Insulin resistance (IR) is a primary contributor to obesity related pathologies including type 2 diabetes. Hepatic IR manifests as a loss of insulin’s suppressive action on hepatic glucose output, and correlates with extracellular matrix (ECM) expansion. Integrin receptors are the primary input for ECM derived signals to the intracellular environment. Given the correlation of ECM deposition with hepatic IR our goal is to define contributions of integrin signaling to this pathologic process.
Integrin receptors are heterodimeric membrane receptors with an α and β subunit. Hepatocytes are involved in hepatic insulin responsiveness and express four integrin subunits. Utilizing mice with hepatocyte specific knockout of integrin α5 (hepα5-KO) or β1 (hepβ1-KO) we aimed to determine contributions of these integrin subunits to IR.
A high-fat (HF) fed model of diet induced obesity (DIO) caused weight gain in hepα5-KO, hepβ1-KO, and respective control littermates. Using hyperinsulinemic-euglycemic clamps in the conscious catheterized mouse we demonstrate that hepα5-KO mice on a standard diet (chow) have normal insulin sensitivity and develop IR during DIO similar to controls. While insulin sensitivity of chow fed hepβ1-KO is no different from controls, DIO hepβ1-KO mice are protected from IR. Significant increases in glucose disappearance (Rd) and suppression of endogenous glucose appearance (EndoRa) during the clamp drive preservation of insulin sensitivity in these mice. Interestingly the primary hepatocyte knockout of the β1 subunit has effects on extrahepatic tissue as DIO hepβ1-KO mice also demonstrate increased glucose metabolic indexes (Rg) in several tissues, likely contributing to enhanced Rd.
Overall, these findings demonstrate the direct link between IR and ECM-integrin signaling through integrin β1. This further establishes the involvement of ECM-integrin signaling during metabolic disease and the potential for this pathway as a novel therapeutic avenue.
E. Trefts: None. D.A. Roby: None. A. Pozzi: None. R. Zent: None. D. Wasserman: None.
National Institutes of Health (DK007563), (DK112553 to E.T.), (DK069221, DK083187 to R.Z.), (CA162433, DK095761 to A.P.), (DK050277, DK054902 to D.W.)