{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T03:54:53Z","timestamp":1785038093905,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovation Engineering Project of the Chinese Academy of Agricultural Sciences","award":["CAAS-ASTIP-2025-IFND"],"award-info":[{"award-number":["CAAS-ASTIP-2025-IFND"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Foods"],"abstract":"<jats:p>The effects of soy protein and whey protein supplementation on glycemic control show inconsistency, and the mechanisms underlying the impact of a high-protein diet on blood glucose regulation remain unclear. This study aimed to explore the impact of a dual-protein (DP) blend comprising soy protein isolate (SPI) and whey protein concentrate (WPC), processed through high-pressure homogenization, on mice with Type 2 diabetes mellitus (T2DM) and its potential mechanisms. In the in vitro experiments, an insulin-resistant (IR) HepG2 cell model was treated with DP, resulting in a significant enhancement of glucose uptake and upregulation of IRS1 and GLUT4 expression. For the in vivo experiments, male C57BL\/6J mice were randomly assigned into four groups (n = 6) based on body weight: normal control, T2DM model group, Metformin-treated group, and DP-treated group. Following a 5-week feeding period, Metformin and DP significantly reduced levels of blood sugar, AUC, TC, TG, and LDL-C in T2DM mice. Additionally, TP and ALB levels in the DP group were notably higher in the model group. In the liver and pancreas, DP alleviated histopathological changes and promoted liver glycogen synthesis in T2DM mice. Moreover, the levels of IRS1 and PI3K in the livers of mice in the DP group were significantly higher than those in the model group. Compared with the model groups, DP significantly reduced the expression of CD45 and increased the expression of CD206 in the pancreas of mice. Furthermore, 16S rRNA analysis revealed that DP altered the composition of the gut microbiota in diabetic mice, increasing the relative abundance of Lactobacillus, Parvibacter, and Lactobacillaceae. This suggested that DP could alleviate functional metabolic disorders in the gut and potentially reverse the risk of related complications. In conclusion, soy whey dual-protein may have an effective nutritional therapeutic effect on T2DM mice by regulating lipid metabolism, the INS\/IRS1\/PI3K signaling pathway, and gut microbiota.<\/jats:p>","DOI":"10.3390\/foods14122115","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T14:03:11Z","timestamp":1750082591000},"page":"2115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Anti-Diabetic Effect of Soy\u2013Whey Dual-Protein on Mice with Type 2 Diabetes Mellitus Through INS\/IRS1\/PI3K Signaling Pathway"],"prefix":"10.3390","volume":"14","author":[{"given":"Na","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duo","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjie","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5603-8495","authenticated-orcid":false,"given":"Di","family":"Han","sequence":"additional","affiliation":[{"name":"Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxin","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41581-020-0278-5","article-title":"Genetics of diabetes mellitus and diabetes complications","volume":"16","author":"Cole","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: Historical overview","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.metabol.2012.10.015","article-title":"The alpha-glucosidase inhibitor miglitol affects bile acid metabolism and ameliorates obesity and insulin resistance in diabetic mice","volume":"62","author":"Hamada","year":"2013","journal-title":"Metabolism"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.2337\/dc18-0344","article-title":"Sex and BMI Alter the Benefits and Risks of Sulfonylureas and Thiazolidinediones in Type 2 Diabetes: A Framework for Evaluating Stratification Using Routine Clinical and Individual Trial Data","volume":"41","author":"Dennis","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1093\/advances\/nmz002","article-title":"High-Protein Diets for Treatment of Type 2 Diabetes Mellitus: A Systematic Review","volume":"10","author":"Malaeb","year":"2019","journal-title":"Adv. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1571S","DOI":"10.1093\/ajcn\/87.5.1571S","article-title":"Protein in optimal health: Heart disease and type 2 diabetes","volume":"87","author":"Layman","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3945\/jn.116.239574","article-title":"A Systematic Review of the Effects of Plant Compared with Animal Protein Sources on Features of Metabolic Syndrome","volume":"147","author":"Arfsten","year":"2017","journal-title":"J. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1017\/S0029665117002002","article-title":"The role of whey protein in postprandial glycaemic control","volume":"77","author":"Stevenson","year":"2018","journal-title":"Proc. Nutr. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.ijbiomac.2021.11.131","article-title":"Antidiabetic potential of soy protein\/peptide: A therapeutic insight","volume":"194","author":"Das","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.clnu.2020.04.035","article-title":"Sex-specific associations of habitual intake of soy protein and isoflavones with risk of type 2 diabetes","volume":"40","author":"Woo","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.3945\/jn.111.139840","article-title":"Whey protein but not soy protein supplementation alters body weight and composition in free-living overweight and obese adults","volume":"141","author":"Baer","year":"2011","journal-title":"J. