Circulating
transthyretin (TTR) is a critical determinant of plasma
retinol-binding protein 4 (RBP4) levels. Elevated RBP4 levels cause
insulin resistance, and the lowering of RBP4 levels improves
glucose homeostasis. Since lowering TTR levels increases renal clearance of RBP4, we determined whether decreasing TTR levels with
antisense oligonucleotides (ASOs) improves
glucose metabolism and
insulin sensitivity in
obesity. TTR-ASO treatment of mice with genetic or diet-induced
obesity resulted in an 80-95% decrease in circulating levels of TTR and RBP4. Treatment with TTR-ASOs, but not control ASOs, decreased
insulin levels by 30-60% and improved
insulin sensitivity in ob/ob mice and high-fat diet-fed mice as early as after 2 weeks of treatment. The reduced
insulin levels were sustained for up to 9 weeks of treatment and were associated with reduced adipose tissue
inflammation.
Body weight was not changed. TTR-ASO treatment decreased
LDL cholesterol in high-fat diet-fed mice. The
glucose infusion rate during a hyperinsulinemic-euglycemic clamp was increased by 50% in high-fat diet-fed mice treated with TTR-ASOs, demonstrating improved
insulin sensitivity. This was also demonstrated by 20% greater inhibition of hepatic
glucose production, a 45-60% increase of
glucose uptake into skeletal and cardiac muscle, and a twofold increase in
insulin signaling in muscle. These data show that decreasing circulating TTR levels or altering TTR-RBP4 binding could be a potential therapeutic approach for the treatment of
type 2 diabetes.