Salk Institute for Biological Studies

CREB Down-Regulation in Treatment of Type II Diabetes

Research Area

Grant Type



Obesity is a leading risk factor for the development of Insulin resistance and type II diabetes. Other tissues that play important roles in this resistance are the liver and muscle. Normally, high insulin levels shut down synthesis of glucose in the liver (gluconeogenesis), and promote uptake of glucose in cells, predominantly skeletal muscle. In type II diabetes these effects are impaired, and result in elevated glucose levels in the blood. The transcription factor CREB is an important regulator in the control of gluconeogenesis; it induces genes that encode key enzymes in this process. In diabetic mice where CREB is inactivated in the liver, glucose levels improve due to impaired gluconeogenesis. Blocking CREB activity may benefit diabetic patients. However, inhibiting gluconeogenesis is not the only effect of inhibiting CREB. Another target of CREB action in the liver is the nuclear hormone receptor PPAR, Blocking CREB activity surprisingly upregulates PPAR activity in liver. However, CREB’s role in skeletal muscle has not been determined. I propose to examine the role of CREB in skeletal muscle metabolism. I will examine the regulation of PGC-1 and PPAR activity by CREB, and the effect of inhibition of CREB on glucose and lipid metabolism. I will also work to identify a peptide that can inhibit CREB activity in vivo, based on hyperactive CREB mutants that have been characterized in the lab. I anticipate that these studies will provide insight into mechanisms by which transcription factors like CREB promote glucose and lipid homeostasis