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Journal articles on the topic 'Exenatide (exendin-4)'

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Published: 10 December 2022
Last updated: 28 January 2023

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1

Wei, Rui, Shifeng Ma, Chen Wang, Jing Ke, Jin Yang, Weihong Li, Ye Liu, et al. "Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner." American Journal of Physiology-Endocrinology and Metabolism 310, no. 11 (June 1, 2016): E947—E957. http://dx.doi.org/10.1152/ajpendo.00400.2015.

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Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9–39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9–39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.
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2

Zhang, Aihong, Yin Lin, Shirly Nong, Wei Zhao, and Mei Dong. "Engineering a protease-based and site-specific PEGylation-based strategy for the controlled release of exenatide." RSC Advances 10, no. 42 (2020): 25013–21. http://dx.doi.org/10.1039/d0ra01010c.

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Using the commercially available antidiabetic drug exenatide (exendin-4) as a model peptide, we designed a novel exenatide derivative, termed LEX-1, comprising a 12-mer albumin-binding peptide, a protease-sensitive linker and a native exenatide.
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3

Zhao, Qian, Chun-ling Xu, Hai-yan Xiong, Wen Huang, Mei Zhang, Yun Wang, Si-yu Wang, and Wen Wang. "Alleviation of Hyperglycemia Induced Vascular Endothelial Injury by Exenatide Might Be Related to the Reduction of Nitrooxidative Stress." BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/843657.

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We will investigate the effects of exenatide on vascular endothelial injury and nitrooxidative stress in hyperglycemia both in vivo and in vitro and explore the role of nitrooxidative stress in endothelium-protective action of exenatide. Healthy male Wistar rats were randomly divided into 4 groups: control, diabetes mellitus (DM) model, low dose of exenatide treatment, and high dose of exenatide treatment. In vitro study showed that, compared with control group, the DM rats exhibited a lowered endothelium-dependent relaxation and damaged structural integrity of thoracic aortas, and there was a significant increase in plasma nitrotyrosine concentration. These parameters were improved after treatment with either low dose or high dose of exenatide for 45 days. In vitro study showed that exendin-4 (the active ingredient of exenatide) attenuated HUVECs injury induced by high glucose, with improving cell viability and attenuating cell apoptosis. Exendin-4 also significantly alleviated the increased malondialdehyde (MDA), nitrotyrosine content, and inducible nitric oxide synthase (iNOS) expression induced by high glucose in HUVECs. In conclusion, this study demonstrates that exenatide treatment can alleviate the vascular endothelial injury, as well as attenuating the nitrooxidative stress in hyperglycemia, implying that the endothelium-protective effect of exenatide might be related to the reduction of nitrooxidative stress.
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4

McCord, Amie D. "Exenatide: A Novel Therapeutic Approach for Type 2 Diabetes Mellitus." Journal of Pharmacy Technology 21, no. 4 (July 2005): 191–96. http://dx.doi.org/10.1177/875512250502100402.

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Objective: To review the pharmacology, pharmacokinetics, clinical efficacy and safety studies, adverse effects, drug interactions, and dosage and administration of exenatide, a novel incretin mimetic agent recently approved for the treatment of type 2 diabetes mellitus. Data Sources: Information was obtained from MEDLINE searches of the English-language literature (1990–November 2004). Search terms included exenatide, synthetic exendin-4, exendin-4, AC2993, and GLP-1 agonist. Study Selection and Data Extraction: All available data were reviewed, including animal and human data disseminated as abstracts, clinical trials, review articles, and press releases. Data Synthesis: Exenatide is a novel therapeutic agent recently approved for the treatment of type 2 diabetes. The unique pharmacologic profile of exenatide offers a promising adjunctive treatment option for this patient population. Conclusions: While the long-term safety and efficacy of this agent are not well documented, the available data indicate the efficacy and safety of exenatide in combination with various oral antidiabetic agents in reducing postprandial glucose concentrations, glycosylated hemoglobin values, and potentially body weight without increasing the risk of hypoglycemia.
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5

Denker, P. S., and P. E. Dimarco. "Exenatide (Exendin-4)-Induced Pancreatitis: A case report." Diabetes Care 29, no. 2 (January 27, 2006): 471. http://dx.doi.org/10.2337/diacare.29.02.06.dc05-2043.

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6

Kosowska, Agnieszka, Enrique Gallego-Colon, Wojciech Garczorz, Agnieszka Kłych-Ratuszny, Mohammad Reza F. Aghdam, Michał Woz´niak, Andrzej Witek, et al. "Exenatide modulates tumor–endothelial cell interactions in human ovarian cancer cells." Endocrine Connections 6, no. 8 (November 2017): 856–65. http://dx.doi.org/10.1530/ec-17-0294.

