• Annals of Pediatric Endocrinology and Metabolism
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• v.22 no.1
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• pp.15-26
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• 2017

The prevalence of type 2 diabetes (T2D) is increasing worldwide. Patients with T2D suffer from various diabetes-related complications. Since there are many patients with T2D that cannot be controlled by previously developed drugs, it has been necessary to develop new drugs, one of which is a glucagon-like peptide-1 (GLP-1) based therapy. GLP-1 has been shown to ameliorate diabetes-related conditions by augmenting pancreatic ${\beta}-cell$ insulin secretion and having the low risk of causing hypoglycemia. Because of a very short half-life of GLP-1, many researches have been focused on the development of GLP-1 receptor (GLP-1R) agonists with long half-lives such as exenatide and dulaglutide. Now GLP-1R agonists have a variety of dosing-cycle forms to meet the needs of various patients. In this article, we review the physiological features of GLP-1, the effects of GLP-1 on T2D, the features of several GLP-1R agonists, and the therapeutic effect on T2D.

• Journal of Integrative Natural Science
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• v.10 no.3
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• pp.125-130
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• 2017

Glucagon like pepide-2, one of the GLPs, is involved in various metabolic functions in the gastrointestinal tract. It plays a major role in the regulation of mucosal epithelium and the intestinal crypt cell proliferation. Because of their therapeutic importance towards the diseases in the gastrointestinal tract, it becomes necessary to study their interaction with its receptor, GLP-2R. In this study, we have developed protein-protein docking complexes of GLP-2 - GLP-2 receptor. Homology models of GLP-2 are developed, and a reliable model out of the predicted models was selected after model validation. The model was bound with the receptor, to study the important interactions of the complex. This study could be useful in developing novel and potent drugs for the diseases related with GLP-2.

• Journal of Microbiology and Biotechnology
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• v.29 no.10
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• pp.1644-1655
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• 2019

Saccharomyces cerevisiae (S. cerevisiae) and glucagon-like peptide-2 (GLP-2) have been employed to improve the intestinal development of weaned animals. The goal of this study was to determine whether either exogenous S. cerevisiae or GLP-2 elicits major effects on fecal microbiotas and cytokine responses in weaned piglets. Ninety-six piglets weaned at 26 days were assigned to one of four groups: 1) Basal diet (Control), 2) empty vector-harboring S. cerevisiae (EV-SC), 3) GLP-2-expressing S. cerevisiae (GLP2-SC), and 4) recombinant human GLP-2 (rh-GLP2). At the start of the post-weaning period (day 0), and at day 28, fecal samples were collected to assess the bacterial communities via sequencing the V1-V2 region of the 16S-rRNA gene, and piglets' blood was also sampled to measure cytokine responses (i.e., IL-$1{\beta}$, TNF-${\alpha}$, and IFN-${\gamma}$). This study revealed that, on the one hand, although S. cerevisiae supplementation did not significantly alter the growth of weaned piglets, it induced increases in the relative abundances of two core genera (Ruminococcaceae_norank and Erysipelotrichaceae_norank) and decreases in the relative abundances of two other core genera (Lachnospiraceae_norank and Clostridiale_norank) and cytokine levels (IL-$1{\beta}$ and TNF-${\alpha}$) (p < 0.05, Control vs EV-SC; p < 0.05, rh-GLP2 vs GLP2-SC). On the other hand, GLP-2 supplementation had no significant influence on fecal bacterial communities and cytokine levels, but it produced better body weight and average daily gain (p < 0.05, Control vs EV-SC; p < 0.05, rh-GLP2 vs GLP2-SC). Therefore, altered fecal microbiotas and cytokine response effects in weaned piglets were due to S. cerevisiae rather than GLP-2.

• Experimental and Molecular Medicine
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• v.50 no.12
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• pp.2.1-2.12
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• 2018

Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH.

• Molecules and Cells
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• v.47 no.1
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• pp.100004.1-100004.11
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• 2024

Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by β-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment.

• Toxicological Research
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• v.23 no.2
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• pp.173-177
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• 2007

The GLP contains specific language concerning characterization of the test, control and reference substances used in toxicity studies. This paper will describe and discuss what types of documents are required to support test/reference substance characterization under GLP system. The purpose of this article is to present an overview of data needed in the characterization package that will adequately define the substance. Most sponsors use a certificate of analysis (COA) to communicate the test sub-stance characterization status information to the contracting research organizations. The COA should provide the test $material^{\circ}{\phi}s$ characterization results, substance storage requirements, expiration dates, verification of the collection of the retention sample, archival location of the data to support the characterization and GLP compliance status of the characterization.

