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- Gustavsson, Johanna, 1956-, et al.
(författare)
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Localization of the insulin receptor in caveolae of adipocyte plasma membrane
- 1999
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 13:14, s. 1961-1971
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Tidskriftsartikel (refereegranskat)abstract
- The insulin receptor is a transmembrane protein of the plasma membrane, where it recognizes extracellular insulin and transmits signals into the cellular signaling network. We report that insulin receptors are localized and signal in caveolae microdomains of adipocyte plasma membrane. Immunogold electron microscopy and immunofluorescence microscopy show that insulin receptors are restricted to caveolae and are colocalized with caveolin over the plasma membrane. Insulin receptor was enriched in a caveolae-enriched fraction of plasma membrane. By extraction with β-cyclodextrin or destruction with cholesterol oxidase, cholesterol reduction attenuated insulin receptor signaling to protein phosphorylation or glucose transport. Insulin signaling was regained by spontaneous recovery or by exogenous replenishment of cholesterol. β-Cyclodextrin treatment caused a nearly complete annihilation of caveolae invaginations as examined by electron microscopy. This suggests that the receptor is dependent on the caveolae environment for signaling. Insulin stimulation of cells prior to isolation of caveolae or insulin stimulation of the isolated caveolae fraction increased tyrosine phosphorylation of the insulin receptor in caveolae, demonstrating that insulin receptors in caveolae are functional. Our results indicate that insulin receptors are localized to caveolae in the plasma membrane of adipocytes, are signaling in caveolae, and are dependent on caveolae for signaling.
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- Magnusson, Cecilia
(författare)
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Breast cancer epidemiology : influence of hormone-related factors
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main purpose of this thesis was to explore how hormone-related factors, including use of hormone replacement therapy and oral contraceptives, body size in different periods of life and reproductive factors, influence the risk of breast cancer. Other aims were to assess how family history of breast cancer modifies the associations between such factors and risk of the disease and how hormone replacement therapy affects tumour characteristics. The principal part of this work was based on a population-based case control study conducted in all of Sweden during October 1993 to March 1995. In this study 3,345 women aged 50-74 years with a diagnosis of primary breast cancer (84% of the eligible) and 3,454 age frequency-matched control women (82% of the selected) were included. Detailed information on hormone-related factors was collected through mailed questionnaires and telephone interviews. In another approach, a pathology register of 1,589 women with primary breast cancer diagnosed in Uppsala county from May 1977 to December 1991 was used. These women's exposure to hormone replacement therapy was determined through cross-linkage with a cohort of 23,234 women in the Uppsala health care region who had received prescriptions of these drugs. We found a duration-dependent increase in breast cancer risk among current as well as past users of oestrogen and oestrogen-progestin replacement therapy (odds ratio 2.23, 95% confidence interval 1.71-2.93 for women who had been treated for at least ten years as compared to those never treated). Only non-obese women seemed to be susceptible to this adverse effect. Breast cancers diagnosed after hormone replacement therapy had apparently less malignant features than other cancers. We also demonstrated a relation between childhood build and breast cancer risk, and women with the leanest constitution at age 7 had an approximately threefold higher risk than those with the most obese (p for trend 0.0009). Weight gain between age 18 and recent ages, rather than obesity per se, was also a convincing predictor of risk. Yet, this association was only demonstrated in older post-menopausal women. Among women who were 20 years past their menopause, the risk for those who had gained 30 kg or more was doubled as compared to those who had maintained their weight. We found a negative association between increasing age at menarche and breast cancer risk in women born before 1925 (p for trend 0.008) but not after. Augmenting number of births was strongly protective of breast cancer, while neither lactation, menopausal symptoms or past use of oral contraceptives were associated with risk. Hormone-related risk factors were similarly related to breast cancer risk among women with and without a family history of the disease.
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- Michaëlsson, Karl, 1959-, et al.
(författare)
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Hormone replacement therapy and hip fracture risk : population based case-control study
- 1998
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Ingår i: BMJ - British Medical Journal. - 1756-1833. ; 316:7148, s. 1858-63
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the relative risk of hip fracture associated with postmenopausal hormone replacement therapy including the effect of duration and recency of treatment, the addition of progestins, route of administration, and dose. DESIGN: Population based case-control study. Setting: Six counties in Sweden. SUBJECTS: 1327 women aged 50-81 years with hip fracture and 3262 randomly selected controls. MAIN OUTCOME MEASURE: Use of hormone replacement therapy. RESULTS: Compared with women who had never used hormone replacement therapy, current users had an odds ratio of 0.35 (95 % confidence interval 0.24 to 0.53) for hip fracture and former users had an odds ratio of 0.76 (0.57 to 1.01). For every year of therapy, the overall risk decreased by 6% (3% to 9%): 4% (1% to 8%) for regimens without progestin and 11% (6% to 16%) for those with progestin. Last use between one and five years previously, with a duration of use more than five years, was associated with an odds ratio of 0.27 (0.08 to 0.94). After five years without hormone replacement therapy the protective effect was substantially diminished (-7% to 48%). With current use, an initiation of therapy nine or more years after the menopause gave equally strong reduction in risk for hip fracture as an earlier start. Oestrogen treatment with skin patches gave similar risk estimates as oral regimens. CONCLUSIONS: Recent use of hormone replacement therapy is required for optimum fracture protection, but therapy can be started several years after the menopause. The protective effect increases with duration of use, and an oestrogen-sparing effect is achieved when progestins are included in the regimen.
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