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Diabetes and cancer are prevalent diseases whose incidence is increasing globally. Diabetic women have a moderate risk increase in ovarian cancer, suggested to be due to an interaction between these two disorders. Furthermore, patients manifesting both diseases have associated worse prognosis, reduced survival and shorter relapse-free survival. According to current recommendations, incretin drugs such as Exenatide, a synthetic analog of Exendin-4, and Liraglutide are used as therapy for the type 2 diabetes (T2D). We studied the effects of GLP-1 and Exendin-4 on migration, apoptosis and metalloproteinase production in two human ovarian cancer cells (SKOV-3 and CAOV-3). Exendin-4 inhibited migration and promoted apoptosis through caspase 3/7 activation. Exendin-4 also modulated the expression of key metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). Vascular endothelial cells, which contribute to the formation and progression of metastasis, were also analyzed. TNF-α-stimulated endothelial cells from iliac artery after Exendin-4 treatment showed reduced production of adhesion molecules (ICAM-1 and VCAM-1). Additionally, incretin treatment inhibited activation of apoptosis in TNF-α-stimulated endothelial cells. In the same experiment, MMPs (MMP-1 and MMP-9), which are relevant for tumor development, were also reduced. Our study demonstrated that incretin drugs may reduce cancer cell proliferation and dissemination potential, hence limiting the risk of metastasis in epithelial ovarian cancer.
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7

Hiles, Richard A., Roger E. Bawdon, and Ezio M. Petrella. "Ex vivo human placental transfer of the peptides pramlintide and exenatide (synthetic exendin-4)." Human & Experimental Toxicology 22, no. 12 (December 2003): 623–28. http://dx.doi.org/10.1191/0960327103ht402oa.

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Two peptides, pramlintide (37 amino acids), an analog of human amylin, and exenatide, synthetic exendin-4 (39 amino acids), are both in late-stage clinical development as potential new treatments for people with diabetes. Both are potential long-term treatments, and there is the likelihood that some women will become pregnant while using one of these peptide therapies. Therefore, it was important to evaluate the potential for each peptide to cross the placental barrier and thereby result in exposure to the fetus. This was examined using ex vivo perfusions of human placentas. The fetal and maternal side of a cotyledon were cannulated and perfused first with buffer, and then with radioactive antipyrine in order to establish the integrity of the system and the perfusion constants. Either pramlintide or exenatide was then added to each acceptable cotyledon perfusate on the maternal side. Each peptide was evaluated at an initial concentration near the therapeutic plasma concentration and at approximately 10-50 times that concentration in each of the three cotyledons. Maternal and fetal perfusate samples were assayed for peptide concentrations using an immunoassay. The ratio of fetal-to-maternal peptide concentrations during equilibrium perfusion were extremely low (pramlintide ≤ 0.006, exenatide 5 ≤ 0.017). These data demonstrate negligible passage of either peptide across the placental barrier. It is, therefore, likely that maternal use of either peptide during gestation will result in negligible exposure to the fetus.
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8

Kawasaki, Yukiko, Yoshiyuki Hamamoto, and Hiroyuki Koshiyama. "Species-Specific Actions of Incretin: From the Evolutionary Perspective." Japanese Clinical Medicine 1 (January 2010): JCM.S5915. http://dx.doi.org/10.4137/jcm.s5915.

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Two modes of incretin-based therapy, incretin mimetics (ie, glucagon-like peptide-1 (GLP-1) agonists) and incretin enhancers (ie, inhibitors of dipeptidyl peptidase IV (DPP-IV)), have recently been introduced into the clinical use. From the viewpoint of evolutionary endocrinology of GLP-1 and their receptors, the incretin action of GLP-1 seems to be relatively recent. Exendin-3 and exendin-4 are paralogs of GLP-1 from the lizards, and the synthetic exendin-4, exenatide, is a paralog of GLP-1. It has recently been indicated that GLP-1 and its receptor are expressed in the taste buds of the tongue, suggesting their possible function in the taste sensing signal pathway. In order to elucidate unknown functions of GLP-1 and its agonists and enhancers, ie, other than incretin actions in humans, it is possibly useful to consider GLP-1 from the viewpoint of integrated systems biology and evolutionary endocrinology.
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9

Nachnani, J. S., D. G. Bulchandani, A. Nookala, B. Herndon, A. Molteni, P. Pandya, R. Taylor, T. Quinn, L. Weide, and L. M. Alba. "Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas." Diabetologia 53, no. 1 (September 13, 2009): 153–59. http://dx.doi.org/10.1007/s00125-009-1515-4.

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10

Calara, F. "Effect of injection site on relative bioavailability of exenatide (synthetic exendin-4)." Clinical Pharmacology & Therapeutics 75, no. 2 (February 2004): P58. http://dx.doi.org/10.1016/j.clpt.2003.11.221.

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11

Chia, Chee W., and Josephine M. Egan. "Incretin-Based Therapies in Type 2 Diabetes Mellitus." Journal of Clinical Endocrinology & Metabolism 93, no. 10 (October 1, 2008): 3703–16. http://dx.doi.org/10.1210/jc.2007-2109.

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Context: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon. Evidence Acquisition: The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin. Evidence Synthesis: Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA1c) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA1c by 0.6–0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA1c by 1.0–1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not. Conclusions: The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on β-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.
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12

Hadjiyanni, Irene, Laurie L. Baggio, Philippe Poussier, and Daniel J. Drucker. "Exendin-4 Modulates Diabetes Onset in Nonobese Diabetic Mice." Endocrinology 149, no. 3 (December 6, 2007): 1338–49. http://dx.doi.org/10.1210/en.2007-1137.

