TGF-1 Signaling Impairs Metformin Action on Glycemic Control.
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abstract
Hyperglycemia is a hallmark of type 2 diabetes (T2D). Metformin, the first-line drug used to treat T2D, maintains blood glucose within a normal range by suppressing hepatic glucose production (HGP). However, resistance to metformin treatment is developed in most T2D patients over time. Transforming growth factor beta 1 (TGF-1) levels are elevated both in the liver and serum of T2D humans and mice. Here, we found that TGF-1 treatment impairs metformin action on suppressing HGP via inhibiting AMPK phosphorylation at Threonine 172 (T172). Hepatic TGF-1 deficiency improves metformin action on glycemic control in high fat diet (HFD)-induced obese mice. In our hepatic insulin resistant mouse model (hepatic insulin receptor substrate 1 (IRS1) and IRS2 double knockout (DKO)), metformin action on glycemic control was impaired, which is largely improved by further deletion of hepatic TGF-1 (TKObeta1) or hepatic Foxo1 (TKOfoxo1). Moreover, blockade of TGF-1 signaling by chemical inhibitor of TGF-1 type I receptor LY2157299 improves to metformin sensitivity in mice. Taken together, our current study suggests that hepatic TGF-1 signaling impairs metformin action on glycemic control, and suppression of TGF-1 signaling could serve as part of combination therapy with metformin for T2D treatment.
