So far I've been thinking about insulin resistance as a normal physiological process for regulating the energy input in to each cell, on an individual metabolic needs basis. There is nothing pathological about this process, regulation is essential. To develop insulin resistance in the immediate aftermath of a single 2000kcal meal or during a 5 day fast is exactly what you need to do. Combining the post prandial state with the fasting state is pathological but could be corrected by simply restoring insulin sensitivity to adipocytes, so allowing them to lower free fatty acids when glucose is elevated.
There are times when I would like there to be differing terms for the insulin resistance of the immediate post prandial period, of starvation and of metabolic broken-ness. It would make for a much clearer picture than saying someone is "insulin resistant".
Now I'd like to think about some pathology.
I’m going to start with this paper on rotenone, with thanks to Mike for the full text. I'm not sure how widely rotenone is used nowadays but, in the lab, it is a freely available inhibitor of complex I. I doubt this toxicosis is particularly prevalent in everyday life, I'm more interested in a basic mechanism which we can extend to other injuries of complex I. Adding rotenone to almost any cell line produces this sort of effect on metabolism, here in C2C12 muscle-like cells (which do it best). From Fig4:
Oxygen consumption is depressed, delta psi is depressed and NADH accumulates at the expense of lowered NAD+ levels. BTW, some authors use the NADH/NAD+ ratio, some the inverse. Ah well, it's still badness. These folks talk about "reductive stress".
The interesting point to note from section D is the rise in acetyl-carnitine, a molecule used to export acetyl-CoA from mitochondria to cytoplasm.
If we block the ability of the mitochondria to feed NADH in to the ETC there is no point in turning the TCA because this generates four NADHs for that single FADH2 from succinate dehydrogenase (which still works if you provide succinate exogenously). Instead the acetyl-CoA is exported as acetyl-carninitine or as citrate after combination with oxaloacetate. Once in to the cytoplasm acetyl-CoA is available for de novo lipogenesis. Does it get used for this?
Here are some C2C12 muscle-like cells which are running on a "low" concentration (probably around 5.0mmol/l) of glucose. The ones on the right are also exposed to 5.0 nanomol of rotenone in the complete absence of insulin or any equivalent. Cytoplasm is pale purple, nucleus is dark purple:
The beautiful orange-red staining droplets are lipid, more clearly visible in this enlargement:
How much lipid is deposited? That depends on how much rotenone is used and how long the complex I has been blocked for. From Fig 2:
You can do exactly the same thing by blocking complex I with piericidin A or by knocking down expression of the gene NDUFV1 (codes for a huge chunk of complex I) in C2C12 cells. From Fig 3:
You get the same effect in people with the misfortune to be born with severe defects in complex I; in the affected tissues there is lipid accumulation. By the time you get down to <5% complex one activity there are quite nasty knock on effects on fatty acid oxidation and cell viability, but that's another story.
Very few people would choose to take rotenone nowadays but there are a number of other complex I inhibitors, some of which are quite widely available. Flunarizine, isoniazid and atrazine spring to mind with bisphenyl A as a more general mitochondrial toxin which includes complex I blockade. None are marketed as weight loss supplements.
I see this as a generic mechanism. Complex I dysfunction leads to intracellular lipid accumulation.
What else is interesting?
These cells are being fed with low levels of glucose without insulin. Glucose uptake will be basal and much of the energy from glycolysis will be diverted to lipogenesis. Again, if ox phos is reduced mitochondrial ATP production will be depressed and glycolysis will be the main source of ATP using substrate level phosphorylation. We know lipogenesis is occurring, so we must be deriving NADPH from glycolysis. If we were to add insulin to the culture medium of a rotenone poisoned cell and perhaps increase the glucose level to 25mmol/l, what would happen?
Assuming we can generate enough of a delta psi to allow insulin signalling we would pour glucose in to the cell and down through glycolysis to pyruvate. This gives us a ton of acetyl-CoA in the mitochondria. Complex I is still blocked. What's a cell to do except de novo lipogenesis in its cytoplasm?
As we allow glucose in to a cell, we push de novo lipogenesis. This is a parody of insulin sensitivity. The faster we allow glucose in to a cell, the faster it is lost to lipid. My line of thought is about how well this ability to sequester glucose as lipid might give the impression of being extremely sensitive to insulin, when the actual mitochondria are dysfunctional and should be signalling insulin resistance.
I can't get away from the unarguable fact that post-obese women perform enough DNL to get their RQ > 1.0 on exposure to 75g of glucose in an OGTT.
Perhaps we need to look at the mitochondrial function of people who's "preferred" metabolic state is best achieved by obesity. And how we might damage complex I without mainlining rotenone.
Better hit "post" as things keep getting in the way of extending this particular entry.