Stearoyl-CoA desaturase (SCD) as a target for diabetes

Obesity and comorbid type 2 diabetes represent a frequent and growing global problem. Both of these markets are expanding significantly. For example as described in “Diabetes, 2003”, our recently featured report of diabetes markets and therapeutic opportunities (click here for access), global retail sales of diabetes drugs which were US$8.1 billion in 1999-2000 are predicted to exceed US$20 billion annually by 2006.

The insulin resistance syndrome was first described in 1988 and contributes to both obesity and diabetes and indeed is generally accepted to represent a pathophysiological link between the two. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues. Considerable attention has been paid to the development of molecules able to reduce insulin resistance. LeadDiscovery has recently published a report overviewing the therapeutic potential of one class of molecules that fit this profile, the GSK-3 inhibitors (Click here for access). Another promising target is PTP1B, which appears critical to maintaining insulin action. PTP1B phosphorylates the insulin receptor causing its inactivation and PTP1B knockout mice are not only insulin sensitive but also maintain euglycemia (in the fed state), with one-half the level of insulin observed in wild-type littermates. Very recent data suggests that inhibiting stearoyl-CoA desaturase (SCD) reduces the expression of PTB1 and therefore inhibitors of this enzyme may be of therapeutic use.

SCD is a microsomal enzyme that catalyzes the synthesis of monounsaturated fatty acids from saturated fatty acyl-CoAs, and which therefore plays a key role in the synthesis of triglycerides, wax esters, cholesteryl esters, and membrane phospholipids. A single human and three mouse SCD isoforms (SCD1, SCD2, and SCD3) are well characterized however the physiological role of each SCD isoform and the reason for having three or more SCD gene isoforms in the rodent genome are currently unknown. James Ntambi from the University of Wisconsin and colleagues have previously shown that mice with a targeted disruption in the SCD1 gene are resistant to diet-induced weight gain and have increased insulin sensitivity relative to the WT controls. More recently they have investigated the link between the loss of SCD1 function and insulin signaling in muscle.

In their recent PNAS paper Ntambi et al report that deletion of SCD1 lowers fasting levels of insulin however in skeletal muscle basal insulin receptor tyrosine phosphorylation was ten-fold higher suggesting an increase in insulin sensitivity. This was paralleled by a 5- and 3-fold increase respectively in the tyrosine phosphorylation levels of IRS-1 and IRS-2, and also by a >66% reduction in PTB1 expression and a 49% reduction in activity. This increase in protein phosphorylation and reduction in PTB1 activity was selective to components of the insulin signaling pathway. Tyrosine phosphorylation of IRS-1 is a positive trigger of insulin action, which initiates numerous signaling components including PI 3-kinase and Akt. Not surprising therefore, phosphorylation of Akt, a key serine/threonine kinase, which mediates many metabolic effects of insulin was increased. Glucose uptake on the GLUT4 transport, glycogen synthesis, and glycogen accumulation, key metabolic effects of insulin in skeletal muscle were also increased.

These studies establish a critical role of SCD1 in the insulin signal transduction in skeletal muscle and suggest that these effects are mediated through a reduction in PTP1B expression and activity. Thus, the development of SCD1 inhibitors represents an excellent target for the treatment of diabetes and other conditions associated with insulin resistance.

Entry date Wednesday, September 17, 2003

Adapted from Rahman et al, Proc Natl Acad Sci U S A. 2003 Sep 5 [Epub ahead of print]