Underlying this study is the hypothesized importance

Underlying this study is the hypothesized importance of insulin and glucose metabolism on bone. In our investigation of GIP and GIPR gene polymorphisms in relation to bone phenotypes in young and old women our findings depict a complex relationship between glucose metabolism genes and bone. In the current setting, it is not possible to explore the reason for these observations. Further studies in equivalent populations are merited to explore these associations further. The following is the supplementary data related to this article.
Conflict of interest
Acknowledgments
This work was supported by grants from the Swedish Research Council (K2012-52X-14691-10-3), FAS (2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, the H Järnhardt Foundation, King Gustav V and Queen Victoria Foundation, Åke Wiberg Foundation, Thelma Zoegas Foundation, the Swedish Rheumatism Association, Stiftelsen för njursjuka, Skåne University Hospital Research Fund, Research and Development Council of Region Skåne, Sweden.
A new dawn – novel drug targets for treating Alzheimer's disease Our understanding what causes progressive neurodegenerative disorders such as Alzheimer's or Parkinson's disease (PD) is still sketchy. The findings of Alois Alzheimer when staining the brain of a patient showed distinct protein Necrosulfonamide mg which appeared to define the disease (Alzheimer, 1907, Alzheimer et al., 1995). However, as a good scientist, Dr. Alzheimer cautioned to jump to conclusions and reminded readers that this does not prove that these aggregates actually cause the disease. Further research appeared to support the concept that amyloid is causal to the disease. Mutations in the APP gene and in presenilin genes were found in familial forms of AD, which demonstrated that these mutations accelerate disease progression (Hardy, 1997). However, since then, a number of clinical trials that tested antibodies directed against various sections and states of aggregation of amyloid or that inhibited secretases which produce the amyloid failed. In an active immunization trial, it was found that the vaccination was successful and cleared the brain of plaques. However, the disease progressed continued unhindered in these patients (Holmes et al., 2008). In the time period of 2002–2012, 413 clinical trials in AD were performed with a failure rate of 96% and only symptom modifying drugs reaching the market (Cummings et al., 2014). Sind then, numerous large scale phase III clinical trials that targeted amyloid in the brain failed to show clear improvements (De Strooper and Karran, 2016, Morris et al., 2014), see also Alzforum comment (Alzforum, 2016). Additionally, brain scans assessing the amyloid plaque load in AD patients did not show a clear correlation with disease progression as one would expect (Edison et al., 2008). These unexpected results led to a change in the concepts and hypotheses of what actually causes AD. New suggestions are bring proposed, eg. the important role that chronic inflammation in the brain plays in disease progression, and how to potentially halt this process (Butchart et al., 2015, Clark and Vissel, 2016, Morris et al., 2014). This review will focus on a different approach, using growth factor analogues as treatments.
The protective roles of growth factors Another key area of research that has shown promise in the past is the research are of growth factors and their roles in cell repair, synaptic protection and maintenance of their functionality, enhanced gene expression of key proteins that normalise energy utilisation, deal with oxidative stress, normalise autophagy, re-sensitise growth factor signalling, block apoptotic signalling, enhance DNA repair, and inhibit chronic inflammation in the brain, see also Figs. 2 and 3 (Allen et al., 2013, Blurton-Jones et al., 2009, Bradbury, 2005, He et al., 2013, Holscher, 2014b, Mickiewicz and Kordower, 2011, Olson, 1993, Yang et al., 2017). Growth factors have shown a range of neuroprotective properties in a large number of studies and in different disease models. However, the main stumbling block for the implementation of the findings into the clinic is that they do not cross the blood-brain barrier (BBB). The highly protective growth factor Brain Derived Neurotrophic Factor (gene delivery systems are under development to circumvent this barrier. The injection of BDNF directly into the brain is not a suitable treatment for the clinic. No such clinical trial has been successful so far (Beck et al., 2005, Gao et al., 2016, Lopes et al., 2017, Schulte-Herbruggen et al., 2007, Zuccato and Cattaneo, 2009) NGF was found to protect memory formation, synapse numbers and LTP in AD mouse models or in nonprimate monkeys (Clarris et al., 1994, Covaceuszach et al., 2009, Kordower et al., 1997). Gene delivery systems have been developed to be able to use NGF as a drug to treat AD. Clinical trials testing this technique have not been successful so far (Bradbury, 2005, Covaceuszach et al., 2009, Heese et al., 2006, Mandel, 2010, Rafii et al., 2014, Schulte-Herbruggen et al., 2007). In PD, glial-cell line derived neurotrophic factor (GDNF) has attracted considerable interest, as it protects dopaminergic neurons from stress and degeneration, and has shown considerable neuroprotective effects in preclinical tests. However, as it does not cross the BBB either, and the same obstacles of enhancing GDNF levels in the brain exist (Blits and Petry, 2016, Tenenbaum and Humbert-Claude, 2017). Ideally, a growth factor that can cross the BBB and has similar neuroprotective effects should be used.