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12836","DOI":"10.1039\/D2FO01935C","article-title":"Whey protein and soy protein prevent obesity by upregulating uncoupling protein 1 to activate brown adipose tissue and promote white adipose tissue browning in high-fat diet-fed mice","volume":"13","author":"Ji","year":"2022","journal-title":"Food Funct."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1017\/S0007114509991802","article-title":"Soya protein does not affect glycaemic control in adults with type 2 diabetes","volume":"103","author":"Gobert","year":"2010","journal-title":"Br. J. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2622057","DOI":"10.1155\/2023\/2622057","article-title":"The Effect of Soy and Whey Protein Supplementation on Glucose Homeostasis in Healthy Normal Weight Asian Indians","volume":"2023","author":"Sambashivaiah","year":"2023","journal-title":"J. Nutr. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1017\/S0007114521001550","article-title":"Comparison of the effect of soya protein and whey protein on body composition: A meta-analysis of randomised clinical trials","volume":"127","author":"Mirzababaei","year":"2022","journal-title":"Br. J. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.tifs.2020.12.010","article-title":"Mixing milk, egg and plant resources to obtain safe and tasty foods with environmental and health benefits","volume":"108","author":"Arvisenet","year":"2021","journal-title":"Trends Food Sci. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1111\/1541-4337.12682","article-title":"Advancement of food-derived mixed protein systems: Interactions, aggregations, and functional properties","volume":"20","author":"Wu","year":"2021","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.foodhyd.2018.05.020","article-title":"Effects of high pressure homogenization on faba bean protein aggregation in relation to solubility and interfacial properties","volume":"83","author":"Yang","year":"2018","journal-title":"Food Hydrocoll."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wu, M., He, X., Feng, D., Li, H., Han, D., Li, Q., Zhao, B., Li, N., Liu, T., and Wang, J. (2023). The Effect of High-Pressure Homogenization on the Structure of Dual-Protein and Its Emulsion Functional Properties. Foods, 12.","DOI":"10.3390\/foods12183358"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrmicro2403","article-title":"The impact of the microbiota on the pathogenesis of IBD: Lessons from mouse infection models","volume":"8","author":"Nell","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yan, F., Li, N., Yue, Y., Wang, C., Zhao, L., Evivie, S.E., Li, B., and Huo, G. (2020). Screening for Potential Novel Probiotics with Dipeptidyl Peptidase IV-Inhibiting Activity for Type 2 Diabetes Attenuation in vitro and in vivo. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.02855"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wu, S., Bhat, Z.F., Gounder, R.S., Mohamed Ahmed, I.A., Al-Juhaimi, F.Y., Ding, Y., and Bekhit, A.E. (2022). Effect of Dietary Protein and Processing on Gut Microbiota\u2014A Systematic Review. Nutrients, 14.","DOI":"10.3390\/nu14030453"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.nutres.2017.08.002","article-title":"Protein blend ingestion before allogeneic stem cell transplantation improves protein-energy malnutrition in patients with leukemia","volume":"46","author":"Ren","year":"2017","journal-title":"Nutr. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111723","DOI":"10.1016\/j.nut.2022.111723","article-title":"Soy-whey dual-protein alleviates osteoporosis of ovariectomized rats via regulating bone fat metabolism through gut-liver-bone axis","volume":"103\u2013104","author":"Zhang","year":"2022","journal-title":"Nutrition"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zheng, X., Ke, Y., Feng, A., Yuan, P., Zhou, J., Yu, Y., Wang, X., and Feng, W. (2016). The Mechanism by Which Amentoflavone Improves Insulin Resistance in HepG2 Cells. Molecules, 21.","DOI":"10.3390\/molecules21050624"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jare.2023.10.008","article-title":"\u03b2-cell neogenesis: A rising star to rescue diabetes mellitus","volume":"62","author":"Niu","year":"2024","journal-title":"J. Adv. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/1475-2840-9-92","article-title":"Insulin resistance in Chinese patients with type 2 diabetes is associated with C-reactive protein independent of abdominal obesity","volume":"9","author":"Lu","year":"2010","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of Insulin Action and Insulin Resistance","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.metabol.2016.02.010","article-title":"Impaired insulin action in the liver, but not in adipose tissue or muscle, is a distinct metabolic feature of impaired fasting glucose in obese humans","volume":"65","author":"Gilijamse","year":"2016","journal-title":"Metabolism"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.7150\/ijbs.27173","article-title":"The PI3K\/AKT pathway in obesity and type 2 diabetes","volume":"14","author":"Huang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41580-021-00390-6","article-title":"The aetiology and molecular landscape of insulin resistance","volume":"22","author":"James","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.2174\/1381612822666160307145801","article-title":"Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter: Intervention Approaches","volume":"22","author":"Alam","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Minami, S., Yokota, N., and Kawahara, H. (2020). BAG6 contributes to glucose uptake by supporting the cell surface translocation of the glucose transporter GLUT4. Biol. Open, 9.","DOI":"10.1242\/bio.047324"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kowalski, G.M., Hamley, S., Selathurai, A., Kloehn, J., De Souza, D.P., O\u2019callaghan, S., Nijagal, B., Tull, D.L., McConville, M.J., and Bruce, C.R. (2016). Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis. Sci. Rep., 6.","DOI":"10.1038\/srep27541"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1039\/C6FO01692H","article-title":"Ingestion of soy-whey blended protein augments sports performance and ameliorates exercise-induced fatigue in a rat exercise model","volume":"8","author":"Ren","year":"2017","journal-title":"Food Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s11886-021-01455-w","article-title":"Mechanisms and Treatment of Dyslipidemia in Diabetes","volume":"23","author":"Bahiru","year":"2021","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"100767","DOI":"10.1016\/j.jlr.2025.100767","article-title":"Altered liver lipidome markedly overlaps with human plasma lipids at diabetes risk and reveals adipose-liver interaction","volume":"66","author":"Sehgal","year":"2025","journal-title":"J. Lipid Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"117237","DOI":"10.1016\/j.atherosclerosis.2023.117237","article-title":"Hepatic fatty acid and glucose handling in metabolic disease: Potential impact on cardiovascular disease risk","volume":"394","author":"Westcott","year":"2024","journal-title":"Atherosclerosis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cmet.2017.08.007","article-title":"Pancreatic \u03b2 Cell Regeneration as a Possible Therapy for Diabetes","volume":"27","year":"2018","journal-title":"Cell Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4635","DOI":"10.1039\/C8FO00919H","article-title":"Enzymatic digest of whey protein and wheylin-1, a dipeptide released in the digest, increase insulin sensitivity in an Akt phosphorylation-dependent manner","volume":"9","author":"Ogiwara","year":"2018","journal-title":"Food Funct."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1152\/physiol.00032.2009","article-title":"Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes","volume":"24","author":"Donath","year":"2009","journal-title":"Physiology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jaut.2013.12.003","article-title":"CD8 T-cell reactivity to islet antigens is unique to type 1 while CD4 T-cell reactivity exists in both type 1 and type 2 diabetes","volume":"50","author":"Sarikonda","year":"2014","journal-title":"J. Autoimmun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3389\/fendo.2019.00451","article-title":"Type 2 Diabetes: How Much of an Autoimmune Disease?","volume":"10","author":"Prattichizzo","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00281-019-00745-4","article-title":"Islet inflammation in type 2 diabetes","volume":"41","author":"Meier","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1017\/S0007114522001787","article-title":"Effects of whey and soy protein supplementation on inflammatory cytokines in older adults: A systematic review and meta-analysis","volume":"129","author":"Prokopidis","year":"2023","journal-title":"Br. J. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1042\/CS20211031","article-title":"Inhibition of Notch activity suppresses hyperglycemia-augmented polarization of macrophages to the M1 phenotype and alleviates acute pancreatitis","volume":"136","author":"Hu","year":"2022","journal-title":"Clin. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101438","DOI":"10.1016\/j.molmet.2022.101438","article-title":"Insulin resistance per se drives early and reversible dysbiosis-mediated gut barrier impairment and bactericidal dysfunction","volume":"57","author":"Gueddouri","year":"2022","journal-title":"Mol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"774203","DOI":"10.3389\/fnut.2021.774203","article-title":"Soy Protein Alleviates Malnutrition in Weaning Rats by Regulating Gut Microbiota Composition and Serum Metabolites","volume":"8","author":"Wei","year":"2021","journal-title":"Front. Nutr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5898","DOI":"10.1039\/C9FO02761K","article-title":"Lactic acid bacteria reduce diabetes symptoms in mice by alleviating gut microbiota dysbiosis and inflammation in different manners","volume":"11","author":"Wang","year":"2020","journal-title":"Food Funct."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"110568","DOI":"10.1016\/j.foodres.2021.110568","article-title":"Vitamin A supplementation ameliorates ulcerative colitis in gut microbiota-dependent manner","volume":"148","author":"Pang","year":"2021","journal-title":"Food Res. 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