Shulman had a "That's interesting" moment in his 2016 paper which unfortunately got filed under "everything else was as we expected", and placed on the penultimate page of the supplementary data.
Here's the moment:
"Basal and clamp plasma insulin levels were subtly increased in [chow fed] InsrT1150A mice (Supplemental Table 1)."
Terminology note and clarifications: InsrT1150A are the Thr1150A mutants discussed the previous posts, ie mice with an un-phosphorylatable alanine in the place of the Thr1150 of their insulin receptor. The during-clamp high insulin looks like a non related phenomenon, more a feature of altered insulin catabolism under clamp conditions. Which might be interesting, but not for today's discussion. Oh, and this didn't show up after a six hour fast (Supplemental Table 2) because there was still a glucose based metabolism at that time. I think the anomaly will be intrinsic to markedly fat based metabolism.
Here's Supplemental Table 1
The change in fasting insulin is in the wrong direction and it's the only statistically significant change, excepting the clamp insulin level.
Shulman is perfectly entitled to use the term "subtly" because the difference between 4.5μU/ml and 6.2μU/ml is unlikely to be of any physiological significance. It's like feeling uranium minerals are slightly warm to the touch, noting it and ignoring it. Whereas the actual follow on from warm uranium was Hiroshima.
These mice which have been engineered to invariably fail to phosphorylate the Thr1150 location on their insulin receptor are more insulin resistant, not less.
So, when assessed using a genuine fasting insulin level, these mice *do* resist insulin more than control mice do, despite their absolute lack of a phosphorylatable Thr1150.
Which brings us back to ROS.
I hope everyone recalls this paper:
Genuine fasting metabolism is based on fatty acids. These, irrespective of the mitochondrial membrane potential, will generate ROS and mediate redox dependent insulin resistance. No cellular caloric overload needed, fatty acid oxidation simply resists insulin signalling.
A layer on top of this is the enzymic phosphorylation of Thr1150 which will reduce insulin facilitated glucose ingress, and oxidation, in addition to the ROS signal, so you need less of an ROS signal.
The ROS signal is still there, you can't oxidise fatty acids without generating ROS. I think you can reduce the need for ROS using the supplementary Thr1150 system to also resist insulin. So, for a given level of ROS, the enzymic mechanism enhances glucose restriction and keeps tighter control over the inner mitochondrial membrane potential. Obviously if delta psi is high ROS are generated by any substrate oxidation at similar levels to those from fatty acid oxidation, as in the above graph.
So the ROS insulin signal is higher in the Thr1150/A mice which gives a mild increase in fasting insulin resistance. The ROS signal is higher either because there is more lipid oxidation occurring or (more likley) some glucose oxidation is occurring when the tissues are already energy replete from FAO. This will raise delta psi and increase ROS production from this source in addition to FAO, providing extra redox mediated insulin resistance.
Obviously once insulin acts on adipocytes to suppress FFA release during a clamp then the FFAs fall, so does the ROS signal and all behaves as normal and Shulman is happy.
That is where I was mentally sitting while thinking about the Thr1150/A mice before Tucker emailed me this paper, explicitly invoking ROS mediated insulin resistance:
In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice
Which is rather nice. The ROS are real.
Sadly the paper a bit like the curate's egg, good in places. I think it's worth a post in its own right.
Peter
No comments:
Post a Comment