Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets

Wang, May Yun; Dean, E. Danielle; Quittner-Strom, Ezekiel B.; Zhu, Yi; Chowdhury, Kamrul Hasan; Zhang, Zhuzhen; Zhao, Shangang; Li, Na; Ye, Reshing; Lee, Young; Zhang, Yiyi; Chen, Shiuhwei; Yu, Xinxin; Leonard, Derek C.; Poffenberger, Greg; Deylen, Alison Von; McCorkle, Sara Kay; Schlegel, Amnon; Sloop, Kyle W.; Efanov, Alexander M.; Gimeno, Ruth E.; Scherer, Philipp E.; Powers, Alvin C.; Unger, Roger H; Holland, William L.

doi:10.1073/pnas.2022142118

Cited by 37 publications

(34 citation statements)

References 29 publications

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“…Aberrant glucagon production correlates with diabetes. Research shown that blockade of glucagon signaling lowers glycemia in mouse models while enhancing formation of functional β cell mass (51). In our study, plasma glucagon levels significantly decreased in KO-HFD mice compared with WT-HFD group.…”

Section: Discussionsupporting

confidence: 54%

Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model

Lei

Chen

Wang

et al. 2022

Endocrine Connections

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Elucidating the mechanisms of regulation of β cell proliferation is key to understanding the pathogenesis of diabetes mellitus. Txnip is a tumor suppressor that is upregulated in diabetes and plays an important role in the regulation of insulin sensitivity; however, its potential effect on pancreatic β cell proliferation remains unclear. Here, we evaluated the role of Txnip in pancreatic β cell compensatory proliferation by subjecting wild-type (WT) and Txnip knockout (KO) mice to a high fat diet (HFD). Our results demonstrate that Txnip deficiency improves glucose tolerance and increases insulin sensitivity in HFD-induced obesity. The antidiabetogenic effect of Txnip deficiency was accompanied by increased β cell proliferation and enhanced β mass expansion. Furthermore, Txnip deficiency modulated the expression of a set of transcription factors with key roles in β cell proliferation and cell cycle regulation. Txnip knockout in HFD mice also led to activated levels of p-P13K, p-AKT, p-mTOR and p-GSK3β, suggesting that Txnip may act via PI3K/AKT signaling to suppress β cell proliferation. Thus, our work provides a theoretical basis for Txnip as a new therapeutic target for the treatment of diabetes mellitus.

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Section: Discussionsupporting

confidence: 54%

Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model

Lei

Chen

Wang

et al. 2022

Endocrine Connections

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“…Glucagon, mainly produced by alpha-pancreatic cells, although it is an important approach to handle hypoglycemic events, has hardly been considered a protagonist of diabetes physiopathology. On the contrary, Unger RH, for a long time has supported the importance of this hormone for diabetes onset [ 120 , 121 ].…”

Section: Glucagon: Insulin Antidote or Main Driver Of Diabetes Homeostasis?mentioning

confidence: 99%

Glucagon as a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin?

et al. 2021

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Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently with respect to past years. Novel scientific evidence leads to advances concerning physiopathological mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the important aspects of this field.

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“…Our previous study, together with others, has proven that GCGR blockage could decrease blood glucose and improve the phenotype of T1D mice. Strikingly, GCGR mAb increased the number of pancreatic β cells and upregulated circulating insulin levels by inducing αto β-cell transdifferentiation in T1D mice [8,11]. However, GCGR mAb substantially increased pancreatic α-cell mass, which brings a safety concern on the α-cell tumor [12].…”

Section: Discussionmentioning

confidence: 99%

Combination of GLP-1 Receptor Activation and Glucagon Blockage Promotes Pancreatic β-Cell Regeneration In Situ in Type 1 Diabetic Mice

Wang

Cui

et al. 2021

Journal of Diabetes Research

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Pancreatic β-cell neogenesis in vivo holds great promise for cell replacement therapy in diabetic patients, and discovering the relevant clinical therapeutic strategies would push it forward to clinical application. Liraglutide, a widely used antidiabetic glucagon-like peptide-1 (GLP-1) analog, has displayed diverse β-cell-protective effects in type 2 diabetic animals. Glucagon receptor (GCGR) monoclonal antibody (mAb), a preclinical agent that blocks glucagon pathway, can promote recovery of functional β-cell mass in type 1 diabetic mice. Here, we conducted a 4-week treatment of the two drugs alone or in combination in type 1 diabetic mice. Although liraglutide neither lowered the blood glucose level nor increased the plasma insulin level, the immunostaining showed that liraglutide expanded β-cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic α cells to β cells. The pancreatic β-cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic β-cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of β cells/α cells. Our study evaluated the effect of liraglutide, GCGR mAb monotherapy, or combined strategy in glucose control and islet β-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.

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Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets

Cited by 37 publications

References 29 publications

Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model

Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model

Glucagon as a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin?

Combination of GLP-1 Receptor Activation and Glucagon Blockage Promotes Pancreatic β-Cell Regeneration In Situ in Type 1 Diabetic Mice

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