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Activation of the glucagon-like peptide-1 receptor (GLP-1R) is associated with expansion of β-cell mass due to stimulation of cell proliferation and induction of antiapoptotic pathways coupled to β-cell survival. Although the GLP-1R agonist Exenatide (exendin-4) is currently being evaluated in subjects with type 1 diabetes, there is little information available about the efficacy of GLP-1R activation for prevention of experimental type 1 diabetes. We examined the consequences of exendin-4 (Ex-4) administration (100 ng once daily and 2 μg twice daily) on diabetes onset in nonobese diabetic mice beginning at either 4 or 9 wk of age prior to the onset of diabetes. Ex-4 treatment for 26 wk (2 μg twice daily) initiated at 4 wk of age delayed the onset of diabetes (P = 0.007). Ex-4-treated mice also exhibited a significant reduction in insulitis scores, enhanced β-cell mass, and improved glucose tolerance. Although GLP-1R mRNA transcripts were detected in spleen, thymus, and lymph nodes from nonobese diabetic mice, Ex-4 treatment was not associated with significant changes in the numbers of CD4+ or CD8+ T cells or B cells in the spleen. However, Ex-4 treatment resulted in an increase in the number of CD4+ and CD8+ T cells in the lymph nodes and a reduction in the numbers of CD4+CD25+Foxp3+ regulatory T cells in the thymus but not in lymph nodes. These findings demonstrate that sustained GLP-1R activation in the absence of concomitant immune intervention may be associated with modest but significant delay in diabetes onset in a murine model of type 1 diabetes.
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13

Victor, Suresh, Eridan Rocha-Ferreira, Ahad Rahim, Henrik Hagberg, and David Edwards. "New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy." European Journal of Pediatrics 181, no. 3 (November 24, 2021): 875–87. http://dx.doi.org/10.1007/s00431-021-04320-8.

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AbstractAround 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.
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14

Holst, Jens Juul. "Pharmacology of GLP-1-based therapies." British Journal of Diabetes & Vascular Disease 8, no. 2_suppl (November 2008): S10—S18. http://dx.doi.org/10.1177/1474651408100523.

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Glucagon-like peptide-1 GLP-1 is a naturally occurring 30-amino acid peptide synthesised in intestinal endocrine L cells. GLP-1 mediates glucose homeostasis through stimulation of glucose-dependent insulin secretion, biosynthesis of insulin and inhibition of glucagon secretion. These effects have potential clinical value in type 2 diabetes. However, because native GLP-1 is rapidly degraded to its inactive form by dipeptidyl peptidase-4 (DPP-4), it has a short half-life in vivo . Strategies to overcome this therapeutic limitation include developing GLP-1 mimetics and analogues with longer half-lives and to inhibit DPP-4. Exenatide (exendin-4) is a 39-amino acid peptide originally derived from the venom of the Gila monster lizard, and shares a 53% sequence identity with human GLP-1. Exenatide has a longer circulating half-life, reflecting relative resistance to DPP-4 degradation, and is administered twice daily. Liraglutide is a once-daily human GLP-1 analogue with high (97%) sequence identity. The specific structural modifications that characterise liraglutide result in increased self-association (allowing slow absorption from the subcutaneous depot), promote albumin binding and reduce susceptibility to DPP-4, giving liraglutide a half-life of 13 hours after once-daily administration. Preliminary studies of exenatide and liraglutide show clinically relevant reductions in glycosylated haemoglobin A1c (HbA1c) compared with placebo, without hypoglycaemia and with weight loss of up to 3 kg. DPP-4 inhibitors, such as vildagliptin (not available in the USA) and sitagliptin can help stabilise postprandial GLP-1 levels and thus produce desirable effects on insulin and glucagon production. The potential for weight reduction with DPP-4 inhibitors appears limited, perhaps reflecting the limited increase in GLP-1 levels achieved with these agents.Br J Diabetes Vasc Dis, 2008;8 (Suppl 2) : S10—S18
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15

Kolterman, Orville G., John B. Buse, Mark S. Fineman, Eling Gaines, Sonja Heintz, Thomas A. Bicsak, Kristin Taylor, et al. "Synthetic Exendin-4 (Exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes." Journal of Clinical Endocrinology & Metabolism 88, no. 7 (July 1, 2003): 3082–89. http://dx.doi.org/10.1210/jc.2002-021545.

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Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 μg/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 μg/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.
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16

Nielsen, Loretta L., Andrew A. Young, and David G. Parkes. "Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes." Regulatory Peptides 117, no. 2 (February 2004): 77–88. http://dx.doi.org/10.1016/j.regpep.2003.10.028.

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17

Degn, K. B., B. Brock, C. B. Juhl, C. B. Djurhuus, J. Grubert, D. Kim, J. Han, K. Taylor, M. Fineman, and O. Schmitz. "Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia." Diabetes 53, no. 9 (August 26, 2004): 2397–403. http://dx.doi.org/10.2337/diabetes.53.9.2397.

