دورية أكاديمية
Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort.
| العنوان: | Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort. |
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| المؤلفون: | Wancewicz B; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Zhu Y; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Fenske RJ; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Weeks AM; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Wenger K; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Pabich S; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Daniels M; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Punt M; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Nall R; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Peter DC; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Brasier A; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Cox ED; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Davis DB; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.)., Ge Y; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.) mkimple@medicine.wisc.edu ying.ge@wisc.edu., Kimple ME; Departments of Cell and Regenerative Biology (B.W., Y.Z., K.W., Y.G., M.E.K.), Pediatrics (E.D.C.), and Chemistry (Y.G.); Human Proteomics Program, School of Medicine and Public Health (Y.Z., K.W., Y.G.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (R.J.F., A.M.W., S.P., M.D., M.P., R.N., D.C.P., A.B., D.B.D., M.E.K.); Interdepartmental Graduate Program in Nutritional Sciences (R.J.F., M.E.K.); and Institute for Clinical and Translational Research (A.B.), University of Wisconsin-Madison, Madison, Wisconsin; and Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin (D.B.D., M.E.K.) mkimple@medicine.wisc.edu ying.ge@wisc.edu. |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 Aug; Vol. 386 (2), pp. 169-180. Date of Electronic Publication: 2023 Mar 14. |
| نوع المنشور: | Observational Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مواضيع طبية MeSH: | Diabetes Mellitus, Type 2*/metabolism , Metformin*/pharmacology , Metformin*/therapeutic use , Cardiovascular Diseases*/prevention & control , Cardiovascular Diseases*/drug therapy, Humans ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Lipidomics ; Glycemic Control ; Pharmaceutical Preparations ; Biomarkers ; Blood Glucose/metabolism |
| مستخلص: | Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide metformin is the most common pharmaceutical therapy. Yet its full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of nondiabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared with nondiabetic subjects, changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. SIGNIFICANCE STATEMENT: This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes. (U.S. Government work not protected by U.S. copyright.) |
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| معلومات مُعتمدة: | I01 BX005804 United States BX BLRD VA; R01 HL109810 United States HL NHLBI NIH HHS; UL1 TR002373 United States TR NCATS NIH HHS; F31 DK109698 United States DK NIDDK NIH HHS; S10 OD018475 United States OD NIH HHS; F31 HL152647 United States HL NHLBI NIH HHS; T32 GM081061 United States GM NIGMS NIH HHS; I01 BX003700 United States BX BLRD VA; R01 DK102598 United States DK NIDDK NIH HHS; R01 GM125085 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 9100L32L2N (Metformin) 0 (Hypoglycemic Agents) 0 (Pharmaceutical Preparations) 0 (Biomarkers) 0 (Blood Glucose) |
| تواريخ الأحداث: | Date Created: 20230314 Date Completed: 20230719 Latest Revision: 20230802 |
| رمز التحديث: | 20240829 |
| مُعرف محوري في PubMed: | PMC10353072 |
| DOI: | 10.1124/jpet.122.001493 |
| PMID: | 36918276 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
|---|---|
| DOI: | 10.1124/jpet.122.001493 |