Caveolin improves glucose metabolism in diabetic mice

The caveolin family of the membrane anchoring proteins accumulates various growth receptors in caveolae and inhibits their function. Here, we identify caveolin as a potent enhancer of insulin signal when overexpressed in the liver in vivo, where endogenous caveolin is little expressed. Adenovirus‐mediated caveolin‐3 gene transfer to the liver led to a marked increase in hepatic glycogen synthesis in diabetic mice (to 468.5 + 219.3%, p<0.05, n=4), but not in non‐diabetic lean mice, and was accompanied by a decrease in mRNA expression of PEPCK (to 49.2 +10.9%, p<0.05, n=5) and an increase in that of Gck (to 166.9 +21.1%, p<0.05, n=5). There was a marked increase in insulin sensitivity in diabetic obese mice as exemplified by decreased fasting blood glucose levels (to 82.1 +2.6%, p<0.05, n=8) and improved glucose tolerant test performance. These effects were attributed mostly to increased insulin receptor activity and caveolin‐mediated, direct inhibition of PTP1B activity (to 52.9 +2.2%, p<0.05, n=4), of which expression was significantly increased in obese mouse liver (to 195.0 +28.1%, p<0.05, n=4). Overexpression of caveolin‐3 in hepatic cells enhanced the insulin receptor signal as well. Our results suggest that caveolin‐3 is an important, endogenous regulator of glucose metabolism that can enhance insulin signal, in particular, under pathological conditions where phosphatase activity is upregulated.