The alpha‐7 nicotinic acetylcholine receptor agonist <scp>GTS</scp>‐21 engages the glucagon‐like peptide‐1 incretin hormone axis to lower levels of blood glucose in db/db mice

Meng, Qinghe; Chepurny, Oleg G.; Leech, Colin A.; Pruekprasert, Napat; Molnar, Megan E.; Collier, J. Jason; Cooney, Robert N.; Holz, George G.

doi:10.1111/dom.14693

Cited by 10 publications

(4 citation statements)

References 37 publications

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“…Wang et al showed that GTS-21 stimulates GLP-1 secretion in vitro from cultured L cells and raises circulating GLP-1 levels in vivo when administered to mice 22 . More recent studies by Meng et al show GTS-21 improves glycemic control in db/db mice and the glycemic effects require α7nAChR and GLP-1R stimulation 8 . These results provide evidence that GTS-21-mediated improvements in glycemic control are likely to contribute to the improvements in DN in the db/db model.…”

Section: Discussionmentioning

confidence: 98%

“…Understanding the genesis and treatment of DN is facilitated by the availability of hyperglycemic, obese, db/db mice in which there is a spontaneous point mutation in the leptin receptor (Lepr) leading to a loss of receptor signaling. These db/db mice are responsive to the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 which exerts a blood glucose-lowering effect 8 , and for this reason GTS-21 might be a previously unrecognized treatment for DN, as explored in the present study.…”

Section: Introductionmentioning

confidence: 99%

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GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice

Meng

Tian

et al. 2022

Sci Rep

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Diabetic nephropathy (DN) is a serious complicating factor in human type 2 diabetes mellitus (T2DM), and it commonly results in end-stage renal disease (ESRD) that requires kidney dialysis. Here, we report that the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a novel anti-inflammatory action to ameliorate DN, as studied using an inbred strain of Leprdb/db mice in which hyperglycemia and obesity co-exist owing to defective leptin receptor (Lepr) signaling. For this analysis, GTS-21 was administered to 10–12 week-old male and female mice as a 4 mg/kg intraperitoneal injection, twice-a-day, for 8 weeks. Kidney function and injury owing to DN were monitored by determination of plasma levels of BUN, creatinine, KIM-1 and NGAL. Histologic analysis of glomerular hypertrophy and mesangial matrix expansion were also used to assess DN in these mice. Concurrently, renal inflammation was assessed by measuring IL-6 and HMGB1, while also quantifying renal cell apoptosis, and apoptotic signaling pathways. We found that Leprdb/db mice exhibited increased markers of BUN, creatinine, NGAL, KIM-1, IL-6, cytochrome C, and HMGB-1. These abnormalities were also accompanied by histologic kidney injury (mesangial matrix expansion and apoptosis). Remarkably, all such pathologies were significantly reduced by GTS-21. Collectively, our results provide new evidence that the α7nAChR agonist GTS-21 has the ability to attenuate diabetes-induced kidney injury. Additional studies are warranted to further investigate the involvement of the vagal cholinergic anti-inflammatory reflex pathway (CAP) in ameliorating diabetic nephropathy.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice

Meng

Tian

et al. 2022

Sci Rep

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“…Our results that galantamine treatment reduced inflammatory cytokines (TNF-α, IL-6, HMGB-1), improved insulin resistance and glycemic control in the db/db mice are consistent with those of the clinical trial of galantamine in patients with metabolic syndrome. Of interest, previous work from our laboratory showed that treatment of db/db mice with α7nAChR agonists (GTS-21 or PNU-282987) increased GLP-1 secretion and improved oral glucose tolerance by a mechanism requiring an intact GLP-1 receptor 21 . This suggests that some, but perhaps not all galantamine’s effects (e.g., decreased food and weight loss) on glycemic control and inflammation are mediated by the α7nAChR and GLP-1 receptor at the tissue level.…”

Section: Discussionmentioning

confidence: 99%

“…Reflex activation of the vagal efferent in the brainstem reduces inflammation by activating the α7nAChR in peripheral tissues. A number of α7nAChR receptor agonists, including GTS-21, an α7 nicotinic acetylcholine receptor (α7nAChR) agonist can improve glycemic control and DN in the db/db mouse 21 – 23 .…”

Section: Introductionmentioning

confidence: 99%

Galantamine improves glycemic control and diabetic nephropathy in Leprdb/db mice

Meng,

Ma,

Suo

et al. 2023

Sci Rep

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Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We investigated the effects of galantamine on glycemic control and development of diabetic nephropathy (DN) in Leprdb/db mice. Galantamine significantly reduced food intake, body weight, blood glucose and HbA1c levels. Insulin resistance (HOMA-IR, QUICKI), HOMA-β and elevations in plasma inflammatory cytokine levels (TNF-α, IL-6 and HMGB-1) were all attenuated by galantamine. Galantamine also ameliorated diabetes-induced kidney injury as evidenced by improvements in renal function (BUN, creatinine, albuminuria), histologic injury and apoptosis. Improved glycemic control and nephropathy were associated with increased circulating GLP-1, decreased renal P-38 MAPK and caspase-1 activation and reduced SGLT-2 expression. These findings provide insights into the mechanisms by which galantamine improves glycemic control and attenuates DN in the Leprdb/db mouse model.

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α7nAChR Activation Combined with Endothelial Progenitor Cell Transplantation Attenuates Lung Injury in Diabetic Rats with Sepsis through the NF-κB Pathway

Zhang,

Wang,

Cai

et al. 2024

Inflammation

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Chronic diabetes mellitus compromises the vascular system, which causes organ injury, including in the lung. Due to the strong compensatory ability of the lung, it always shows subclinical symptoms. Once sepsis occurs, the degree of lung injury is more severe under hyperglycemia. α7 nicotinic acetylcholine receptors (α7nAChRs) play an important role in regulating in ammation and metabolism, which could improve endothelial progenitor cell functions. In this study, we examined the role of diabetes mellitus during sepsis and whether α7nAChR activation combined with endothelial progenitor cell transplantation can protect the lung from septic and diabetic impairments. Type 2 diabetic model rats were induced by a high-fat diet and streptozotocin. Then, these rats were exposed to lipopolysaccharide in a two-hit manner to cause sepsis. The oxygenation index, wet-to-dry ratio and histopathological score of the lungs were tested after PNU282987 treatment and EPC transplantation. IL-6, IL-8, TNF-α and IL-10 levels were measured. Caspase-3, Bax, Bcl-2, NF-κB levels were blotted. Sepsis caused obvious lung injury, which was exacerbated by diabetic conditions. α7nAChR activation and endothelial progenitor cell injection reduced injury in diabetic rats with sepsis, alleviating in ammation and decreasing apoptosis. This treatment was more effective when PNU282987 and endothelial progenitor cells were administered together. The phosphorylation of NF-κB was inhibited during this process. Activating α7nAChRs and endothelial progenitor cell transplantation alleviated the lung injury in diabetic rats with sepsis. During this process, the phosphorylation of NF-κB was reduced.

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The alpha‐7 nicotinic acetylcholine receptor agonist GTS‐21 engages the glucagon‐like peptide‐1 incretin hormone axis to lower levels of blood glucose in db/db mice

Cited by 10 publications

References 37 publications

GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice

GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice

Galantamine improves glycemic control and diabetic nephropathy in Leprdb/db mice

α7nAChR Activation Combined with Endothelial Progenitor Cell Transplantation Attenuates Lung Injury in Diabetic Rats with Sepsis through the NF-κB Pathway

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