Liraglutide inhibits the progression of prediabetes in rats by reducing Raf-1 kinase inhibitor protein

Abstract

Background: The cleavage product of Raf-1 kinase inhibitor protein (RKIP), hippocampal cholinergic neurostimulating peptide (HCNP) is involved in the promotion of insulin secretion. Studies have shown that liraglutide can inhibit the progression of prediabetes. This study aims to investigate whether the above effects of liraglutide are related to RKIP and HCNP.Methods: Insulin-1 (INS-1) cells were divided into control group (CON), HCNP group, and HCNP + darifenacin group (H-DAR). The three groups were cultured with Roswell Park Memorial Institute (RPMI) 1640, synthetic HCNP (50 pg/mL) and RPMI 1640, and HCNP + RPMI 1640 + darifenacin respectively. Subsequently, twelve 12-to 14-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were randomly divided into 2 groups: the placebo group (PBO) and the liraglutide treatment group (LIRA). Six Long Evans Tokushima Otsuka (LETO) rats were used as the control group (CON). The LIRA group was given liraglutide 200 μg/kg intraperitoneally twice a day. After 12 weeks, body weight, fasting blood glucose, 2 hours postprandial blood glucose, and insulin resistance index were recorded. Western blot was used to detect expression level of C-RKIP, N-RKIP, and extracellular signal-regulated kinase of phosphorylation (p-ERK). Real-time quantitative polymerase chain reaction (qRT-PCR) to detect pancreatic tissue choline acetyltransferase (ChAT) and M3 cholinergic receptor (M3R) gene expression levels.Results: At glucose concentrations of 5.6 and 16.7 mmol/L, the insulin content in the HCNP group was higher than that in the CON and H-DAR groups (all P<0.01). The body weight and fasting serum insulin (FINS) of rats in the PBO group were higher than those in the LIRA group and the CON group (P<0.01).The relative content of C-RKIP protein in the PBO group was higher than that in the LIRA and CON groups (P<0.01). The relative content of N-RKIP protein and p-ERK protein was lower than that in the LIRA and CON group (P<0.05 and P<0.01, respectively). ChAT and M3R gene expression levels in PBO group were lower than those in LIRA and CON group (P<0.01).Conclusions: Liraglutide promotes the production of HCNP, can increase ChAT activity, activate M3R, and further promote the secretion of insulin.

Metabolic Alteration Bridging the Prediabetic State and Colorectal Cancer

“…Treatment with GLP1-RA and GLP1-RA supplemented with GIP reduced body weight by 15% and 20% and decreased IR progression to DM [165], as the GLP1-RA liraglutide ameliorated IR and weight loss independently of GLP1-R signaling [166]. Liraglutide promoted insulin secretion, increasing the production of hippocampal cholinergic neurostimulating peptide (HCNP), choline acetyltransferase, and muscarinic receptor 3 (M3R) in prediabetic rat models [167], and, as in the case of other GLP1-RAs, improved glycemic control and thermogenesis and induced systemic and monocyte-derived IL-6 expression [168]. Exposure to liraglutide counteracted monocyte chemoattractant protein-1 (MCP-1) release, ameliorating inflammatory and atherosclerotic parameters [169], and promoted cardiovascular function by reducing tumorigenesis-2 (sST2) and troponin I inhibition (Eudract: 2013-001356-36) [170].…”

“…Glucose homeostasis enhancement [164,168] Weight loss promotion [164,171] Amelioration of insulin sensitivity [166] Insulin secretion enhancement via HCNP, M3R [167] Choline acetyltransferase upregulation [167] Reduced systemic inflammation [168,169] Cardiovascular function enhancement [170] Suppression of cell survival [189] Suppression of cell migration ability [189] Inhibition of PI3K/Akt/mTOR pathway [189] Reduced cancer relative risk [190] Moreover, a recent cohort study described a protective role of GLP1-RAs against CRC in normal-weight diabetic patients and even more in obese diabetic patients [190]. Metformin, SGLT2i, GLP1-RA, and other antidiabetic drugs, by targeting some biological mechanisms, e.g., oxidative stress and mitochondrial dysfunction, demonstrated antioxidant and ROS scavenger properties in in vitro and in vivo models, a common feature of prediabetes and CRC [191,192].…”