Research published in the October Molecular and Cellular Biology moves us closer to developing drugs
that could mitigate diabetes.

Diabetes afflicts an estimated 26 million Americans, while
79 million have prediabetes. In other words, one in three Americans confronts
this disease. Diabetes raises the risk of heart disease and stroke by as much
as fourfold, and it is the leading cause of blindness among adults 20-74. It is
also the leading cause of kidney failure.

In earlier research, four years ago another team of
researchers showed that they could boost insulin sensitivity in experimental
rodents by giving the animals a drug called myriocin. People with diabetes have
a condition called insulin resistance, which renders them poorly able to
process sugar. That results in high blood sugar, which damages the blood
vessels, leading to many of diabetes’ ills. In their study, that team, led by
Johannes M. Aerts of the University of Amsterdam, observed a decrease in a
compound called ceramide, which sits on cell membranes in the circulatory system,
which they postulated was responsible for the rise in insulin sensitivity.

In the new study, Xian-Cheng Jiang of Downstate Medical
Center, Brooklyn, NY, and his collaborators set out to confirm this earlier
work, using a genetic approach.

The new research provides strong evidence that ceramide was
not causing insulin sensitivity, but that another membrane-bound compound,
sphingomyelin, might be doing so.

Ceramide is the substrate for the last step in a five step
cascade that produces sphingomyelin. In that step an enzyme called
sphingomyline synthase 2 (SMS2) cleaves ceramide to produce sphingomyelin. The
first enzyme in this pathway is called serine palmitoyltransferase (SPT).

To test the hypothesis that ceramide is involved in
modulating insulin resistance the researchers used knockout mice for each of
these enzymes. They postulated that (partially) knocking out the first enzyme
in the cascade would decrease ceramide levels while knocking out the last
enzyme in the sphingomyelin pathway would boost ceramide levels, since that
enzyme uses ceramide to produce sphingomyelin. Thus, SPT knockout mice would
have greater insulin sensitivity, while SMS knockout mice would have reduced
insulin sensitivity.

Surprisingly, while ceramide levels changed as predicted,
that change did not influence insulin sensitivity, which was higher in both
groups.

The research has important implications for drug development
for mitigating diabetes. Myriocin proved highly toxic and major efforts to
modify the drug to reduce that toxicity have been fruitless. Myriocin’s
toxicity probably stems from the fact that it inhibits the first step of the
sphingomyelin biosynthetic pathway, affecting all the downstream biology, says
Jiang. The discovery that knocking out the last step in the biosynthetic
pathway improves insulin sensitivity means that drug treatments could target
that last enzyme, SMS, leaving the rest of that biosynthetic pathway to
function normally.