Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

Lang, Shan; Yang, Jin; Yang, Kun; Gu, Liangbiao; Cui, Xiaona; Wei, Tianjiao; Liu, Junling; Le, Yunyi; Wang, Haining; Wei, Rui; Hong, Tianpei

doi:10.1136/bmjdrc-2019-001025

Cited by 32 publications

(30 citation statements)

References 46 publications

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“…It further suggested the rapid proliferation state of endothelial cells when QKI-7 was highly expressed, and the results of CCK-8 finally showed that the overexpression of QKI-7 led to a significant increase in cell proliferation efficiency. It showed that QKI-7 overexpression had a remarkable stimulating effect on endothelial cell development, which was also consistent with the endothelial cell proliferation observed in patients with diabetes and atherosclerosis in the clinic [ 33 ]. In further research, we also found that after knocking down the QKI-7 expression level in hiPSC by siRNA, the expression levels of key endothelial cell genes CD144, NLGN1, and TSG6 were significantly increased; the expression of endothelial cell proliferation-related cytokine TNF - α , IL-1 β , IFN- γ , and PGI2 also decreased; the proliferation efficiency of endothelial cells was significantly reduced.…”

Section: Discussionsupporting

confidence: 76%

Regulation of the Proliferation of Diabetic Vascular Endothelial Cells by Degrading Endothelial Cell Functional Genes with QKI‐7

Zhao

Zhang

et al. 2022

Contrast Media & Molecular Imaging

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Background. Diabetes has emerged as one of the most serious and common chronic diseases of our times, causing life-threatening, disabling and costly complications, and reducing life expectancy. Studies have shown that cardiovascular morbidity is 1–3 times higher in diabetic patients than in normal people. There are many clinical and experimental data that prove that most of the complications of diabetes are related to atherosclerosis, which suggests that chronic hyperglycemia may induce an imbalance in the proliferation of vascular endothelial cells. Purpose. This study aims to explore the relationship between QKI-7 and vascular endothelial cell dysfunction and lay a foundation for further clarifying the molecular mechanism of endothelial cell damage in the process of diabetes with atherosclerosis. Methods. We chose blood samples and pluripotent stem cells and vascular endothelial cells of hospitalized patients with diabetes and diabetes atherosclerosis as research subjects. The expression levels of endothelial cell proliferation and genes related to endothelial cell proliferation were analyzed by RT-qPCR and Western blot, to study the influence of QKi-7 on the physiological state of endothelial cells. Through gene knockdown experiment, the effects of QKi-7 knockdown on functional genes and physiological functions of endothelial cells were analyzed. Finally, RNA immunoprecipitation was used to test the mutual effect among QKI-7 and the transcription level of functional genes, and the mRNA attenuation experiment proved that QKI-7 participated in the degradation process of functional genes. Results. The findings of the RT-qPCR and Western blot tests revealed that QKI-7 was highly expressed in blood samples of diabetic patients and atherosclerosis as well as in endothelial cells induced by human pluripotent stem cells and human vascular endothelial cells after high-glucose treatment. Overexpression and high glucose of QKI-7 resulted in inhibiting expressed function genes CD144, NLGN1, and TSG6 and upregulation of inflammatory factors TNF-α, IL-1β, and IFN-γ, leading to excessive proliferation of endothelial cells. After QKI-7 gene knockdown, the expression levels of CD144, NLGN1, and TSG6, inflammatory factors TNF-α, IL-1β, and IFN-γ, and the cell proliferation rate all returned to normal levels. RNA immunoprecipitation showed that QKi-7 interacted with CD144, NLGN1, and TSG6 mRNAs and was involved in the transcriptional degradation of functional genes through their interactions. Conclusion. This research initially revealed the relevant molecular mechanism of QKI-7 leading to the excessive proliferation of endothelial cells in diabetic and atherosclerotic patients. In view of the role of QKI-7 in diabetic vascular complications, we provided a potential target for clinical diabetes treatment strategies in the future.

