January 21, 2022

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Glycogen metabolism-a good target for screening of hypoglycemic drugs?

Glycogen metabolism-a good target for screening of hypoglycemic drugs?

Glycogen metabolism-a good target for screening of hypoglycemic drugs? The 24th National Academic Conference of Diabetes Branch of the Chinese Medical Association (CDS2020) officially opened on November 26. Academician Li Peng from the School of Life Sciences, Tsinghua University made a speech on “Glycogen Metabolism and Steady-state Regulation of Sugar Metabolism” Theme report.

Academician Li Peng pointed out that glycogen is the most mobilized storage substance in energy metabolism. When the body needs energy, glycogen can be quickly broken down into glucose for the body to need. When there is excess energy, the body will quickly convert glucose into glycogen and store it in order to reduce blood sugar levels. Academician Li Peng introduced their research on glycogen metabolism and the two signal pathways discovered in the report.

New pathway to regulate glycogen synthesis

The synthesis of glycogen is an important way for insulin to lower blood sugar levels. When eating causes high blood sugar levels, insulin can activate AKT to phosphorylate and inactivate glycogen synthase kinase (GSK3), thereby reducing the phosphorylation level of glycogen synthase (GS), increasing its activity, and promoting glycogen The generation.

In addition, glycogen synthase is not only regulated by phosphorylation, but also regulated by dephosphorylation. Protein phosphatase (PP1), as the dephosphorylase of glycogen synthase, plays a key role in glucose metabolism. However, the signal regulation pathway of PP1 is not clear. The latest edition of Lehninger’s biochemistry textbook also proposes that an “insulin-sensitive protein kinase” is needed to regulate PP1, but the specific kinase is unknown.

Through the analysis of the liver phosphorylation database under insulin stimulation and the characteristic sequence of AKT substrates, combined with the analysis of the KEGG metabolic pathway and the verification of phosphorylation in vivo, members of the Li Peng team identified PPP1R3g as a new substrate of AKT. PPP1R3g is a glycogen targeting regulatory subunit of PP1. When the blood glucose level rises after a meal, it will stimulate the pancreatic β-cells to secrete insulin, act on the liver cells and activate the AKT pathway, thereby phosphorylating the PPP1R3g Ser79 site.

At the physiological level, through the AAV virus-mediated overexpression system, they found that phosphorylation of PPP1R3g can speed up glucose clearance and improve insulin sensitivity. In terms of mechanism, phosphorylation of PPP1R3g can enhance the combination with phosphorylated GS, and accelerate the dephosphorylation of GS by PP1c. At the same time, it was found that PPP1R3b can act as the downstream of PPP1R3g, and stimulate the synthesis of glycogen by binding to the dephosphorylated GS dissociated from PPP1R3g, thereby achieving the transmission of insulin signals.

Therefore, the team of Academician Li Peng confirmed that PP1 is connected to the synthesis of PKB and glucose. This is a very important two-way regulatory mechanism for glycogen synthesis. In the pathway that responds to insulin signals, a “double insurance” is formed to ensure the effective storage of glycogen.

 

Glycogen metabolism-a good target for screening of hypoglycemic drugs?

New pathway to regulate glycogen degradation

In the case of starvation, when the blood glucose concentration is relatively low, the alpha cells of the pancreas secrete glucagon, which acts on the receptors on the liver cells to activate cAMP-PKA. The activation of PKA promotes the increase of glycogen phosphatase kinase (PHK) activity, and PHK can phosphorylate and activate glycogen phosphorylase (PYGL), thereby promoting the degradation of glycogen and raising blood sugar.

Through the screening of PKA specific substrates, the team of Academician Li Peng identified that PYGL can be used as a direct substrate of PKA. They observed in vitro that PYGL can significantly enhance the activity of PKA, and after mutating the phosphorylation site of PYGL, the enzyme activity is completely lost. In primary hepatocytes, their study found that the phosphorylation of PYGL is necessary for the decomposition of liver glycogen in the body.

In order to explore the in vivo function of PYGL’s new phosphorylation site, Professor Li Peng’s team constructed a PYGL phosphorylation inactivation point mutation mouse model. The study found that the liver of this point-mutant mouse showed an obvious hepatic hypertrophy phenotype and a mild hypoglycemic phenotype. Moreover, due to the lack of PYGL enzyme activity, a large amount of glycogen is accumulated in the liver.

They found that this kind of glycogen accumulation had little effect on liver function when the mice were younger, while in old age, excessive glycogen accumulation would cause slight liver fibrosis and decreased liver function.

In addition, due to high blood sugar levels in type 2 diabetes patients, inhibiting the release of liver glucose seems to be an effective method. Through this mouse model, Professor Li Peng’s team proved that inhibiting the activity of PYGL can reduce the diabetic phenotype of diabetic mice and improve liver and kidney function, which to some extent suggests that glucagon-PKA-glycogen phosphatase can As a new target for the treatment of type 2 diabetes.

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