When testing the novel DA CH peptide

When testing the novel DA-CH3 peptide, it was found that it is superior to liraglutide in the MPTP mouse model of PD at a dose of 25 nmol/kg ip once-daily for 7 days. In the Rotarod and grip strength assessment, DA-CH3 was superior to liraglutide in reversing the MPTP–induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH3 reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone (Yuan et al., 2017). The novel DA-JC4 peptide was tested in the icv. STZ rat model of insulin de-sensitisation. Treatment with DA-JC4 (10 nmol/kg ip.) once-daily for 14 days after STZ icv. administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the Thiomyristoyl receptor (activated astrocytes and microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti-apoptotic Bcl-2 levels. Importantly, insulin signalling was re-sensitized as demonstrated by a reduction of phospho-IRS1Ser1101 levels and phospho-AktSer473 up-regulation (Shi et al., 2017). When comparing the 3 novel dual agonists DA-JC1, DA-JC4 and DA-CH5 with the GLP-1 analogue liraglutide (all drugs at 25 nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD, DA-JC4 and DA-CH5 were most effective. In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP–induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was most effective in reversing this. Pro-inflammatory cytokines were reduced the most by DA-CH5, while expression levels of the neuroprotective growth factor GDNF was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects (Feng et al., 2018). Furthermore, novel triple receptor agonists that activate GLP-1, GIP and glucagon receptors have been developed and first preclinical studies show encouraging effects (Tai et al., 2018).
Conflict of interest declaration
Introduction GIP(1–42) is known as a postprandial gut hormone secreted from enteroendocrine K cells of the small intestine [1] together with other gut hormones [2], [3]. Following a meal, GIP(1–42) enters the circulation and potentiates glucose-mediated insulin secretion from the pancreas [4]. Additional pancreatic effects may include stimulation of glucagon secretion from the α-cells [5], [6] and somatostatin release from δ-cells [7], [8]. The GIP receptor (GIPR) is widely expressed in various tissues besides the pancreas including adipose, bone, and lung tissue [9], [10]. Particularly, the relationship between adipose tissue biology and the GIP system has received much interest. GIPR knock out mice are resistant to diet-induced obesity and crossing this mouse with the leptin mutant (ob/ob) mouse, which is an established mouse model for hyperphagic obesity, reduced weight gain by 23% [11], whereas transgenic GIPR expression in adipose tissue in global GIPR knock out mice restores diet-induced body weight gain [12]. Moreover, a recent study showed that heterogeneous abrogation of the GIP gene displays an intermediate phenotype in regard to high fat diet-induced insulin resistance and weight gain when compared to wild type and homogenous abrogation [13]. If GIP’s physiology in rodents is mirrored in humans, these results support the use of GIPR antagonists as potential therapeutics for the treatment of obesity.