Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice

Diabetologia. 2014 Mar;57(3):603-13. doi: 10.1007/s00125-013-3128-1. Epub 2013 Dec 4.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Collagen Type V / metabolism*
  • Diet, High-Fat
  • Extracellular Matrix / metabolism*
  • Gene Deletion
  • Glucose Clamp Technique
  • Immunohistochemistry
  • Insulin / metabolism*
  • Insulin Resistance*
  • Insulin Secretion
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Muscle, Skeletal / immunology
  • Muscle, Skeletal / metabolism*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • Blood Glucose
  • Collagen Type V
  • Insulin
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Matrix Metalloproteinase 9