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

Diabetes mellitus is an important public health problem worldwide. Insulin deficiency caused by pancreatic β cell dysfunction is an important pathogenic factor of diabetes mellitus. This study evaluated whether empagliflozin (EMPA) protects the pancreas from diabetes mellitus-induced injury by downregulating the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/caspase-1/Gasdermin D (GSDMD) pyroptosis-related inflammasome pathway in vitro and in vivo. In vivo, animals were separated into blank control (control, C57/bl6j wild-type mice), diabetes model (db/db mice, BKS-Leprem2Cd479/Gpt mice), and db/db mice+EMPA (db/db+EMPA) groups. In vitro, pancreatic β cells were separated into low glucose (control), high glucose (HG), and HG+EMPA groups. The db/db+EMPA group were administered empagliflozin at 10 mg/(kg·day) by gavage for six months. Histological changes in the pancreatic tissues were observed by hematoxylin-eosin staining, and levels of the pyroptosis-related inflammatory factors NLPR3, caspase-1, and GSDMD were measured by immunohistochemistry and immunofluorescence staining methods. The Cell Counting Kit-8 assay was used to detect the effect of different concentrations of glucose and empagliflozin on the proliferation of mouse insulinoma islet β (β TC-6) cells. NLRP3/caspase-1/GSDMD expression was assessed by western blotting and immunofluorescent labeling in the β TC-6 cells. The results showed that empagliflozin reduced the pathological changes and inflammatory cell infiltration in the pancreatic tissues of db/db mice. Furthermore, empagliflozin not only reduced the expression levels of NLRP3/caspase-1/GSDMD in vitro, but also reduced their expression levels in vivo. In summary, our data suggested that empagliflozin protects the pancreatic tissues from diabetes mellitus-induced injury by downregulating the NLRP3/caspase-1/GSDMD pyroptosis-related inflammasome pathway.

Empagliflozin protects diabetic pancreatic tissue from damage by inhibiting the activation of the NLRP3/caspase-1/GSDMD pathway in pancreatic β cells: in vitro and in vivo studies.

The discovery of non-coding RNAs (ncRNAs) has opened a new paradigm to use ncRNAs as biomarkers to detect disease progression. Long non-coding RNAs (lncRNA) have garnered the most attention due to their specific cell-origin and their existence in biological fluids. Type 2 diabetes patients will develop cardiovascular disease (CVD) complications, and CVD remains the top risk factor for mortality. Understanding the lncRNA roles in T2D and CVD conditions will allow the future use of lncRNAs to detect CVD complications before the symptoms appear. This review aimed to discuss the roles of lncRNAs in T2D and CVD conditions and their diagnostic potential as molecular biomarkers for CVD complications in T2D.

https://www.mdpi.com/2075-4418/11/1/145/pdf

Long Non-Coding RNAs (lncRNAs) in Cardiovascular Disease Complication of Type 2 Diabetes.

OBJECTIVE To investigate the effect of long non-coding RNA (LncRNA) PTGS2 on islet β-cell function via the miR-146a-5p/Retinol binding protein 4 (RBP4) axis and its diagnostic value in type 2 diabetes mellitus (T2DM). METHODS The Gene Expression Omnibus (GEO) was analyzed and LncRNA PTGS2 was identified as a potential regulator of T2DM. Mouse pancreatic β cell INS-1 cells were cultured with high glucose, and the relative expression of LncRNA PTGS2 in the serum of T2DM patients and INS-1 cells was detected by Fluorescence Quantitative PCR (qRT-PCR) and its diagnostic value for T2DM was analyzed. The PTGS2/miR-146a-5p/RBP4 axis in INS-1 cells was intervened to observe the changes in cell function. The proliferation of INS-1 cells was detected by CCK8, and the level of insulin secretion was detected by enzyme linked immunosorbent assay (ELISA). The regulatory relationship among LncRNA PTGS2, miR-146a-5p and RBP4 was determined by dual-luciferase reporter assay. RESULTS The expression of LncRNA PTGS2 in the serum of T2DM patients increased, and the expression of LncRNA PTGS2 was positively correlated with the fasting blood glucose level of patients (R=0.306, P<0.05). Knockdown of LncRNA PTGS2 could promote the proliferation and insulin secretion of INS-1 cells, while overexpression of LncRNA PTGS2 showed the opposite results (all P<0.05). Knockdown of LncRNA PTGS2 could up-regulate the expression of miR-146a-5p. Overexpression of LncRNA PTGS2 inhibited the proliferation and insulin secretion of INS-1 cells, while miR-146a-5p could partially reverse this effect. RBP4 has been identified as a downstream target gene of miR-146a-5p. Overexpression of miR-146a-5p could inhibit the expression of RBP4, which was positively correlated withLncRNA PTGS2 regulation. The effect of RBP4 on INS-1 cells was the same as that of LncRNA PTGS2. CONCLUSION LncRNA PTGS2 can damage islet β-cell function by regulation of miR-146a-5p and up-regulation of RBP4. LncRNA PTGS2 has potential value in the diagnosis of T2DM.

LncRNA PTGS2 regulates islet β-cell function through the miR-146a-5p/RBP4 axis and its diagnostic value in type 2 diabetes mellitus.

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.

Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection in β cells

Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection in β cells.

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.

Angiotensin II type 1 receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the effects of ARBs on insulin secretion remain unclear. Here, we investigated the insulinotropic effects of ARBs (telmisartan, valsartan, and irbesartan) and the underlying electrophysiological mechanism in rat islets. We found that only telmisartan among the three ARBs exhibited an insulin secretagogue role. Distinct from other ARBs, telmisartan exerted effects on ion channels including voltage-gated potassium (Kv) channels and voltage-gated Ca2+ channels to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. We observed that the peroxisome proliferator-activated receptor γ pathway was not involved in these telmisartan-induced effects. Furthermore, we identified that telmisartan at least directly inhibited Kv2.1 channel through construction of a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of type 2 diabetes model (db/db) mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in the oral glucose tolerance test. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets isolated from db/db mice. Collectively, our results establish an important function of telmisartan distinct from other ARBs in the treatment of diabetes.

/pdf/telmisartan-potentiates-insulin-secretion-via-ion-channels-4uj0c3nk3u.pdf

Huan Xue

Papers

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

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

Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection in β cells.

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

Telmisartan potentiates insulin secretion via ion channels, independent of the AT1 receptor and PPARγ