Although obesity is often associated with insulin resistance and a cluster of metabolic disturbances, the existence of a subgroup of healthy but obese individuals has been postulated. It is unclear why some obese individuals fail to show traditional risk factors associated with the insulin resistance syndrome despite having a very high accumulation of body fat. To address this issue, we identified and studied a subgroup of metabolically normal but obese (MNO) postmenopausal women to gain insight into potential physiological factors that may protect them against the development of obesity-related comorbidities. We carefully examined the metabolic characteristics of 43 obese, sedentary postmenopausal women (mean +/- SD, 58.0 +/- 6.0 yr). Subjects were classified as MNO or as metabolically abnormal obese (MAO) based on an accepted cut-point for insulin sensitivity (measured by the hyperinsulinemic/euglycemic clamp technique). Thereafter, we determined 1) body composition (fat mass and lean body mass), 2) body fat distribution (abdominal visceral and sc adipose tissue areas, midthigh sc adipose tissue and muscle attenuation), 3) plasma lipid-lipoprotein levels, 4) plasma glucose and insulin concentrations, 5) resting blood pressure, 6) peak oxygen consumption, 7) physical activity energy expenditure, and 8) age-related onset of obesity with a questionnaire as potential modulators of differences in the risk profile. We identified 17 MNO subjects who displayed high insulin sensitivity (11.2 +/- 2.6 mg/min.kg lean body mass) and 26 MAO subjects with lower insulin sensitivity (5.7 +/- 1.1 mg/min.kg lean body mass). Despite comparable total body fatness between groups (45.2 +/- 5.3% vs. 44.8 +/- 6.6%; P: = NS), MNO individuals had 49% less visceral adipose tissue than MAO subjects (141 +/- 53 vs. 211 +/- 85 cm(2); P: < 0.01). No difference was noted between groups for abdominal sc adipose tissue (453 +/- 126 vs. 442 +/- 144 cm(2); P: = NS), total fat mass (38.1 +/- 10.6 vs. 40.0 +/- 11.8 kg), muscle attenuation (42.2 +/- 2.6 vs. 43.6 +/- 4.8 Houndsfield units), and physical activity energy expenditure (1060 +/- 323 vs. 1045 +/- 331 Cal/day). MNO subjects had lower fasting plasma glucose and insulin concentrations and lower insulin levels during the oral glucose tolerance test (P: values ranging between 0.01-0.001). No difference was observed between groups for 2-h glucose levels and glucose area during the oral glucose tolerance test. MNO subjects showed lower plasma triglycerides and higher high density lipoprotein cholesterol concentrations than MAO individuals (P: < 0.01 in both cases). Results from the questionnaire indicated that 48% of the MNO women presented an early onset of obesity (<20 yr old) compared with 29% of the MAO subjects (P: = 0.09). Stepwise regression analysis showed that visceral adipose tissue and the age-related onset of obesity explained 22% and 13%, respectively, of the variance observed in insulin sensitivity (total r(2) = 0.35; P: < 0.05 in both cases). Our results support the existence of a s...

801 In humans, the menopause transition marks the cessation of ovarian function and dramatic reductions in circulating estrogen and progesterone concentrations (1). Both estrogen and progesterone have been shown to influence insulin sensitivity (2-5). A preliminary longitudinal study from our laboratory found an increase in fasting insulin levels in women as they traverse from the premenopausal to postmenopausal state, suggesting reduced insulin sensitivity with ovarian hormone deficiency. More detailed evidence for an effect of ovarian hormones on insulin sensitivity is provided by animal studies, which show that ovariectomy reduces whole-body insulin-stimulated glucose disposal (4,5). In rats, Kumagai et al. (4) found that an ovariectomy decreased insulin-stimulated glucose disposal by decreasing skeletal muscle glucose uptake and glycogen synthesis. Similarly, Puah and Bailey (3) found that an ovariectomy decreased insulin-stimulated skeletal muscle glucose uptake in mice. Finally, Rincon et al. (5) showed that ovariectomized rats exhibited decreased insulin-stimulated glucose disposal and reduced skeletal muscle glycogen synthase expression. Taken together, these results suggest that ovarian hormone deficiency is associated with decreased insulin-stimulated glucose uptake. Moreover, ovarian hormones may influence glucose uptake by regulating nonoxidative glucose disposal in skeletal muscle. These preliminary studies support the notion that postmenopausal status might be associated with reduced insulin sensitivity.Contrary to this hypothesis, however, the 1 study that measured insulin sensitivity in pre-and postmenopausal women found a 50% greater insulin sensitivity in postmenopausal women (6). Therefore, the effect of ovarian hormone deficiency on glucose metabolism remains unclear and understudied. To address this question, we measured whole-body insulin-stimulated glucose disposal in healthy middle-aged premenopausal and early postmenopausal women using the hyperinsulinemic-euglycemic clamp technique. Based on animal studies (3-5) and our previous longitudinal work (2), we hypothesized that insulinstimulated glucose disposal would be lower in postmenopausal compared with premenopausal women. RESEARCH DESIGN AND METHODS SubjectsVolunteers were recruited from 2 ongoing studies from Burlington, Vermont, and surrounding areas through advertisements in local newspapers. Premenopausal volunteers were recruited to participate in the Vermont Longitudinal Study of the Menopause, a 5-year study examining changes in energy expenditure, body composition, abdominal fat distribution, and metabolic function in Effect of Menopausal Status on Insulin-Stimulated Glucose DisposalComparison of middle-aged premenopausal and early postmenopausal womenOBJECTIVE -Studies in animal models suggest that ovarian hormone deficiency is associated with the development of insulin resistance. In women, ovarian hormone levels are dramatically reduced after the menopause transition. However, the effect of the menopause transition on insu...

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Objective: To assess the efficacy, side effects and progression-free interval of a modified regimen of the combination of gemcitabine and cisplatin among women with recurrent epithelial ovarian cancer. Methods: Twenty-eight women with recurrent epithelial ovarian, primary peritoneal or fallopian tube cancers were treated with gemcitabine (500 mg/m 2) followed by cisplatin (50 mg/m 2) on days one and eight every three weeks. Patients' demographics, response, side effects, and progression-free interval were recorded. Result: The median age of patients was 61 (range 44-74 years). Twenty-three (82.1%) patients had platinum-sensitive and five (17.9%) had platinum-resistant tumors. The median number of prior chemotherapy regimens was two (range 1-4) and nine patients had > three prior regimens. The median number of cycles was six (range 2-10). Seventeen (60.7%) patients responded to chemotherapy (11 complete and six partial), six had stable disease and five had progression. The response rate was 69.6% and 20% among women with platinum-sensitive and platinum-resistant tumors, respectively (P = .024). The median (range) progression-free interval was six (2-12) and nine (4-12) months among all patients and patients who responded to chemotherapy, respectively. Four patients had dose reductions, four had delays and three had their chemotherapy terminated secondary to toxicity or patient desire. There were no chemotherapy-related mortality or hospital admissions. The incidence of grade 3-4 neutropenia, anemia, thrombocytopenia, and nausea or vomiting was 32.1%, 10.7%, 35.7%, and 10.7%, respectively. Conclusion: The combination gemcitabine and cisplatin is highly effective among women with recurrent ovarian cancer including those who are heavily pre-treated and is reasonably tolerated. Although, the combination is effective among women with plantinum-resistant tumors, these women have a lower response than women with platinum-sensitive tumors.