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18

Calara, Federico, Kristin Taylor, Jenny Han, Evelyn Zabala, Eh Moo Carr, Matthew Wintle, and Mark Fineman. "A randomized, open-label, crossover study examiningthe effect of injection site on bioavailability of exenatide (synthetic exendin-4)." Clinical Therapeutics 27, no. 2 (February 2005): 210–15. http://dx.doi.org/10.1016/j.clinthera.2005.02.008.

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19

Figat, Magdalena, Grzegorz Kardas, Piotr Kuna, and Michał G. Panek. "Beneficial Influence of Exendin-4 on Specific Organs and Mechanisms Favourable for the Elderly with Concomitant Obstructive Lung Diseases." Brain Sciences 12, no. 8 (August 17, 2022): 1090. http://dx.doi.org/10.3390/brainsci12081090.

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Exendin-4 (Ex-4), better known in its synthetic form and used clinically as exenatide, currently applied in the treatment of diabetes, induces a beneficial impact on nerve cells, and shows promising effects in obstructive lung diseases. At an advanced age, the development of the neurodegenerative process of brain tissue is masked by numerous concomitant diseases. The initial latent phase of neurodegenerative disease results in occurrence of manifestations at an advanced stage. To protect the brain and to simultaneously ensure proper treatment of common coexisting conditions in late life, such as diabetes, chronic obstructive pulmonary disease, or asthma, a pleiotropic medication should be chosen. Molecular mechanisms of Ex-4 exert neuroprotective effects or lead to secondary neurogenesis. Additionally, Ex-4 plays an important role in anti-inflammatory actions which are necessary both in the case of asthma and Parkinson’s disease. Specific receptors in the lungs also reduce the secretion of surfactants, which decreases the risk of exacerbation in chronic obstructive lung disease. In a great number of patients suffering from diabetes, asthma, or chronic lung disease, there is a great potential for both treatment of the main condition and protection against brain neurodegeneration.
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20

Gallwitz, Baptist. "GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond – New Insights 2015." US Endocrinology 11, no. 01 (2015): 47. http://dx.doi.org/10.17925/use.2015.11.1.47.

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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them shortacting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for once-weekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has been approved for treatment of obesity at a higher dose than that used for diabetes therapy. This mini-review gives a short overview of the novel long-acting GLP-1 RAs albiglutide and dulaglutide and also reviews the studies of liraglutide in treatment of obesity leading to its approval for this use. These studies were largely presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in fall 2014.
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21

Gallwitz, Baptist. "GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond – New Insights 2015." European Endocrinology 11, no. 1 (2015): 21. http://dx.doi.org/10.17925/ee.2015.11.01.21.

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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them short-acting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for onceweekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has been approved for treatment of obesity at a higher dose than that used for diabetes therapy. This mini-review gives a short overview of the novel long-acting GLP-1 RAs albiglutide and dulaglutide and also reviews the studies of liraglutide in treatment of obesity leading to its approval for this use. These studies were largely presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in fall 2014.
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22

Buse, J. B., R. R. Henry, J. Han, D. D. Kim, M. S. Fineman, and A. D. Baron. "Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes." Diabetes Care 27, no. 11 (October 25, 2004): 2628–35. http://dx.doi.org/10.2337/diacare.27.11.2628.

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23

DeFronzo, R. A., R. E. Ratner, J. Han, D. D. Kim, M. S. Fineman, and A. D. Baron. "Effects of Exenatide (Exendin-4) on Glycemic Control and Weight Over 30 Weeks in Metformin-Treated Patients With Type 2 Diabetes." Diabetes Care 28, no. 5 (April 26, 2005): 1092–100. http://dx.doi.org/10.2337/diacare.28.5.1092.

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24

Mack, C. M., C. X. Moore, C. M. Jodka, S. Bhavsar, J. K. Wilson, J. A. Hoyt, J. L. Roan, et al. "Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures." International Journal of Obesity 30, no. 9 (March 14, 2006): 1332–40. http://dx.doi.org/10.1038/sj.ijo.0803284.

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25

Wright, F. L., and R. J. Rodgers. "G.11 - BEHAVIOURAL PROFILE OF GLP-1 RECEPTOR AGONIST, EXENDIN-4 (EXENATIDE), IN NON-DEPRIVED MALE RATS PRESENTED WITH PALATABLE MASH." Behavioural Pharmacology 24 (October 2013): e59. http://dx.doi.org/10.1097/01.fbp.0000434879.77693.f7.

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26

Fineman, Mark S., Larry Z. Shen, Kristin Taylor, Dennis D. Kim, and Alain D. Baron. "Effectiveness of progressive dose-escalation of exenatide(exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes." Diabetes/Metabolism Research and Reviews 20, no. 5 (August 27, 2004): 411–17. http://dx.doi.org/10.1002/dmrr.499.

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27

Gedulin, Bronislava R., Svetlana E. Nikoulina, Pamela A. Smith, George Gedulin, Loretta L. Nielsen, Alain D. Baron, David G. Parkes, and Andrew A. Young. "Exenatide (Exendin-4) Improves Insulin Sensitivity and β-Cell Mass in Insulin-Resistant Obesefa/faZucker Rats Independent of Glycemia and Body Weight." Endocrinology 146, no. 4 (April 2005): 2069–76. http://dx.doi.org/10.1210/en.2004-1349.

