Restricted accessResearch articleFirst published online 2026-2
Proanthocyanidins from Chinese dwarf cherry [ Cerasus humilis (Bge.) Sok.] pomace ameliorate hepatic glucose-lipid metabolism abnormalities in T2DM mice via PI3K/Akt/FoxO1 and AMPK/ACC signaling pathways
Chinese dwarf cherry (Cerasus humilis) pomace is rich in proanthocyanidins, which exhibit antidiabetic activity.
Objective
This study investigates the protective effect of proanthocyanidins extracted from C. humilis pomace by regulating hepatic glucose-lipid metabolism in streptozotocin (STZ)-induced type 2 diabetic mellitus (T2DM) mice fed a high-fat diet (HFD).
Methods
The antidiabetic activities of Cerasus humilis pomace proanthocyanidins (CPPs) were evaluated through fasting blood glucose (FBG), oral glucose tolerance test (OGTT), and biochemical analysis, including AST, ALT, C-peptide, and hepatic glycogen in mouse serum, TC, TG, HDL-C, and LDL-C levels in the liver, as well as MDA and SOD levels. Thereafter, transcriptomic analysis, coupled with western blot and RT-qPCR, was employed to validate the molecular mechanism by which CPPs improved T2DM pathology in mice.
Results
CPPs significantly attenuated body weight gain, hyperglycemia, hepatic lipid accumulation, and liver injury in T2DM mice. Transcriptomics implicated the PI3K/Akt/FoxO1 and AMPK/ACC signaling pathways in mediating CPPs’ anti-diabetic effects. Subsequently, western blot, immunohistochemistry, and RT-qPCR analyses confirmed that CPPs regulate these pathways and demonstrated significant suppression of key gluconeogenic enzymes, PEPCK and G6Pase.
Conclusion
CPPs can effectively ameliorate T2DM by suppressing hepatic glucolipid metabolism abnormalities, primarily through regulation of the PI3K/Akt/FoxO1 and AMPK/ACC signaling pathways.
SunHSaeediPKarurangaS, et al.IDF Diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract2022; 183: 109119.
2.
ArtasensiAPedrettiAVistoliG,et al.Type 2 diabetes mellitus: a review of multi-target drugs. Molecules2020; 25: 1987.
3.
HackettRASteptoeA. Type 2 diabetes mellitus and psychological stress—a modifiable risk factor. Nat Rev Endocrinol2017; 13: 547–560.
4.
Weinberg SibonyRSegevODorS,et al.Drug therapies for diabetes. Int J Mol Sci2023; 24: 17147.
5.
Barrientos-ÁvalosJRMorel-CerdaECFélix-TéllezFA, et al.Gastrointestinal adverse effects of old and new antidiabetics: how do we deal with them in real life?Rev Gastroenterol México (Engl. Ed.)2024; 89: 521–532.
QaedEAlmoiliqyMAl-HamyariB, et al.Procyanidins: a promising anti-diabetic agent with potential benefits on glucose metabolism and diabetes complications. Wound Repair Regen2023; 31: 688–699.
8.
Cádiz-GurreaMDLLBorrás-LinaresILozano-SánchezJ, et al.Cocoa and grape seed byproducts as a source of antioxidant and anti-inflammatory proanthocyanidins. Int J Mol Sci2017; 18: 376.
9.
LiXLiuJChangQ, et al.Antioxidant and antidiabetic activity of proanthocyanidins from Fagopyrum dibotrys. Molecules2021; 26: 2417.
10.
RavindranathanPPashamDBalajiU, et al.Mechanistic insights into anticancer properties of oligomeric proanthocyanidins from grape seeds in colorectal cancer. Carcinogenesis2018; 39: 767–777.
11.
NunesMAPimentelFCostaAS, et al.Cardioprotective properties of grape seed proanthocyanidins: an update. Trends Food Sci Tech2016; 57: 31–39.
12.
ZhangYGuJWangY, et al.The anti-tumor activity and critical active compounds of polyphenols from Chinese dwarf cherry (Cerasus humilis). J Berry Res2023; 13: 211–225.
13.
