Investigating the role of MT1-MMP in the regulation of insulin sensitivity and the therapeutic potential of MT1-MMP inhibition in Type 2 diabetes mellitus

Project: Research project

Project Details


Type 2 diabetes mellitus, characterized by systemic insulin resistance, has emerged to be a major threat to public health. Insulin receptor (IR) plays a key role in the control of insulin sensitivity, but the regulation of IR in both physiological and pathological conditions remains unclear.

Recent studies showed that genetic polymorphisms of Membrane-type 1 Matrix Metalloproteinase (MT1-MMP/MMP14), a membrane-bound protease, have been associated with human diabetic traits. Loss of MT1-MMP leads to hypoglycemia in mice. Despite the genetic association between MMP14 and diabetic traits, the role of MT1-MMP in insulin resistance and the molecular mechanism by which MT1- MMP regulates insulin sensitivity remain unelucidated. We found that the expression of MT1-MMP is elevated in the liver tissues isolated from both young mice on high fat diet and aged chow-diet fed mice. Haplodeficiency in MT1-MMP improved glucose tolerance along with enhanced systemic insulin sensitivity both in mice on high fat diet as well as in 16-months-old chow-diet fed mice. As IR is important for the regulation of insulin sensitivity, we therefore sought to investigate if MT1-MMP regulates the expression of IR. The protein expression of IR was elevated significantly in both Mmp14-/- livers and skeletal muscles, but the transcriptional level of IR was not altered by the loss of MT1-MMP. Consistently, MT1-MMP deficiency increased IR protein level in primary hepatocytes and re-introducing wild-type MT1-MMP, but not catalytically inactive MT1-MMP, into Mmp14-/- hepatocytes restored the expression of IR to near wild-type levels, suggesting that MT1-MMP regulates the expression of IR in a catalytic activity-dependent manner. Importantly, we found that loss of MT1-MMP enhanced insulin-induced IR signaling in hepatocytes. These observations reveal a novel role for MT1-MMP in insulin resistance. Based on these new findings, we hypothesize that MT1-MMP may cleave IR to inhibit insulin/IR signaling, thereby suppressing systematic insulin sensitivity.

To further explore the interplay between MT1-MMP and IR signaling, we propose to investigate (1) the molecular mechanism by which MT1-MMP cleaves IR and inhibits insulin signaling; (2) whether overexpression of MT1-MMP induces insulin resistance in vitro and in vivo; (3) whether pharmacological inhibition of MT1-MMP improves insulin sensitivity and glucose tolerance in both diet-induced obese and aged mouse models. The information derived from the above studies will provide new molecular insights into the MT1-MMP-dependent regulation of insulin sensitivity, laying a foundation for innovative approaches to treating type 2 diabetes.
Effective start/end date1/07/1930/06/22

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being


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