Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R(-/-)), or neuronal insulin receptor (nIR(-/-)), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays beta-amyloid (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R(-/-)Tg2576 mice were protected from premature death in the presence of decreased Abeta accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.

In different clinical studies, an association of type 2 diabetes and Alzheimer's disease (AD) has been described. However, the underlying mechanisms are still unclear. One explanation could be that vascular complications of diabetes result in neurodegeneration. Alternatively, the mechanism might be directly related to insulin and insulin-like growth factor(IGF)-1 signaling, leading to the proposal that AD is a "brain-type diabetes". Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration. These findings raise the question, whether this phenomenon is cause or consequence of neurodegeneration. Recently, Cohen and coworkers have show that knocking down DAF-2 in C. elegans, the homolog of the mammalian IR/IGF-1R, reduces beta-amyloid(Abeta)(1-42) toxicity. Cell based experiments suggest a specific role for the IGF 1/IRS-2 signaling pathway in regulating alpha-/beta-secretase activity. Moreover circulating IGF-1 might influence Abeta clearance from the brain by promoting Abeta transport over the blood brain barrier. Interestingly, brain specific deletion of IRS-2 increases life span, suggesting that long term neuronal IGF-1R signaling might be harmful. Taken together, the data from humans and different model organisms indicate a role of IR/IGF-1R signaling in Abeta metabolism, and clearance as well as longevity. Since more studies are needed to elucidate the impact of insulin and/or IGF-1 treatment in AD, the time to propose these hormones as a potential treatment option for AD has not come yet.

No abstract

© 2012 Springer-Verla

BI 135585 was safe and well tolerated over 14 days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11β-HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.

Insulin‐like growth factor (IGF)‐1 increases proliferation, inhibits apoptosis and promotes differentiation of oligodendrocytes and their precursor cells, indicating an important function for IGF‐1 receptor (IGF‐1R) signaling in myelin development. The insulin receptor substrates (IRS), IRS‐1 and ‐2 serve as intracellular IGF‐1R adaptor proteins and are expressed in neurons, oligodendrocytes and their precursors. To address the role of IRS‐2 in myelination, we analyzed myelination in IRS‐2 deficient (IRS‐2−/−) mice and age‐matched controls during postnatal development. Interestingly, expression of the most abundant myelin proteins, myelin basic protein and proteolipid protein was reduced in IRS‐2−/− brains at postnatal day 10 (P10) as compared to controls. myelin basic protein immunostaining in P10‐IRS‐2−/− mice revealed a reduced immunostaining, but an unchanged regional distribution pattern. In cerebral myelin isolates at P10 unaltered relative expression of different myelin proteins was found, indicating quantitatively reduced but not qualitatively altered myelination. Interestingly, up‐regulation of IRS‐1 expression and increased IGF‐1R signaling were observed in IRS‐2−/− mice at P10‐14, indicating a compensatory mechanism to overcome IRS‐2 deficiency. Adult IRS‐2−/− mice showed unaltered myelination and motor function. Furthermore, in neuronal/brain‐specific insulin receptor knockout mice myelination was unchanged. Thus, our experiments reveal that IGF‐1R/IRS‐2 mediated signals are critical for appropriate timing of myelination in vivo.

Low-grade inflammation is important in the development of obesity related pathologies such as insulin resistance and type 2 diabetes, and also cardiovascular disease. Visfatin/PBEF/Nampt and resistin are proinflammatory adipokines secreted from adipocytes, monocytes, and macrophages, and have been linked to atherosclerotic plaque formation, recently. The aim of the present study was to investigate if the expression of these molecules in circulating blood monocytes is altered in obese and/or type 2 diabetic human subjects. Monocytes were isolated by CD14-antibody based magnetic cell sorting from blood samples of 17 lean controls, 20 obese nondiabetic subjects, and 19 obese patients with type 2 diabetes. FACS analysis was performed to test purity of the cell preparations. Expression of the different adipokines was measured by multiplex real-time PCR on RNA-level. Visfatin/PBEF/Nampt was found to be very strongly expressed in monocytes, whereas resistin levels were significantly lower. Furthermore, visfatin/PBEF/Nampt expression was significantly upregulated in obese type 2 diabetic patients, whereas obese nondiabetics exhibited similar levels compared to lean controls, indicating that visfatin/PBEF/Nampt levels are related to type 2 diabetes rather than to obesity. In contrast, resistin expression displayed a different pattern being significantly increased in obese subjects compared to controls but not related to type 2 diabetes. These data suggest a differential role for these two proinflammatory adipokines in linking metabolic diseases to atherosclerosis with visfatin/PBEF/Nampt being more important in patients with type 2 diabetes and resistin in obese but nondiabetic human subjects.

Objective: To compare the effects of two treatment modalities of testosterone on sexual functioning and mood. Design: Forty men were randomized to receive either parenteral testosterone enanthate (TE) or longacting parenteral testosterone undecanoate (TU) over a period of 30 weeks. Thereafter, 20 men who had received TU and 16 men who had received TE continued with TU and completed another 65 weeks to study longer-term effects of TU. Methods: The following variables of sexual functioning were studied: sexual thoughts and fantasy, sexual interest and desire, satisfaction with sex life, number of erections and ejaculations per week, and number of spontaneous morning erections per week. Also variables related to mood were analyzed. Results: Improvements in these variables were significant and were of a similar magnitude in the group treated with TU and TE for 30 weeks. Improvements were maintained at the same levels over a period of another 65 weeks when all men received TU. Effects on mood were recorded for 30 weeks, but were more difficult to establish in the study population. There were significant differences in baseline values between the two groups and scores showed wide S.D. Conclusions: Both TE and TU were effective in improving sexual functions in hypogonadal men. An advantage of TU over TE is its lower frequency of administration and its better tolerability and safety profile.