ChenJHuangYLiuC, et al.The role of C-peptide in diabetes and its complications: an updated review. Front Endocrinol2023; 14: 1256093.
14.
LeeSDongHH. Foxo integration of insulin signaling with glucose and lipid metabolism. J Endocrinol2017; 233: R67.
15.
XingY-qLiAYangY, et al.The regulation of FOXO1 and its role in disease progression. Life Sci2018; 193: 124–131.
16.
De MeytsP. The insulin receptor and its signal transduction network. Endotext [Internet]2016.
17.
HuangXLiuGGuoJ,et al.The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sciences2018; 14: 1483.
18.
ZhuY-XHuH-QZuoM-L, et al.Effect of oxymatrine on liver gluconeogenesis is associated with the regulation of PEPCK and G6Pase expression and AKT phosphorylation. Biomed Rep2021; 15: 1–10.
19.
BurgessSCHauslerNMerrittM, et al.Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase. J Biol Chem2004; 279: 48941–48949.
20.
MutelEAbdul-WahedARamamonjisoaN, et al.Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas. J Hepatol2011; 54: 529–537.
21.
BrunetABonniAZigmondMJ, et al.Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell1999; 96: 857–868.
22.
ParadisSRuvkunG. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev1998; 12: 2488–2498.
23.
LuMWanMLeavensKF, et al.Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med2012; 18: 388–395.
24.
LangletFHaeuslerRALindénD, et al.Selective inhibition of FOXO1 activator/repressor balance modulates hepatic glucose handling. Cell2017; 171: 824–835.e18.
25.
BhattamisraSKKohHMLimSY, et al.Molecular and biochemical pathways of catalpol in alleviating diabetes mellitus and its complications. Biomolecules2021; 11: 323.
26.
WangQLiuSZhaiA, et al.AMPK-mediated regulation of lipid metabolism by phosphorylation. Biol Pharm Bull2018; 41: 985–993.
LabaziHTraskAJ. Coronary microvascular disease as an early culprit in the pathophysiology of diabetes and metabolic syndrome. Pharmacol Res2017; 123: 114–121.
29.
MursuJVirtanenJKTuomainenT-P, et al.Intake of fruit, berries, and vegetables and risk of type 2 diabetes in Finnish men: the Kuopio Ischaemic heart disease risk factor study. Am J Clin Nutr2014; 99: 328–333.
30.
SunCZhaoCGuvenEC, et al.Dietary polyphenols as antidiabetic agents: advances and opportunities. Food Front2020; 1: 18–44.
31.
ZhaoCWanXZhouS,et al.Natural polyphenols: a potential therapeutic approach to hypoglycemia. eFood2020; 1: 107–118.
32.
LiuXFuYMaQ, et al.Anti-Diabetic effects of different phenolic-rich fractions from Rhus Chinensis Mill. Fruits in vitro. eFood2021; 2: 37–46.
33.
MiaoLZhangHCheongMS, et al.Anti-diabetic potential of apigenin, luteolin, and baicalein via partially activating PI3K/Akt/Glut-4 signaling pathways in insulin-resistant HepG2 cells. Food Sci Hum Wellness2023; 12: 1991–2000.
34.
BarrettANdouTHugheyCA, et al.Inhibition of α-amylase and glucoamylase by tannins extracted from cocoa, pomegranates, cranberries, and grapes. J Agric Food Chem2013; 61: 1477–1486.
35.
AnhêFFRoyDPilonG, et al.A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut2015; 64: 872–883.
36.
RanBGuoC-EZhangY, et al.Preventive effect of Chinese dwarf cherry [Cerasus humilis (Bge.) Sok.] fermentation juice on dextran sulfate sodium-induced ulcerative colitis rats through the regulation of IgA and the intestinal immune barrier. Food Funct2022; 13: 5766–5781.
37.
ZhangYCuiQGuoC-e, et al.A rapid chemometrics model for antioxidant substance mining of Chinese dwarf cherry [Cerasus humilis (Bge.) Sok.] based on polyphenol profile and antioxidant capacity of 30 germplasms. Food Biosci2023; 53: 102795.
