Fetuin inhibits insulin-induced insulin receptor (IR)autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg tm1Mbl ). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P ‫؍‬ 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions. Diabetes 51:2450 -2458, 2002

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: Telemonitoring of BP resulted in clinically and statistically significant reductions in systolic BP over a 12-month period; if maintained over a longer period of time, the reductions could improve care and outcomes significantly for African Americans with hypertension.

Objective To develop an adaptive behavioral treatment for African American adolescents with obesity. Method In a sequential multiple assignment randomized trial, 181 youth ages 12 to 16 years with primary obesity and their caregiver were first randomized to 3 months of home-based versus office-based delivery of motivational interviewing plus skills building. After 3 months, non-responders to first phase treatment were re-randomized to continued home-based skills or contingency management. Primary outcome was percent overweight and hypothesized moderators were adolescent executive functioning and depression Results There were no significant differences in primary outcome between home-based or office-based delivery or between continued home-based skills or contingency management for non-responders to first-phase treatment. However, families receiving home-based treatment initially attended significantly more sessions in both phases of the trial, and families receiving contingency management attended more sessions in the second phase. Overall, participants demonstrated decreases in percent overweight over the course of the trial (3%), and adolescent executive functioning moderated this effect such that those with higher functioning lost more weight. Conclusions More potent behavioral treatments to address the obesity epidemic are necessary, targeting new areas such as executive functioning. Delivering treatment in the home with contingency management may increase session attendance for this population.

We have previously identified in fasting monkeys large amplitude, rapid oscillations in plasma levels of insulin, glucagon, and glucose. To determine whether such spontaneous oscillations also occur in man, we studied 9 healthy normal weight subjects and 11 obese volunteers (145-316% ideal body weight). During the morning hours after a 16-h fast, peripheral venous blood was withdrawn at precise 1- or 2-min intervals over 40-120 min. Spectral analysis of the assay results showed significant oscillations in plasma levels of insulin and glucose, with periods ranging from 8-16 min (P less than 0.05). In this range, the means of the oscillatory periods in normal weight subjects were 12.1 +/- 1.0 min for insulin and 11.2 +/- 0.8 min for glucose. The oscillatory periods on obese subjects were not different from those in normal weight subjects (12.4 +/- 0.7 min for insulin and 12.1 +/- 0.9 min for glucose). Periodicity in plasma levels of glucagon was observed in the range of 12-23 min. Based on cross-correlation analysis, the periodic fluctuations in insulin, glucose, and glucagon showed no consistent relationships; the patterns observed did not support the presence of feedback loops among these parameters as the mechanism of these spontaneous fluctuations. Our data indicate that basal plasma levels of insulin, glucagon, and glucose fluctuate rapidly in man. The physiological function of these oscillations is yet to be identified; they may play a role in the regulation of responsiveness of the respective target tissues or of their own release into the circulation.

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Consuming omega-3 fatty acids (ω-3 FA) during pregnancy and lactation is beneficial to fetal and infant development and might reduce the incidence and severity of preterm births by prolonging pregnancy. Consequently, supplementing maternal diets with large amounts of ω-3 FA is gaining acceptance. However, both over-and under-supplementation with ω-3 FA can harm offspring development. Adverse fetal and neonatal conditions in general can enhance age-related neural degeneration, shorten life span and cause other adult-onset disorders. We hypothesized that maternal over-and under-nutrition with ω-3 FA would shorten the offspring's life span and enhance neural degeneration in old adulthood. To test these hypotheses, female Wistar rats were randomly assigned to one of the three diet conditions starting from day 1 of pregnancy through the entire period of pregnancy and lactation. The three diets were Control ω-3 FA (ω-3/ω-6 ratio ~ 0.14), Excess ω-3 FA (ω-3/ω-6 ratio ~ 14.5) and Deficient ω-3 FA (ω-3/ω-6 ratio ~ 0% ratio). When possible, one male and female offspring from each litter were assessed for life span and sensory/neural degeneration (n=15 litters/group). The Excess offspring had shorter life spans compared to their Control and Deficient cohorts (mean±SEM=506±24, 601±14 and 585±21 days, p≤0.004) when the study terminated on postnatal day 640. The Excess offspring had a higher incidence of presbycusis than the Control and Deficient groups (33.3, 4.3 and 4.5%, p=0.011) and a persistence of other sensory/ neurological abnormalities and lower body weights in old adulthood. In conclusion, ω-3 FA overnutrition or imbalance during pregnancy and lactation had adverse effects on life span and sensory/ neurological function in old adulthood. The adverse outcomes in the Excess offspring were likely due to a "nutritional toxicity" during fetal and/or neonatal development that programmed them for life-long health disorders. The health implication is that consuming or administering large amounts Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of interestThere were no conflicts of interest. NIH Public Access

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