Abstract
Insulin resistance is a risk factor for type 2 diabetes mellitus. We investigated the effect of ApoA-IV on glucose uptake in the adipose and muscle tissues of mice and cultured 3T3-L1 adipocytes. We found that treatment with ApoA-IV lowered fasting blood glucose in both WT and diabetic KKAy mice by increasing glucose uptake in cardiac muscle, white adipose tissue, and brown adipose tissue through a mechanism that was partially insulin independent. Cell culture experiments showed that ApoA-IV improved glucose uptake in adipocytes in the absence of insulin by upregulating GLUT4 translocation by PI3K mediated activation of Akt signaling pathways. Considering our previous finding that ApoA-IV treatment enhanced pancreatic insulin secretion, these results suggests that ApoA-IV acts directly upon adipose tissue to improve glucose uptake and indirectly via insulin signaling. Our findings warrant future studies to identify the receptor for ApoA-IV and the downstream targets of PI3K-Akt signaling that regulate glucose uptake in adipocytes as potential therapeutic targets for treating insulin resistance.
Highlights
Apolipoprotein A-IV (ApoA-IV) is a major component of high-density lipoprotein and chylomicrons, both of which function in the transport of serum lipids[6]
We investigated the effect of ApoA-IV on insulin sensitivity in WT (C57BL/6J strain) and KKAy diabetic mice
We found that treatment with ApoA-IV lowered fasting blood glucose in both WT and KKAy diabetic mice by increasing glucose uptake in cardiac muscle (CM), white adipose tissue (WAT), and brown adipose tissue (BAT) through a mechanism that is at least partially independent of insulin
Summary
Apolipoprotein A-IV (ApoA-IV) is a major component of high-density lipoprotein and chylomicrons, both of which function in the transport of serum lipids[6]. We showed that treatment with exogenous ApoA-IV improved glucose homeostasis by suppressing hepatic gluconeogenesis and enhancing insulin secretion in both KKAy diabetic mice and ApoA-IV−/− knockout (ApoA-IV-KO) mice with elevated serum glucose[8,9]. It is unclear whether ApoA-IV treatment enhances insulin sensitivity and glucose uptake in skeletal muscle, adipocytes, or other tissues. We investigated the effects of ApoA-IV treatment on blood glucose levels and glucose homeostasis in adipocytes and muscle cells in mice. The downstream effectors of ApoA-IV that mediate enhanced glucose uptake in adipocytes might represent potential therapeutic targets for the treatment of IR and T2DM
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