Erschienen in:
01.03.2014 | Article
Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice
verfasst von:
Li Kang, Wesley H. Mayes, Freyja D. James, Deanna P. Bracy, David H. Wasserman
Erschienen in:
Diabetologia
|
Ausgabe 3/2014
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Abstract
Aims/hypothesis
Increased extracellular matrix (ECM) collagen is a characteristic of muscle insulin resistance. Matrix metalloproteinase (MMP) 9 is a primary enzyme that degrades collagen IV (ColIV). As a component of the basement membrane, ColIV plays a key role in ECM remodelling. We tested the hypotheses that genetic deletion of MMP9 in mice increases muscle ColIV, induces insulin resistance in lean mice and worsens diet-induced muscle insulin resistance.
Methods
Wild-type (Mmp9
+/+) and Mmp9-null (Mmp9
−/−) mice were chow or high-fat (HF) fed for 16 weeks. Insulin action was measured by the hyperinsulinaemic–euglycaemic clamp in conscious weight-matched surgically catheterised mice.
Results
Mmp9
−/− and HF feeding independently increased muscle ColIV. ColIV in HF-fed Mmp9
−/− mice was further increased. Mmp9
−/− did not affect fasting insulin or glucose in chow- or HF-fed mice. The glucose infusion rate (GIR), endogenous glucose appearance (EndoRa) and glucose disappearance (Rd) rates, and a muscle glucose metabolic index (Rg), were the same in chow-fed Mmp9
+/+ and Mmp9
−/− mice. In contrast, HF-fed Mmp9
−/− mice had decreased GIR, insulin-stimulated increase in Rd and muscle Rg. Insulin-stimulated suppression of EndoRa, however, remained the same in HF-fed Mmp9
−/− and Mmp9
+/+ mice. Decreased muscle Rg in HF-fed Mmp9
−/− was associated with decreased muscle capillaries.
Conclusions/interpretation
Despite increased muscle ColIV, genetic deletion of MMP9 does not induce insulin resistance in lean mice. In contrast, this deletion results in a more profound state of insulin resistance, specifically in the skeletal muscle of HF-fed mice. These results highlight the importance of ECM remodelling in determining muscle insulin resistance in the presence of HF diet.