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28

Blase, Erich, Kristin Taylor, Hong-ye Gao, Matthew Wintle, and Mark Fineman. "Pharmacokinetics of an Oral Drug (Acetaminophen) Administered at Various Times in Relation to Subcutaneous Injection of Exenatide (Exendin-4) in Healthy Subjects." Journal of Clinical Pharmacology 45, no. 5 (May 2005): 570–77. http://dx.doi.org/10.1177/0091270004274432.

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29

Kendall, D. M., M. C. Riddle, J. Rosenstock, D. Zhuang, D. D. Kim, M. S. Fineman, and A. D. Baron. "Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 Diabetes Treated With Metformin and a Sulfonylurea." Diabetes Care 28, no. 5 (April 26, 2005): 1083–91. http://dx.doi.org/10.2337/diacare.28.5.1083.

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30

Fineman, M. S., T. A. Bicsak, L. Z. Shen, K. Taylor, E. Gaines, A. Varns, D. Kim, and A. D. Baron. "Effect on Glycemic Control of Exenatide (Synthetic Exendin-4) Additive to Existing Metformin and/or Sulfonylurea Treatment in Patients With Type 2 Diabetes." Diabetes Care 26, no. 8 (July 25, 2003): 2370–77. http://dx.doi.org/10.2337/diacare.26.8.2370.

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31

Kennedy, L. "Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 Diabetes Treated With Metformin and a Sulfonylurea." Yearbook of Endocrinology 2006 (January 2006): 1–4. http://dx.doi.org/10.1016/s0084-3741(08)70258-0.

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32

Sathavarodom, Nattapol, Thanasate Roongjiraroj, and Verapon Pinphanichakarn. "ODP222 Liragluitde Increased IL-1RA Concentrations in Obese Type 2 Diabetes: A Small Randomized Controlled Trial." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A325. http://dx.doi.org/10.1210/jendso/bvac150.673.

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Abstract Background Therapy with exenatide, exendin-4-based glucagon liked peptide-1 receptor agonist (GLP-1 RA) increased plasma interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein which protected pancreatic ß cells independent of glycemic and weight controlled. We hypothesized that liraglutide, long-acting GLP-1 analogue might contribute to a potential protective effect on ß cells in diabetes. Methods Twenty-four obese patients with type 2 diabetes receiving oral hypoglycemic agents with insulin therapy, except pioglitazone or incretin-based therapy, were randomly assigned to receive either maximum tolerate dose of liraglutide (n=12) or standard therapy (n=12) for twelve weeks. Results Among 24 participants who completed over 12 weeks of this study, median change was +258.7% (78.7, 656.6) and +101. 0% (-3.3, 189.4) of IL-1RA; P<0. 04, and -1.2% (-1.7, -0.8) and -0.4% (-1. 0, 0.3) of A1c; P<0. 03 in liraglutide and standard group, respectively. Percent changes of fasting plasma glucose, body weight, neck circumference and body mass index were all not statistically significant, when comparing between group. Pearson correlation between percent change of IL-1RA and percent change of A1c response to therapy were also not statistically significant. Conclusion Liraglutide might have anti-inflammatory effect independent of the glycemic control during initial short-term duration. Keywords: Liraglutide, Interleukin-1 receptor antagonist, obese type 2 diabetes. Presentation: No date and time listed
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33

Bailey, Clifford J. "origins of type 2 diabetes medications." British Journal of Diabetes 22, no. 2 (December 21, 2022): 112–20. http://dx.doi.org/10.15277/bjd.2022.388.

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The origins of diabetes medications provide an intriguing catalogue of clinical serendipity and scientific design. Use of insulin (beyond 1922) gave recognition to insulin resistance and the categorisation of type 2 diabetes (T2DM). The first sulphonylurea (carbutamide, 1956) emerged from its use as an antibacterial sulphonamide prone to cause hypoglycaemia, and biguanides were first used to treat diabetes in 1957 despite their glucose-lowering properties having been known since the 1920s. Alpha-glucosidase inhibitors arose from a screening programme for amylase inhibitors by Bayer in the 1970s and acarbose was introduced in 1990. The first thiazolidinedione (ciglitazone; not developed) was identified in a screening programme for triglyceride-lowering compounds by Takeda in the late 1970s and gave rise to pioglitazone (approved 1999), although first to market was troglitazone (from Warner Lambert 1997, withdrawn 2000). Exendin, an analogue of the incretin hormone glucagon-like peptide-1 (GLP-1), was identified in 1992 in the saliva of a lizard (Heloderma suspectum), and took until 2005 to be marketed as exenatide. To promote the efficacy of endogenous GLP-1, its rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP4) was blocked by clever molecular design of the first DPP4 inhibitors (vildagliptin and sitagliptin, approved in 2006). SGLT2 inhibitors are based on phlorizin, identified in apple tree bark (1835) and modified (2000) to avoid intestinal degradation: further modifications to increase selectivity against SGLT2 gave dapagliflozin and canagliflozin - approved 2012 and 2013, respectively, in Europe.
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Martins, Flavia L., Matthew A. Bailey, and Adriana C. C. Girardi. "Endogenous Activation of Glucagon-Like Peptide-1 Receptor Contributes to Blood Pressure Control." Hypertension 76, no. 3 (September 2020): 839–48. http://dx.doi.org/10.1161/hypertensionaha.120.14868.

