{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:53:47Z","timestamp":1792688027501,"version":"4.5.0"},"reference-count":33,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jiangsu Funding Program for Excellent Postdoctoral Talent","award":["2024ZB779"],"award-info":[{"award-number":["2024ZB779"]}]},{"name":"Jiangsu Funding Program for Excellent Postdoctoral Talent","award":["32402267"],"award-info":[{"award-number":["32402267"]}]},{"name":"Jiangsu Funding Program for Excellent Postdoctoral Talent","award":["JSSCBS20230184"],"award-info":[{"award-number":["JSSCBS20230184"]}]},{"name":"Jiangsu Funding Program for Excellent Postdoctoral Talent","award":["3501230357"],"award-info":[{"award-number":["3501230357"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2024ZB779"],"award-info":[{"award-number":["2024ZB779"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32402267"],"award-info":[{"award-number":["32402267"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["JSSCBS20230184"],"award-info":[{"award-number":["JSSCBS20230184"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["3501230357"],"award-info":[{"award-number":["3501230357"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Innovative and Entrepreneurial Talents Program","award":["2024ZB779"],"award-info":[{"award-number":["2024ZB779"]}]},{"name":"Jiangsu Innovative and Entrepreneurial Talents Program","award":["32402267"],"award-info":[{"award-number":["32402267"]}]},{"name":"Jiangsu Innovative and Entrepreneurial Talents Program","award":["JSSCBS20230184"],"award-info":[{"award-number":["JSSCBS20230184"]}]},{"name":"Jiangsu Innovative and Entrepreneurial Talents Program","award":["3501230357"],"award-info":[{"award-number":["3501230357"]}]},{"name":"Nanjing Science and Technology Innovation Project","award":["2024ZB779"],"award-info":[{"award-number":["2024ZB779"]}]},{"name":"Nanjing Science and Technology Innovation Project","award":["32402267"],"award-info":[{"award-number":["32402267"]}]},{"name":"Nanjing Science and Technology Innovation Project","award":["JSSCBS20230184"],"award-info":[{"award-number":["JSSCBS20230184"]}]},{"name":"Nanjing Science and Technology Innovation Project","award":["3501230357"],"award-info":[{"award-number":["3501230357"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Camel milk is considered to be an important source of bioactive peptides with potential anti-diabetic effects. However, the mechanism by which these active peptides exert their anti-diabetic effects is not clear. The aim of this study was to systematically evaluate the in vivo anti-diabetic effects of Leucine-Leucine-Proline-Lysine (LLPK), a novel dipeptidyl peptidase-4 (DPP-4) inhibitory peptide identified from the in vitro gastrointestinal digestion product of camel milk. Methods: A db\/db diabetic mouse model was used, and LLPK was administered to mice at doses of 50 mg\/kg BW and 100 mg\/kg BW as a daily oral gavage for 30 days. The effects of LLPK on fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and serum lipid levels were monitored, and possible mechanisms of action were elucidated using proteomics. Results: The results demonstrated that LLPK significantly improved diabetic symptoms, including FBG, OGTT, ITT, and serum lipid levels in db\/db diabetic mice. Furthermore, significantly increased levels of serum glucagon-like peptide 1 (GLP-1) and reduced serum DPP-4 activity were observed in the LLPK-treated group compared to the control group. Hepatic proteomics indicated that LLPK improved glucose and lipid metabolism via the PPAR signaling pathway, where the key targets were Scd1, Acox1, Acaa1b, Slc27a1, Acsl1, and Ehhadh. Conclusions: In summary, this study provided new insights into the anti-diabetic mechanisms of camel milk and supported the development of camel milk-based anti-diabetic functional foods or nutraceuticals.<\/jats:p>","DOI":"10.3390\/nu17101693","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:11:57Z","timestamp":1747372317000},"page":"1693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel Camel Milk-Derived Peptide LLPK Improves Glucose-Lipid Metabolism in db\/db Mice via PPAR Signaling Pathway"],"prefix":"10.3390","volume":"17","author":[{"given":"Binsong","family":"Han","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Food Safety and Nutrition, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China"},{"name":"School of Food Science and Technology, Jiangnan University, Wuxi 214122, China"},{"name":"International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2488-5491","authenticated-orcid":false,"given":"Yuhui","family":"Ye","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Food Safety and Nutrition, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5702-7480","authenticated-orcid":false,"given":"Cunzheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Food Safety and Nutrition, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3039-1597","authenticated-orcid":false,"given":"Lina","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Food Science and Technology, Jiangnan University, Wuxi 214122, China"},{"name":"International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Food Science and Technology, Jiangnan University, Wuxi 214122, China"},{"name":"International Joint Research Laboratory for Dairy Science and Technology, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Antar, S.A., Ashour, N.A., Sharaky, M., Khattab, M., Ashour, N.A., Zaid, R.T., Roh, E.J., Elkamhawy, A., and Al-Karmalawy, A.A. (2023). Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments. Biomed. Pharmacother., 168.","DOI":"10.1016\/j.biopha.2023.115734"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S154","DOI":"10.1016\/j.jcjd.2017.10.023","article-title":"Complementary and Alternative Medicine for Diabetes","volume":"42","author":"Grossman","year":"2018","journal-title":"Can. J. Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1080\/10408398.2022.2120454","article-title":"Food-derived dipeptidyl peptidase IV inhibitory peptides: Production, identification, structure-activity relationship, and their potential role in glycemic regulation","volume":"64","author":"Zhang","year":"2024","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s13668-023-00472-1","article-title":"Dairy Milk Protein-Derived Bioactive Peptides: Avengers Against Metabolic Syndrome","volume":"12","author":"Koirala","year":"2023","journal-title":"Curr. Nutr. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Khalid, N., Abdelrahim, D.N., Hanach, N., Alkurd, R., Khan, M., Mahrous, L., Radwan, H., Naja, F., Madkour, M., and Obaideen, K. (2023). Effect of camel milk on lipid profile among patients with diabetes: A systematic review, meta-analysis, and meta-regression of randomized controlled trials. BMC Complement. Med. Ther., 23.","DOI":"10.1186\/s12906-023-04257-5"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"111254","DOI":"10.1016\/j.foodres.2022.111254","article-title":"Phosphoproteomics reveals that camel and goat milk improve glucose homeostasis in HDF\/STZ-induced diabetic rats through activation of hepatic AMPK and GSK3-GYS axis","volume":"157","author":"Han","year":"2022","journal-title":"Food Res. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113278","DOI":"10.1016\/j.foodres.2023.113278","article-title":"Camel milk peptides alleviate hyperglycemia by regulating gut microbiota and metabolites in type 2 diabetic mice","volume":"173","author":"Zhang","year":"2023","journal-title":"Food Res. Int."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Xie, Y., Wang, J., Wang, S., He, R., Wang, Z., Zhao, L., and Ge, W. (2024). Preparation, characterization, and mechanism of DPP-IV inhibitory peptides derived from Bactrian camel milk. Int. J. Biol. Macromol., 277.","DOI":"10.1016\/j.ijbiomac.2024.134232"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3168\/jds.2020-18627","article-title":"Molecular basis of the anti-diabetic properties of camel milk through profiling of its bioactive peptides on dipeptidyl peptidase IV (DPP-IV) and insulin receptor activity","volume":"104","author":"Ashraf","year":"2021","journal-title":"J. Dairy Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15248","DOI":"10.1021\/acs.jafc.4c01008","article-title":"Ovalbumin Hydrolysates Enhance Skeletal Muscle Insulin-Dependent Signaling Pathway in High-Fat Diet-Fed Mice","volume":"72","author":"Elhadad","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1021\/acs.jafc.0c07630","article-title":"Hypoglycemic Effects of Licochalcone A on the Streptozotocin-Induced Diabetic Mice and Its Mechanism Study","volume":"69","author":"Luo","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100063","DOI":"10.1016\/j.mcpro.2021.100063","article-title":"Quantitative Proteomics and Phosphoproteomics Support a Role for Mut9-Like Kinases in Multiple Metabolic and Signaling Pathways in Arabidopsis","volume":"20","author":"Wilson","year":"2021","journal-title":"Mol. Cell. Proteom."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113748","DOI":"10.1016\/j.foodres.2023.113748","article-title":"Bioactive peptides in hydrolysates of bovine and camel milk proteins: A review of studies on peptides that reduce blood pressure, improve glucose homeostasis, and inhibit pathogen adhesion","volume":"175","author":"Althnaibat","year":"2024","journal-title":"Food Res. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/s12276-023-00958-6","article-title":"Evogliptin, a DPP-4 inhibitor, prevents diabetic cardiomyopathy by alleviating cardiac lipotoxicity in db\/db mice","volume":"55","author":"Pham","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10909","DOI":"10.1002\/jcb.28467","article-title":"Natural compounds with DPP-4 inhibitory effects: Implications for the treatment of diabetes","volume":"120","author":"Yaribeygi","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cmet.2018.03.001","article-title":"Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1","volume":"27","author":"Drucker","year":"2018","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1007\/s00394-023-03162-4","article-title":"Whey protein hydrolysates improve high-fat-diet-induced obesity by modulating the brain-peripheral axis of GLP-1 through inhibition of DPP-4 function in mice","volume":"62","author":"Rai","year":"2023","journal-title":"Eur. J. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1007\/s00125-015-3525-8","article-title":"Pathophysiology of diabetic dyslipidaemia: Where are we?","volume":"58","year":"2015","journal-title":"Diabetologia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s42000-018-0014-8","article-title":"Diabetes and lipid metabolism","volume":"17","author":"Athyros","year":"2018","journal-title":"Hormones"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.cmet.2018.02.011","article-title":"Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence","volume":"27","author":"Rajman","year":"2018","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nrendo.2016.135","article-title":"PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD","volume":"13","author":"Gross","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tibori, K., Orosz, G., Z\u00e1mb\u00f3, V., Szel\u00e9nyi, P., Sarnyai, F., Tam\u00e1si, V., R\u00f3nai, Z., M\u00e1ty\u00e1si, J., T\u00f3th, B., and Csala, M. (2022). Molecular Mechanisms Underlying the Elevated Expression of a Potentially Type 2 Diabetes Mellitus Associated SCD1 Variant. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116221"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"G\u00f6rgens, S.W., Jahn-Hofmann, K., Bangari, D., Cummings, S., Metz-Weidmann, C., Schwahn, U., Wohlfart, P., Sch\u00e4fer, M., and Bielohuby, M. (2019). A siRNA mediated hepatic DPP-4 knockdown affects lipid, but not glucose metabolism in diabetic mice. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0225835"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zou, J., Song, Q., Shaw, P.C., and Zuo, Z. (2024). Dendrobium officinale regulate lipid metabolism in diabetic mouse liver via PPAR-RXR signaling pathway: Evidence from an integrated multi-omics analysis. Biomed. Pharmacother., 173.","DOI":"10.1016\/j.biopha.2024.116395"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4214","DOI":"10.1038\/s41467-024-48471-2","article-title":"Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling","volume":"15","author":"Lu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1194\/jlr.M024463","article-title":"Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids","volume":"53","author":"Houten","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Dave, A., Park, E.-J., Kumar, A., Parande, F., Idle, J.R., Pezzuto, J.M., and Beyoglu, D. (2022). Consumption of Grapes Modulates Gene Expression, Reduces Non-Alcoholic Fatty Liver Disease, and Extends Longevity in Female C57BL\/6J Mice Provided with a High-Fat Western-Pattern Diet. Foods, 11.","DOI":"10.3390\/foods11131984"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.molcel.2020.05.007","article-title":"Acetyl-CoA Derived from Hepatic Peroxisomal \u03b2-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation","volume":"79","author":"He","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, C.Q., Hu, M.H., Yi, Y.H., Wen, X.N., Lv, C.H., Shi, M., and Zeng, C.X. (2022). Multiomic analysis of dark tea extract on glycolipid metabolic disorders in db\/db mice. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.1006517"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.mam.2012.07.010","article-title":"SLC27 fatty acid transport proteins","volume":"34","author":"Anderson","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.cmet.2020.10.010","article-title":"TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation","volume":"32","author":"Huh","year":"2020","journal-title":"Cell Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1080\/09637486.2020.1849041","article-title":"Hepatoprotective and anti-inflammatory effects of a standardized pomegranate (Punica granatum) fruit extract in high fat diet-induced obese C57BL\/6 mice","volume":"72","author":"Pfohl","year":"2021","journal-title":"Int. J. Food Sci. Nutr."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/10\/1693\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:33:45Z","timestamp":1760031225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/10\/1693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,16]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["nu17101693"],"URL":"https:\/\/doi.org\/10.3390\/nu17101693","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,16]]}}}