• Journal of Integrative Natural Science
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• v.10 no.3
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• pp.119-124
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• 2017

Glucagon-like peptide 2 receptor, a GPCR, binds with the glucagon-like peptide, GLP-2 and regulates various metabolic functions in the gastrointestinal tract. It plays an important role in the nutrient homeostasis related to nutrient assimilation by regulating mucosal epithelium. GLP-2 receptor affects the cellular response to external injury, by controlling the intestinal crypt cell proliferation. As they are therapeutically attractive towards diseases related with the gastrointestinal tract, it becomes essential to analyse their structural features to study the pathophysiology of the diseases. As the three dimensional structure of the protein is not available, in this study, we have performed the homology modelling of the receptor based on single- and multiple template modeling. The models were subjected to model validation and a reliable model based on the validation statistics was identified. The predicted model could be useful in studying the structural features of GLP-2 receptor and their role in various diseases related to them.

• Journal of mucopolysaccharidosis and rare diseases
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• v.2 no.2
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• pp.50-51
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• 2016

Combining basal insulin therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) has clear clinical advantages, and is supported by the latest EASD/ADA position statement (1). IDegLira is a once-daily combination of the basal insulin, degludec, and the GLP-1RA, liraglutide, in one pen. The DUAL phase 3 clinical trial program provides important evidence about the efficacy and safety of IDegLira in three different populations of patients with type 2 diabetes (T2D): insulin naïve subjects uncontrolled on oral antidiabetic drugs (OADs), subjects uncontrolled on OAD(s) and a GLP-1 RA, and subjects uncontrolled on OAD(s) and basal insulin. Treatment with IDegLira reduced mean HbA1c to below the EASD/ADA treatment target of 7.0% in all five trials. The mean reduction of HbA1c from baseline ranged from 1.3% and 1.9%. IDegLira resulted in weight loss for subjects uncontrolled on basal insulin, was weight neutral for subjects on OADs and weight gain was minimal (2 kg) for subjects previously treated with a GLP-1 RA. Rates of hypoglycaemia were low across all the trials, particularly considering the level of glycaemic control achieved.

• BMB Reports
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• v.46 no.12
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• pp.606-610
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• 2013

Glucagon like peptide-1 (GLP-1) regulates glucose mediated-insulin secretion, nutrient accumulation, and ${\beta}$-cell growth. Despite the potential therapeutic usage for type 2 diabetes (T2D), GLP-1 has a short half-life in vivo ($t_{1/2}$ <2 min). In an attempt to prolong half-life, GLP-1 fusion proteins were genetically engineered: GLP-1 human serum albumin fusion (GLP-1/HSA), AGLP-1/HSA which has an additional alanine at the N-terminus of GLP-1, and AGLP-1-L/HSA, in which a peptide linker is inserted between AGLP-1 and HSA. Recombinant fusion proteins secreted from the Chinese Hamster Ovary-K1 (CHO-K1) cell line were purified with high purity (>96%). AGLP-1 fusion protein was resistant against the dipeptidyl peptidase-IV (DPP-IV). The fusion proteins activated cAMP-mediated signaling in rat insulinoma INS-1 cells. Furthermore, a C57BL/6N mice pharmacodynamics study exhibited that AGLP-1-L/HSA effectively reduced blood glucose level compared to AGLP-1/HSA.

• Biomedical Science Letters
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• v.6 no.4
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• pp.229-235
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• 2000

In situ brain-pancreas perfusion was performed on male adult Sprague-Dawley rats, of which the central nervous systems (CNS) were intact during the perfusion procedure. The modified Krebs-Ringer buffer with 100 mg/dL of glucose and 20 mM of arginine was perfused for 30 min. In the experimental groups, a cephalic glucopenia was induced at 0 min (GLP1 group) or at 16 min (GLP2 group). The glucopenia was not induced in the control (CONT group). Insulin and glucagon concentrations in the effluent samples from the pancreas were measured using a RIA method. In all three groups, the first and second phases in the dynamics of the insulin and glucagon secretion were observed, which was a typical biphasic secretory pattern. The amount of insulin secretion tended to decrease in the GLP1 and GLP2 groups, but there was no statistically significant difference among the groups. However, the amount of glucagon secretion during 0~15 min of the perfusion period in the GLP1 group was greater as compared to the CONT group (p<0.05). The amount of glucagon secretion during 16~30 min of the perfusion period in the GLP2 group tended to be greater as compared to the CONT group, however there was no statistical significance. These data indicate that the cephalic glucopenia stimulates the direct secretion of glucagon from the pancreas during the early period of perfusion in the CNS-intact pancreatic perfused rats.