Yale University. US: Yale researchers developed a controlled-release oral therapy that
reversed type 2 diabetes and fatty liver disease in rats, according to a
study published on Feb. 26 by Science.
Existing therapies for
type 2 diabetes, and the closely associated conditions of nonalcoholic
fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH),
have had limited success at treating the root causes of these diseases.
Building on earlier research, the Yale team — led by Dr. Gerald I. Shulman,
the George R. Cowgill Professor of Physiological Chemistry, and
professor of medicine and cellular & molecular physiology at Yale
School of Medicine — decided to investigate whether an agent that had
originally been used for weight loss more than 70 years ago could be
reformulated to safely treat NAFLD/NASH and type 2 diabetes in rodent
models of these diseases.
Based on their earlier studies, the
researchers determined that toxicity associated with the agent —
mitochondrial protonophore 2,4-dinitrophenol (DNP) was related to its
peak plasma concentrations. They discovered that DNP’s efficacy in
reducing liver fat and liver inflammation could be achieved with plasma
concentrations that were more than a 100-fold less than the toxic
levels.
“Besides reversing fatty liver disease in a rodent model
of NALFD, a low-dose intragastric infusion of DNP that was 100-fold
lower than toxic levels also significantly reduced blood glucose,
triglyceride, and insulin concentrations in a rodent model of NAFLD and
type 2 diabetes”, said Shulman, who is also an investigator with the
Howard Hughes Medical Institute.
In the next phase of the study,
Shulman and his team developed a new oral, controlled-release form of
DNP, known as CRMP, which maintained the drug at concentrations that
were more than a 100-fold lower than the toxic threshold. Administered
once daily, CRMP delivered similar positive results, reversing fatty
liver, insulin resistance, and hyperglycemia in rat models of NAFLD and
type 2 diabetes, as well as liver inflammation and liver fibrosis in a
rodent model of NASH, with no adverse effects.
“Given these
promising results in animal models of NAFLD/NASH and type 2 diabetes we
are pursuing additional preclinical safety studies to take this
mitochondrial protonophore approach to the clinic” said Shulman.
Other Yale authors include Rachel J. Perry, Dongyan Zhang, Xian-Man Zhang, and James L. Boyer.
This
research was supported by grants from the National Institutes of Health
(R01 DK-40936, R24 DK-085638, U24 DK-059635, T32 DK-101019, P30
DK-45735, P30 DK-34989 and UL1 TR-000142) and the Novo Nordisk
Foundation Center for Basic Metabolic Research, University of
Copenhagen, Copenhagen, Denmark.
Citation: Science