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Section: Discussionsupporting

confidence: 76%

Regulation of the Proliferation of Diabetic Vascular Endothelial Cells by Degrading Endothelial Cell Functional Genes with QKI‐7

Zhao

Zhang

et al. 2022

Contrast Media & Molecular Imaging

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“…The most relevant aspect is the complex and unexploited network of interactions between pancreatic and gut hormones. The model proposed by Unger and Lee [7,8] consisting in an increase of GLP-1 circulating levels by glucagon receptor blocking, was confirmed later by other experimental data [14,15]. Interesting information was provided by an in vivo mouse model in which both the action of glucagon and that of GLP-1 was inhibited.…”

Section: Gastrointestinal Hormone Networkmentioning

confidence: 80%

The entero-insular axis: a journey in the physiopathology of diabetes

Malaguarnera

Scamporrino

Filippello

et al. 2020

Exploration of Medicine

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Glycemic homeostasis is an essential mechanism for the proper working of an organism. However, balance in blood lipid and protein levels also plays an important role. The discovery of the hormone insulin and the description of its function for glycemic control made fundamental scientific progress in this field. However, since then our view of the problem has been deeply influenced only in terms of glucose and insulin (in an insulin-centric and glucose-centric way). Based on recent scientific discoveries, a fine and sophisticated network of hormonal and metabolic interactions, involving almost every apparatus and tissue of the human body, has been theorized. Efficient metabolic homeostasis is founded on these intricate interactions. Although it is still not fully defined, this complex network can undergo alterations that lead to metabolic disorders such as diabetes mellitus (DM). The endocrine pancreas plays a crucial role in the metabolic balance of an organism, but insulin is just one of the elements involved and each single pancreatic islet hormone is worthy of our concern. Moreover, pancreatic hormones need to be considered in a general view, concerning both their systemic function as direct mediators and as hormones, which, in turn, are regulated by other hormones or other substances. This more complex scenario should be taken into account for a better understanding of the pathophysiology and the therapeutic algorithms of DM. As a consequence, improvements in modern medicine could help to contemplate this new perspective. This review is focused on some aspects of gut-pancreas interaction, aiming to integrate this synergy into a wider context involving other organs and tissues.

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“…According to this report, glucagon secretion in the intestine is part of normal physiology, and not a compensatory mechanism for disrupted pancreatic secretion, since all donors in the study had a healthy pancreas. Another recent study revealed a paracrine modulation of GCGR in L-cells, since GCGR antagonism increases the L-cell population [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

GLP1 Exerts Paracrine Activity in the Intestinal Lumen of Human Colon

Grau-Bové

González-Quilen

Cantini

et al. 2022

IJMS

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GLP1 produced in the upper part of the gut is released after food intake and acts by activating insulin secretion, but the role of GLP1 in the colon, where it is predominantly produced, remains unknown. Here we characterized the apical versus basolateral secretion of GLP1 and PYY and the paracrine mechanisms of action of these enterohormones in the human colon. We stimulated human colon tissue in different ex vivo models with meat peptone and we used immunofluorescence to study the presence of canonical and non-canonical receptors of GLP1. We found that PYY and GLP1 are secreted mainly at the gut lumen in unstimulated and stimulated conditions. We detected DPP4 activity and found that GLP1R and GCGR are widely expressed in the human colon epithelium. Unlike GLP1R, GCGR is not expressed in the lamina propria, but it is located in the crypts of Lieberkühn. We detected GLP1R expression in human colon cell culture models. We show that the apical secretion of PYY and GLP1 occurs in humans, and we provide evidence that GLP1 has a potential direct paracrine function through the expression of its receptors in the colon epithelium, opening new therapeutic perspectives in the use of enterohormones analogues in metabolic pathologies.

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Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

Cited by 32 publications

References 46 publications

Regulation of the Proliferation of Diabetic Vascular Endothelial Cells by Degrading Endothelial Cell Functional Genes with QKI‐7

Regulation of the Proliferation of Diabetic Vascular Endothelial Cells by Degrading Endothelial Cell Functional Genes with QKI‐7

The entero-insular axis: a journey in the physiopathology of diabetes

GLP1 Exerts Paracrine Activity in the Intestinal Lumen of Human Colon

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