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The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous GLP-1R signaling influences the regulation of BP. To this end, SHRs (spontaneously hypertensive rats) and Wistar rats were treated with the GLP-1R antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving the GLP-1R agonist Ex4 (exenatide) were used as an additional control. We found that blockade of baseline GLP-1R signaling by Ex9 increased systolic BP in both SHR and Wistar rats, compared with vehicle-treated animals, while Ex4 only reduced systolic BP in SHR. Higher systolic BP induced by Ex9 was accompanied by reduced lithium clearance and lower levels of NHE3 (Na + /H + exchanger isoform 3) phosphorylation at the serine 552, indicative of increased proximal tubule sodium reabsorption. Additionally, urinary AGT (angiotensinogen) and renal cortical concentration of Ang II (angiotensin II) were enhanced by Ex9. Conversely, Ex4 decreased both urinary AGT and cortical Ang II but exclusively in SHRs. Moreover, both SHR and Wistar rats treated with Ex9 displayed hyperinsulinemia as compared with vehicle-treated rats, whereas Ex4 reduced fasting insulin concentration in SHR. Collectively, these results suggest that endogenous GLP-1R signaling exerts a physiologically relevant effect on BP control, which may be attributable, in part, to its tonic actions on the proximal tubule NHE3-mediated sodium reabsorption, intrarenal renin-angiotensin system, and insulin sensitivity. The possible role of impaired GLP-1R signaling in the pathogenesis of hypertension warrants further investigation.
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Poon, Terri, Kristin Taylor, Loretta Nielsen, Sarah Boies, Dongliang Zhuang, Amanda Varns, Jay Zhou, et al. "Abstract #20: Effects of Exenatide (Synthetic Exendin-4) on Glucose Control and Safety in Patients with Type 2 Diabetes Treated with Metformin, a Sulfonylurea, or Both: An Ongoing, Open-Label Phase 3 Trial." Endocrine Practice 10 (March 2004): 7. http://dx.doi.org/10.1016/s1530-891x(20)46299-8.

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36

Wajchenberg, Bernardo L. "β-Cell Failure in Diabetes and Preservation by Clinical Treatment." Endocrine Reviews 28, no. 2 (March 12, 2007): 187–218. http://dx.doi.org/10.1210/10.1210/er.2006-0038.

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There is a progressive deterioration in β-cell function and mass in type 2 diabetics. It was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in β-cell mass of about 60% was shown at necropsy. The reduction of β-cell mass is attributable to accelerated apoptosis. The major factors for progressive loss of β-cell function and mass are glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Impaired β-cell function and possibly β-cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased β-cell mass has probably not been passed. Among the interventions to preserve or “rejuvenate” β-cells, short-term intensive insulin therapy of newly diagnosed type 2 diabetes will improve β-cell function, usually leading to a temporary remission time. Another intervention is the induction of β-cell “rest” by selective activation of ATP-sensitive K+ (KATP) channels, using drugs such as diazoxide. A third type of intervention is the use of antiapoptotic drugs, such as the thiazolidinediones (TZDs), and incretin mimetics and enhancers, which have demonstrated significant clinical evidence of effects on human β-cell function. The TZDs improve insulin secretory capacity, decrease β-cell apoptosis, and reduce islet cell amyloid with maintenance of neogenesis. The TZDs have indirect effects on β-cells by being insulin sensitizers. The direct effects are via peroxisome proliferator-activated receptor γ activation in pancreatic islets, with TZDs consistently improving basal β-cell function. These beneficial effects are sustained in some individuals with time. There are several trials on prevention of diabetes with TZDs. Incretin hormones, which are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas, aid the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion, and control of body weight. From the two major incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), only the first one or its mimetics or enhancers can be used for treatment because the diabetic β-cell is resistant to GIP action. Because of the rapid inactivation of GLP-1 by dipeptidyl peptidase (DPP)-IV, several incretin analogs were developed: GLP-1 receptor agonists (incretin mimetics) exenatide (synthetic exendin-4) and liraglutide, by conjugation of GLP-1 to circulating albumin. The acute effect of GLP-1 and GLP-1 receptor agonists on β-cells is stimulation of glucose-dependent insulin release, followed by enhancement of insulin biosynthesis and stimulation of insulin gene transcription. The chronic action is stimulating β-cell proliferation, induction of islet neogenesis, and inhibition of β-cell apoptosis, thus promoting expansion of β-cell mass, as observed in rodent diabetes and in cultured β-cells. Exenatide and liraglutide enhanced postprandial β-cell function. The inhibition of the activity of the DPP-IV enzyme enhances endogenous GLP-1 action in vivo, mediated not only by GLP-1 but also by other mediators. In preclinical studies, oral active DPP-IV inhibitors (sitagliptin and vildagliptin) also promoted β-cell proliferation, neogenesis, and inhibition of apoptosis in rodents. Meal tolerance tests showed improvement in postprandial β-cell function. Obviously, it is difficult to estimate the protective effects of incretin mimetics and enhancers on β-cells in humans, and there is no clinical evidence that these drugs really have protective effects on β-cells.
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Winkler, Gábor. "Incretin enhancers, incretin mimetics – from therapeutic concept to clinical application." Orvosi Hetilap 148, no. 13 (April 1, 2007): 579–87. http://dx.doi.org/10.1556/oh.2007.28093.

