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    • Insulin de sensitization has been

    2022-01-21

    Insulin de-sensitization has been observed in the brains of people with AD [51], [52], [53] and we previously demonstrated that the GLP-1 analogue liraglutide was able to reverse this [54]. Importantly, caspofungin mg insulin de-sensitization correlates well with cognitive decline [15], [55] and with tau protein phosphorylation levels [56], and the application of insulin via nasal spray showed good improvements in AD patients [57], [58]. The chronic inflammation response in the brain plays a key role in the progression of neurodegenerative disorders [59], and a reduction of this process most likely also plays a part in the overall improvement of the pathophysiology. GLP-1 has anti-inflammatory properties [60], and we have shown previously that single GLP-1 or GIP receptor agonists can reduce the chronic inflammation response in the brain [16], [17], [26]. Novel dual GLP-1/GIP receptor agonists have the advantage of activating two signaling pathways, and have been shown to be superior to single GLP-1 receptor agonists [31], [61]. We previously reported that another dual agonists named DA-JC1 showed good neuroprotective effects in the MPTP mouse model of Parkinson’s disease [33], [62]. That dual agonist was not as effective as a single GLP-1 receptor agonist [63] and had to be injected at a higher dose (50nmol/kg ip). In this study, we used the much lower dose of DA-JC4 (10 nmol/kg ip) for the evaluation of the neuroprotective effects of DA-JC4 in the Alzheimer Rat Model induced by STZ, which compares well to the effective dose of liraglutide of 25nmol/kg ip. [26]. This first study shows promise that such dual agonists may be superior to single incretin analogues, but further dose response tests need to be conducted in order to find the most potent drug dose for this dual agonist. This is of importance as liraglutide has shown first neuroprotective effects in a pilot clinical study of AD patients. Brain activity and energy turnover was assessed by 18FDG-PET brain imaging, and after 6 months of treatment, brain scans revealed that there was significant deterioration in cortical activity in the placebo group. In contrast, the liraglutide treated group showed no deterioration at all [29]. A larger phase II trial is currently ongoing (clinical trial ID NCT01843075). Furthermore, another GLP-1 receptor agonist, exendin-4, has shown good protective effects in a pilot study in patients with Parkinson’s disease [64]. It is therefore of interest to develop more efficient drugs that can activate not just GLP-1 but also the sister incretin signaling pathway GIP, which has shown neuroprotective effects on its own in preclinical studies of AD (Duffy and Holscher, 2013; Faivre and Holscher, 2013) and PD [65], [66]. Novel dual agonists therefore may be superior in the clinic for treating chronic neurodegenerative disorders such as AD or PD.
    Conflict of interest
    Acknowledgements This study was supported by the Shanxi Science and Technology Department (2010081062) and a grant to C.H. under the ‘100 foreign talents’ of the Shanxi province government.
    Introduction Aging is associated with a progressive worsening in glucose tolerance and a decreased ability of the pancreatic beta-cell to secrete insulin in response to glucose [4]. In addition, insulin sensitivity progressively deteriorates resulting in a higher susceptibility to impaired glucose tolerance in older populations [22], [24]. Importantly, development of impaired glucose tolerance is a forerunner of later type 2 diabetes [6]. With the rising burden of related health care problems it is increasingly necessary to develop novel therapeutic strategies for type 2 diabetes. One promising therapeutic approach may be the use of prolonged activation of the glucose-dependent insulinotropic polypeptide (GIP) receptor. GIP is a 42 amino acid hormone which is released from intestinal K-cells in response to oral nutrient absorption [5]. Once released into the circulation, GIP binds to its receptor on pancreatic beta-cells to improve insulin secretion and reduce postprandial hyperglycemia [14]. Other important pancreatic effects include promoting beta-cell growth, differentiation, proliferation and survival [7], [25]. Furthermore, GIP receptors have been identified on numerous extrapancreatic sites including adipose [26], bone [28] and brain [19].