Contemporary medical, device, and surgical therapies for obesity in adults

Currently, there is no disease-modifying treatment available for Alzheimer’s and Parkinson’s disease (AD and PD) and that includes the highly controversial approval of the Aβ-targeting antibody aducanumab for the treatment of AD. Hence, there is still an unmet need for a neuroprotective drug treatment in both AD and PD. Type 2 diabetes is a risk factor for both AD and PD. Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor that has shown neuroprotective effects in preclinical studies, and the success of GLP-1 mimetics in phase II clinical trials in AD and PD has raised new hope. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. GLP-1 analogs are safe, well tolerated, resistant to desensitization and well characterized in the clinic. Herein, we review the existing evidence and illustrate the neuroprotective pathways that are induced following GLP-1R activation in neurons, microglia and astrocytes. The latter include synaptic protection, improvements in cognition, learning and motor function, amyloid pathology-ameliorating properties (Aβ, Tau, and α-synuclein), the suppression of Ca2+ deregulation and ER stress, potent anti-inflammatory effects, the blockage of oxidative stress, mitochondrial dysfunction and apoptosis pathways, enhancements in the neuronal insulin sensitivity and energy metabolism, functional improvements in autophagy and mitophagy, elevated BDNF and glial cell line-derived neurotrophic factor (GDNF) synthesis as well as neurogenesis. The many beneficial features of GLP-1R and GLP-1/GIPR dual agonists encourage the development of novel drug treatments for AD and PD.

https://www.frontiersin.org/articles/10.3389/fnins.2022.970925/pdf

The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review

Neuroprotective effects of glucagon-like peptide-1 (GLP-1) analogues in epilepsy and associated comorbidities

We hypothesized that sphingolipids may be early biomarkers of gestational diabetes mellitus (GDM). Here, 520 women with normal fasting plasma glucose levels were recruited in the first trimester and tested with a 75 g oral glucose tolerance test in the 24th–28th week of pregnancy. Serum sphingolipids concentrations were measured in the first and the second trimester by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC/MS/MS) in 53 patients who were diagnosed with GDM, as well as 82 pregnant women with normal glucose tolerance (NGT) and 32 non-pregnant women. In the first trimester, pregnant women showed higher concentrations of C16:0, C18:1, C22:0, C24:1, and C24:0-Cer and lower levels of sphinganine (SPA) and sphingosine-1-phosphate (S1P) compared to non-pregnant women. During pregnancy, we observed significant changes in C16:0, C18:0, C18:1, and C24:1-Cer levels in the GDM group and C18:1 and C24:0-Cer in NGT. The GDM (pre-conversion) and NGT groups in the first trimester differed solely in the levels of C18:1-Cer (AUC = 0.702 p = 0.008), also considering glycemia. Thus, C18:1-Cer revealed its potential as a GDM biomarker. Sphingolipids are known to be a modulator of insulin resistance, and our results indicate that ceramide measurements in early pregnancy may help with GDM screening.

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Serum C18:1-Cer as a Potential Biomarker for Early Detection of Gestational Diabetes

Purpose Ferroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC). Methods The ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs' expression was further evaluated by quantitative real-time polymerase chain reaction in HCC. Results A total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues. Conclusion These results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.

Prognostic Role and Potential Mechanisms of the Ferroptosis-Related Metabolic Gene Signature in Hepatocellular Carcinoma

Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.

/pdf/glp-1-receptor-agonists-beyond-their-pancreatic-effects-58xbi4c2fp.pdf

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

Metabolic reprogramming for adaptation to the tumor microenvironment is recognized as a hallmark of cancer. Although many altered metabolic genes have been reported to be associated with tumor pathological processes, systematic analysis of metabolic genes implicated in hepatocellular carcinoma prognosis remains rare. The aim of this study was to identify key metabolic genes related to hepatocellular carcinoma, and to explore their clinical significance. We downloaded mRNA expression profiles and clinical hepatocellular carcinoma data from The Cancer Genome Atlas database to explore the prognostic roles of metabolic genes. Five prognosis-associated metabolic genes, including POLA1, UCK2, ACYP1, ENTPD2, and TXNRD1, were screened via univariate Cox regression analysis and a LASSO Cox regression model, which divided patients into high- and low-risk groups. Furthermore, gene set enrichment analysis revealed that significantly-enriched gene ontology terms and pathways involving high-risk patients were focused on regulation of nucleic and fatty acid metabolism. Taken together, our study identified five metabolic genes related to survival, which can be used to predict the prognosis of patients with hepatocellular carcinoma. These genes may play essential roles in metabolic microenvironment regulation, and represent potentially important candidate targets in metabolic therapy.

Prognostic roles of metabolic reprogramming-associated genes in patients with hepatocellular carcinoma.

Recent studies suggest that Sphingosine 1-phosphate (S1P) plays an important role in regulating glucose metabolism in type 2 diabetes. However, its effects and mechanisms of promoting insulin secretion remain largely unknown. Here, we found that S1P treatment decreased blood glucose level and increased insulin secretion in C57BL/6 mice. Our results further showed that S1P promoted insulin secretion in a glucose-dependent manner. This stimulatory effect of S1P appeared to be irrelevant to cyclic adenosine monophosphate signaling. Voltage-clamp recordings showed that S1P did not influence voltage-dependent Ca2+ channels, but significantly blocked voltage-dependent potassium (Kv) channels, which could be reversed by inhibition of phospholipase C (PLC) and protein kinase C (PKC). Calcium imaging revealed that S1P increased intracellular Ca2+ levels, mainly by promoting Ca2+ influx, rather than mobilizing intracellular Ca2+ stores. In addition, inhibition of PLC and PKC suppressed S1P-induced insulin secretion. Collectively, these results suggest that the effects of S1P on glucose-stimulated insulin secretion (GSIS) depend on the inhibition of Kv channels via the PLC/PKC signaling pathway in pancreatic β cells. Further, S1P improved β cell survival; this effect was also associated with Kv channel inhibition. This work thus provides new insights into the mechanisms whereby S1P regulates β cell function in diabetes.

/pdf/sphingosine-1-phosphate-stimulates-insulin-secretion-and-2fkjbly8i1.pdf

Sphingosine 1-phosphate Stimulates Insulin Secretion and Improves Cell Survival by Blocking Voltage-dependent K+ Channels in β Cells.

Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future.

/pdf/novel-small-molecule-glucagon-like-peptide-1-receptor-203fvf65l1.pdf

Zhihong Lu

Papers

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

Prognostic roles of metabolic reprogramming-associated genes in patients with hepatocellular carcinoma.

Sphingosine 1-phosphate Stimulates Insulin Secretion and Improves Cell Survival by Blocking Voltage-dependent K+ Channels in β Cells.

Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist S6 Stimulates Insulin Secretion From Rat Islets.