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Inkretineknek az emésztőtraktus speciális sejtjeiben termelődő, peptid természetű hormonokat nevezzük, amelyek a táplálék összetevői, elsősorban szénhidrátkomponensei hatására elválasztódva, közvetett módon, összetett hatásmechanizmussal – döntően a postprandialis vércukorszint csökkentésével – részt vesznek a glükózhomeosztázis biztosításában. Az összefoglaló közlemény a két legfontosabb inkretin, a glükagonszerű peptid (GLP)-1 és a glükózdependens inzulinotróp polipeptid (GIP) élettani termelődésének áttekintése mellett részletesen foglalkozik a szénhidrát-anyagcsere tekintetében meghatározó jelentőségű tényező, a GLP-1 hatástani sajátosságaival és ezek farmakológiai hasznosításának, a 2-es típusú diabétesz kezelésében való felhasználásának lehetőségeivel. A humán GLP-1 rövid felezési ideje folytán a napi gyakorlatban nem alkalmazható. A lebontását végző szerin-peptidáz típusú enzim, a dipeptidil-peptidáz (DPP) IV gátlásával azonban hatástartama megnyújtható. Sikerült is előállítani e hatással rendelkező vegyületeket, amint kifejlesztésre kerültek DPP IV-rezisztens, a GLP-1-től eltérő szerkezetű, de receptorán agonista hatást kifejtő származékok is. Előbbiek az incretin (GLP-1) hatásfokozók („enhancers”), utóbbiak az ún. mimetikumok. Mindkét csoport képviselői törzskönyvezésre is kerültek. Az inkretin hatásfokozók, az ún. „gliptinek” közül a sita- és vildagliptinnel ismertek hosszabb távú klinikai megfigyelések. Az inkretinomimeticumok egy képviselője, az exenatid – szintetikus exendin-4 – került eddig klinikai forgalomba, több mint egy éves alkalmazásáról ugyancsak ismertek tapasztalatok. A rendelkezésre álló adatok alapján mindegyik felsorolt származék a 2-es típusú diabétesz vércukorcsökkentő kezelésének új, hatékony alternatívája lehet. A terápialáncban képviselt helyük ma még egyértelműen nem körvonalazható. Bár érvek sorakoztathatók fel monoterápiában történő korai adásuk mellett is, elsősorban más antidiabetikumokkal kombinált alkalmazásuk látszik reális indikációnak.
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38

Akter, Shammi, Shajia Afrin, Jaeyoon Kim, Joohyun Kang, Md Abdur Razzak, Per-Olof Berggren, and Inhwan Hwang. "Production of active Exendin-4 in Nicotiana benthamiana and its application in treatment of type-2 diabetics." Frontiers in Plant Science 13 (December 22, 2022). http://dx.doi.org/10.3389/fpls.2022.1062658.

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GLP-1 (Glucagon-like peptide-1) is a peptide that stimulates insulin secretion from the β-cell for glycemic control of the plasma blood glucose level. Its mimetic exenatide (synthetic Exendin-4) with a longer half-life of approximately 3.3–4 h is widely used in clinical application to treat diabetes. Currently, exenatide is chemically synthesized. In this study, we report that the GLP-1 analogue recombinant Exendin-4 (Exdn-4) can be produced at a high level in Nicotiana benthamiana, with an estimated yield of 50.0 µg/g fresh biomass. For high-level expression, we generated a recombinant gene, B:GB1:ddCBD1m:8xHis : Exendin-4 (BGC : Exdn-4), for the production of Exendin-4 using various domains such as the BiP signal peptide, the GB1 domain (B1 domain of streptococcal G protein), a double cellulose binding domain 1 (CBD1), and 8 His residues (8xHis) to the N-terminus of Exendin-4. GB1 was used to increase the expression, whereas double CBD1 and 8xHis were included as affinity tags for easy purification using MCC beads and Ni2+-NTA resin, respectively. BGC : Exdn-4 was purified by single-step purification to near homogeneity using both Ni2+-NTA resin and microcrystalline cellulose (MCC) beads. Moreover, Exdn-4 without any extra residues was produced from BGC : Exdn-4 bound onto MCC beads by treating with enterokinase. Plant-produced Exdn-4 (Exendin-4) was as effective as chemically synthesized Exendin-4 in glucose-induced insulin secretion (GIIS) from mouse MIN6m9 cells a pancreatic beta cell line.
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ROSSELOT, CAROLINA, YANSUI LI, DANIELA GUEVARA, KARA A. BELIARD, RANDY KANG, PENG WANG, KEYA THAKKAR, et al. "14-OR: Harmine and Exenatide Combination Increases Human ß-Cell Survival." Diabetes 71, Supplement_1 (June 1, 2022). http://dx.doi.org/10.2337/db22-14-or.

