Diabetologia: Hong Tianpei's team found that the pancreatic α cell glucagon-liver FGF21 axis regulates cell regeneration β in a mouse model of type 2 diabetes

On November 4, 2022, the research team of Wei Rui, researcher of the Department of Endocrinology, Peking University Third Hospital/Professor Hong Tianpei, published online in Diabetologia, a β top journal specializing in endocrinology and metabolism, "Pancreatic alpha cell glucagon–liver FGF21 axis regulates beta cell" as α"Pancreatic alpha cell glucagon–liver FGF21 axis regulates beta cell" Regeneration in a mouse model of type 2 diabetes
).

Diabetes is a major disease
that endangers human health and life.
Restoring the total number of functional islets β cells is a potential hope for improving the long-term efficacy of diabetes (or even curing diabetes), so the research on β cell regeneration and its mechanism has always been a hot spot and difficulty in the field of diabetes
.

Researcher Wei Rui/Professor Hong Tianpei's research team first reported in iScience in 2019 that glucagon receptor (GCGR) monoclonal antibody (mAb) blocking glucagon signaling can induce islet α cells to β cells in mice with absolute β cell deficiency, thereby promoting β cell regeneration
.
The findings of this study were validated
by the findings of a 2021 study published in PNAS by Professor Holland's team at the University of Texas.

In 2022, the research team of researcher Wei Rui / Professor Hong Tianpei reported in iScience that GCGR mAbs promote the regeneration of β cells in β cell-deficient type 2 diabetic mice by promoting the transdifferentiation of α cells to β cells and inducing β cell regeneration
derived from pancreatic stem cells.
However, the mechanism by which glucagon-GCGR signaling is blocked leads to β cell regeneration is unclear
.

This article is one of a series of studies on β cell regeneration and its mechanism by the research team of Prof.
Wei Rui / Professor Hong Tianpi, aiming to elucidate the mechanism
of β cell regeneration caused by GCGR block.

Figure | Pattern diagram of α cellular glucagon–liver FGF21 axis in regulating cell regeneration in β cells

First, GCGR mAb was shown to promote islet cell regeneration
in a type 2 diabetes model (db/db mice and high-fat feeding + low-dose streptoxin diabetic mice).

Secondly, plasma condition culture or co-culture with primary mouse pancreatic islets using mouse β cell lines and primary mouse islets found that there were regulators of ex vivo β cell phenotype in the plasma or primary hepatocytes extracted from GCGR
mAb-treated mice.

Subsequently, plasma cytokine profiles were analyzed by solid-phase antibody chip technology and compared with liver mRNA sequencing data to determine fibroblast growth factor 21 (FGF21) as a potential mediating factor
.

Furthermore, FGF21 neutralizing antibody, systemic Fgf21 knockout, hepatocyte-specific Fgf21 knockout and other blockades proved that liver-derived FGF21 not only participates in the regulation of GCGR mAb on the phenotype of ex vivo β cells, but also mediates β cell regeneration
in diabetic mice caused by GCGR mAb.

This study revealed a new mechanism of GCGR block to improve diabetes control and promote β cell regeneration, and found that the α-cell glucagon-liver FGF21 axis plays an important role in cell regeneration in diabetic mic β e, providing a new perspective
for further development of therapeutic strategies to promote β cell regeneration.

Diabetologia, the official journal of the European Diabetes Society (EASD), is one of
the oldest and most influential professional journals on diabetes.
The Wei Rui/Hong Tianbei research team has been committed to islet regeneration and β cell function regulation for a long time, and has published more than 10 related papers in SCI journals such as Diabetologia, Metabolism, EBioMedicine, and iScience
in the past 3 years.

Cui Xiaona, a postdoctoral fellow in the Department of Endocrinology, and Feng Jin, a master student, are the co-first authors of this paper, and researcher Wei Rui and Professor Hong Tianbei are the co-corresponding authors
.
This paper is supported
by the National Natural Science Foundation of China and the Beijing Municipal Natural Science Foundation.