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

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.