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GLP1R agonists such as Exendin-4 (E) together with DYRK1A inhibitors such as Harmine (H) significantly increase human β-cell replication in vitro and in vivo. Importantly, 3-month treatment with H+E combination markedly increases human beta cell mass (∼7-fold) in islets transplanted in immunosuppressed mice, beyond the increase induced by proliferation. Therefore, we addressed whether H+E also enhances β-cell survival and that contributes to the increased human β-cell mass expansion in vivo. Treatment with H+E significantly decreased β-cell apoptosis in dispersed primary human islet cells treated in vitro with either thapsigargin (ER stress) , cytokines (inflammation) and H2O2 (ROS) , while the drugs alone or vehicle (V) did not induce such effect. Importantly, H+E treatment for 7 days significantly reduced β-cell apoptosis in human islet grafts transplanted in immunosuppressed mice assessed by insulin and TUNEL staining. Human β-cell mass analysis of these grafts by iDISCO+ revealed a significant ∼50% increase in H+E-treated mice compared with mice treated with drugs alone or V. Human α-cell mass was unchanged. To address the signaling pathways modulated by H+E after 7-day treatment, we performed RNA-seq analysis of these human islet grafts. We identified 29 differentially expressed human genes (> 2-fold, p<0.05) in H+E-treated human islet grafts. GSEA analysis revealed cell adhesion, survival, vascularization and secretion as the main pathways induced by H+E. Among the upregulated genes, VGF (VGF Nerve Growth Factor Inducible) is known to regulate insulin secretion and β-cell survival. We found that H+E treatment of human islets in vitro increases 2-to-3-fold VGF mRNA and secretion. We are now determining VGF involvement in H+E-induced human β-cell survival. In conclusion, we have uncovered a novel prosurvival function of H+E in human β-cells with the potential implication of VGF in these effects. These studies can lead to the discovery of future β-cell protection and regeneration therapies for diabetes. Disclosure C.Rosselot: None. A.F.Stewart: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. Y.Li: None. D.Guevara: None. K.A.Beliard: None. R.Kang: None. P.Wang: None. K.Thakkar: None. G.Lu: None. R.J.Devita: None. Funding DYRK Inhibitors for Human Beta Cell Expansion RDK105015
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SU, YANNA, BEISI LIN, YALAN CHEN, ZIYU LIU, LU GAN, and WEN XU. "1518-PUB: Role of PPARd in Regulating Autophagy Pathway in Improving Islet ß-Cell Function with GLP-1 Receptor Agonist." Diabetes 71, Supplement_1 (June 1, 2022). http://dx.doi.org/10.2337/db22-1518-pub.

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Aim: To investigate the effect and mechanism of glucagon-like peptide-1 receptor agonist (GLP-1 RA) on the function of islet β cells. Methods: Type 2 diabetes C57BL/6J mice were successfully induced by high fat diet (HFD) feeding for 12 weeks then were randomly divided into HFD+NaCl group (n=5) , HFD+Exenatide group (n=5, 24 nmol•kg-1­•d‑1) and NC group (n=5) . Tolerance tests and insulin measurement were performed after 8 weeks of drug therapy. Weight was measured weekly and fasting blood glucose was measured every 4 weeks. The pancreas were stained with LC3B Immunofluorescence at the end of the experiment. The PA induced primary islet β cells were treated with exendin-4 and PA induced Min6 cells were treated with exendin-4, GW501516 for 24h, which BSA as the control group, then detected the protein levels of PPARδ, LC3B-II and P62. At the same time, PA induced MIN6 cells were treated with GSIS. What's more, we silenced PPARδ transfected with siRNA to verify the role of PPARδ in GLP-1 receptor agonist activation of β-cell autophagy. Results: Compared with the normal control group, the body weight and fasting blood glucose increase and significant peripheral insulin resistance in the high fat group, while the above indexes are significantly improved in the high-fat fed mice after GLP-1 RA treatment. Immunofluorescence biopsies of pancreatic tissue show that LC3B expression decrease after high fat diet, while GLP-1 RA intervention significantly increase. In addition, GLP-1 RA not only can promote the expression of PPARδ and LC3B-II protein and inhibit the expression of P62 protein in primary islet β cells and MIN6 cells, but also significantly increase glucose stimulation insulin secretion in MIN6 cells. More importantly, GW501516 is found to be consistent with GLP-1 RA in MIN6 cells, while GLP-1 RA promote autophagy disappeare after PPARδ expression is silenced. Conclusion: GLP-1 RA can improve the function of islet β cells by activating the autophagy pathway through PPARδ. Disclosure Y.Su: None. B.Lin: None. Y.Chen: None. Z.Liu: None. L.Gan: None. W.Xu: None. Funding Science & Technology Project of Guangzhou（202102010175）
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