I started here with with DNP
Several links came out of the paper. First was this one from Shulman's group
The paper contains a great deal of information about the development of the sustained release DNP formulation, which sounds good. All we know about the rats and diets are that they were Sprague Dawley rats or Zucker Diabetic Fatty rats and the diets are minimally described as safflower oil 60% fat for NAFLD or methionine/choline deficient for NASH.
Bottom line is that a sustained release hepatic targeted DNP preparation is enormously safe and produces marked amelioration of liver disease in all of the models tested.
Using Bl/6 mice they also show that the degree of hepatocyte mitochondrial uncoupling was so minor as to be undetectable in a CLAMS apparatus.
Next is this one, again from Shulman's lab, where the hydrogen of the DNP hydroxyl group was replaced with a methyl moiety, rendering this DNP derivative inactive. This was then converted to active DNP primarily in the liver by cytochrome P450, with no detectable toxicity and no detectable increase in oxygen consumption on a whole body basis:
There is pretty convincing evidence that both of the above modified DNP delivery systems were fairly tightly targeted to the liver. Relatively little appeared to act on other organs and there is no information about the action on adipose tissue, but then these experiments were not looking for weight loss, merely controlling the liver damage/dysfunction of metabolic syndrome.
And the drugs do control metabolic syndrome. Here are the intraperitoneal glucose tolerance test results for the high fat fed Sprague Dawley rats, red being the treatment groups throughout:
and the insulin levels at the same times:
and the results for the Zucker Diabetic Fatty rats are even more impressive:
and insulin levels:
All of this is merely by limiting lipid accumulation within hepatocytes.
And the rats stayed fat.
You have to look at this and wonder: Here we have an intervention which primarily blunts insulin signalling originating from the mitochondria of hepatocytes. A drug which reduces insulin signalling and yet leads to a dramatic improvement of of whole body insulin sensitivity.
The parallels with metformin are striking
Peter
