 to 19.3 μU/mL). In contrast, fasting glucose levels in the placebo group rose slightly from 77.2 to 82.3 mg%, and fasting insulin levels did not change. Insulin sensitivity, as assessed by the ratio of fasting insulin to glucose concentrations and the quantitative insulin sensitivity check index (1/[log fasting insulin + log fasting glucose]) and homeostasis model assessment insulin resistance index (fasting insulin × fasting glucose/22.5) indices, increased slightly in the metformin-treated participants. However, the insulin sensitivity measured using Bergman9s minimal model did not change. There were also no significant changes in glucose effectiveness, hemoglobin A1c, serum lipids, or serum lactate in the metformin or placebo groups. Metformin was tolerated well by the majority of patients. Transient abdominal discomfort or diarrhea occurred in 40% of treated participants; there were no episodes of vomiting or lactic acidosis. Conclusions. The treatment of obesity and insulin resistance in adults often proves ineffective because the vicious cycle leading to type 2 diabetes may have become entrenched and, to some extent, may be irreversible. Early detection and therapy of the obese adolescent with a family history of type 2 diabetes may interrupt the cycle of weight gain and insulin resistance that leads to glucose intolerance in adulthood. Through its ability to reduce fasting blood glucose and insulin concentrations and to moderate weight gain, metformin might complement the effects of dietary and exercise counseling and reduce the risk of type 2 diabetes in selected patients.

Objective: Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. Methods: We used targeted and nontargeted metabolomic analysis to characterize changes in a broad array of hormones, cytokines, growth factors, and metabolites during treatment of severe childhood malnutrition. Children aged 6 months to 5 years were studied at presentation to Mulago Hospital and during inpatient therapy with milk-based formulas and outpatient supplementation with ready-to-use food. We assessed the relationship between baseline hormone and metabolite levels and subsequent mortality. Results: Seventy-seven patients were enrolled in the study; a subset was followed up from inpatient treatment to the outpatient clinic. Inpatient and outpatient therapies increased weight/height z scores and induced striking changes in the levels of fatty acids, amino acids, acylcarnitines, inflammatory cytokines, and various hormones including leptin, insulin, GH, ghrelin, cortisol, IGF-I, glucagon-like peptide-1, and peptide YY. A total of 12.2% of the patients died during hospitalization; the major biochemical factor predicting mortality was a low level of leptin (P = .0002), a marker of adipose tissue reserve and a critical modulator of immune function. Conclusions: We have used metabolomic analysis to provide a comprehensive hormonal and metabolic profile of severely malnourished children at presentation and during nutritional rehabilitation. Our findings suggest that fatty acid metabolism plays a central role in the adaptation to acute malnutrition and that low levels of the adipose tissue hormone leptin associate with, and may predict, mortality prior to and during treatment.

To explore potential roles for lactogenic hormones in human fetal development, we examined the distribution and ontogenesis of expression of prolactin receptors (PRLRs) in human fetal tissues at 7.5-14 wk of gestation and in tissues of the embryonic and fetal rat on days e12.5-e20.5. Histochemical analysis of PRLR immunoreactivity in the human fetus and fetal rat revealed novel and unexpected patterns of receptor expression. Most remarkable was the appearance in early fetal development of intense PRLR immunoreactivity in tissues derived from embryonic mesoderm, including the periadrenal and perinephric mesenchyme, the pulmonary and duodenal mesenchyme, the cardiac and skeletal myocytes, and the mesenchymal precartilage and maturing chondrocytes of the endochondral craniofacial and long bones, vertebrae and ribs. Striking changes in the cellular distribution and magnitude of expression of PRLRs were noted in many tissues during development. In the fetal adrenal the initial mesenchymal PRLR expression is succeeded by the emergence of PRLR immunoreactivity in deeper fetal cortical cell layers. In the fetal kidney and lung, the invagination of cortical mesenchyme is accompanied by progressive PRLR immunoreactivity in bronchial and renal tubular epithelial cells. In the pancreas, the PRLR is expressed primarily in acinar cells and ducts in early gestation; in late gestation and in the postnatal period, the PRLR is expressed predominantly in pancreatic islets, co-localizing with insulin and glucagon. Finally in fetal hepatocytes, PRLR immunoreactivity increases significantly between embryonic days e52 and e96 in the human fetus and between days e16.5 and e18.5 in the fetal rat. In addition to playing important roles in reproduction, lactation, and immune function, the lactogenic hormones likely play roles in tissue differentiation and organ development early in gestation.

This review outlines the regulation of maternal metabolism by hormones, cytokines and growth factors, highlighting recent studies that implicate disordered somatolactogen signalling in the pathogenesis of perinatal growth failure and the development of the metabolic syndrome.