38.
LiPChenJGuoC-e, et al.Lactobacillus co-fermentation of Cerasus humilis juice alters chemical properties, enhances antioxidant activity, and improves gut microbiota. Food Funct2023; 14: 8248–8260.
39.
WangYHanCChengJ, et al.Fermented Cerasus humilis fruits protect against high-fat diet induced hyperlipidemia which is associated with alteration of gut microbiota. J Sci Food Agric2023; 103: 2554–2563.
40.
GuoC-eCuiQChengJ, et al.Probiotic-fermented Chinese dwarf cherry [Cerasus humilis (Bge.) Sok.] juice modulates the intestinal mucosal barrier and increases the abundance of Akkermansia in the gut in association with polyphenols. J Funct Foods2021; 80: 104424.
41.
TongALiZLiuX, et al.Laminaria japonica polysaccharide alleviates type 2 diabetes by regulating the microbiota-gut-liver axis: a multi-omics mechanistic analysis. Int J Biol Macromol2024; 258: 128853.
42.
HattingMTavaresCDSharabiK, et al.Insulin regulation of gluconeogenesis. Ann NY Acad Sci2018; 1411: 21–35.
43.
TikhanovichICoxJWeinmanSA. Forkhead box class O transcription factors in liver function and disease. J Gastroenterol Hepatol2013; 28: 125–131.
44.
GuoHGuoDAnM, et al.Angiotensin-(1-7) improves islet β-cell dedifferentiation by activating PI3K/Akt/FoxO1 pathway. Protein Pept Lett2023; 30: 1009–1019.
45.
ZhangBSunPLiuX, et al.Role and mechanism of PI3K/AKT/FoxO1/PDX-1 signaling pathway in functional changes of pancreatic islets in rats after severe burns. Life Sci2020; 258: 118145.
46.
CabezasMCBurggraafBKlopB. Dyslipidemias in clinical practice. Clinica Chim Acta2018; 487: 117–125.
47.
CarlingDThorntonCWoodsA,et al.AMP-activated protein kinase: new regulation, new roles?Biochem J2012; 445: 11–27.
48.
WoodsAWilliamsJRMuckettPJ, et al.Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep2017; 18: 3043–3051.
49.
SmithBKMarcinkoKDesjardinsEM, et al.Treatment of nonalcoholic fatty liver disease: role of AMPK. Am J Physiol-Endocr M2016; 311: E730–E740.
50.
AhmadBSerpellCJFongIL,et al.Molecular mechanisms of adipogenesis: the anti-adipogenic role of AMP-activated protein kinase. Front Mol Biosci2020; 7: 76.
51.
ZhangZLiangXTongL, et al.Effect of Inonotus obliquus (Fr.) Pilat extract on the regulation of glycolipid metabolism via PI3K/akt and AMPK/ACC pathways in mice. J Ethnopharmacol2021; 273: 113963.
52.
ZangLKagotaniKHayakawaT, et al.The hexane extract of Citrus sphaerocarpa ameliorates visceral adiposity by regulating the PI3K/AKT/FoxO1 and AMPK/ACC signaling pathways in high-fat-diet-induced obese mice. Molecules2023; 28: 8026.
53.
LiBFuRTanH, et al.Characteristics of the interaction mechanisms of procyanidin B1 and procyanidin B2 with protein tyrosine phosphatase-1B: analysis by kinetics, spectroscopy methods and molecular docking. Spectrochim Acta A Mol Biomol Spectrosc2021; 259: 119910.
54.
YinMZhangPYuF, et al.Grape seed procyanidin B2 ameliorates hepatic lipid metabolism disorders in db/db mice. Mol Med Rep2017; 16: 2844–2850.
55.
YinWLiBLiX, et al.Anti-inflammatory effects of grape seed procyanidin B2 on a diabetic pancreas. Food Funct2015; 6: 3065–3071.
56.
TieFWangJLiangY, et al.Proanthocyanidins ameliorated deficits of lipid metabolism in type 2 diabetes mellitus via inhibiting adipogenesis and improving mitochondrial function. Int J Mol Sci2020; 21: 2029.
