I wanted to look at insulin resistance, uncoupling and metabolic rate. If we just review the effect of an intravenous bolus of palmitic acid on an anaesthetised rat we can see that the bolus produces a period of increased oxygen consumption, ie an increased metabolic rate, in a then-uncoupled healthy rat. From Curi again:
This next graphic is looking at glucose oxidation, rather than oxygen consumption, from the same paper.
The left hand graph shows what happens under basal metabolism, ie glucose is being taken up by isolated muscle cells without help from insulin facilitated GLUT4 translocation. Fatty acids uncouple, ATP levels fall, there is an increase in glucose oxidation to compensate, ATP levels are corrected. Presumably some of the fatty acids get metabolised too.
On the right is the effect under supra maximal insulin. We have no idea of dose response curve to insulin from this study, it describes either using none or using 10mU/ml. That's mU, not microU! At a concentration of 10mU/ml insulin will overcome any suggestion of insulin resistance, short of a knockout model. Insulin supports glucose oxidation, uncoupling increases this. The set up is not designed to look at insulin resistance as might be related to that uncoupling. But the effects on overall metabolic rate, at 5.6mmol of glucose, are quite clear cut.
What if that elevated FFA level was maintained long term?
As adipocytes become progressively more resistant to the the anti-lipolytic effect of insulin (why is another whole ball game), plasma free fatty acids rise even under levels of insulin which should be suppressing them. Unless these free fatty acids are converted to CoA derivatives they are will uncouple respiration. This should reduce delta psi and increase metabolic rate.
A reduced delta psi will not support reverse electron flow through complex I. The essential insulin induced pulse of superoxide, converted to H2O2, will not occur. There will be fasting insulin resistance. This paper spelled it out. In brief:
The insulin signalling cascade is tonically restrained by a phosphatase which deactivates the insulin/receptor complex (which activates itself by auto-phosphorylation) as soon as the process tries to get started. For insulin to signal you need to have an elevated delta psi which allows a nanomolar pulse of H2O2 to cripple this phosphatase and so allow the insulin/receptor complex to get signalling.
With reduced delta psi this isn't going to happen. We have enhanced insulin resistance of starvation until the time when food arrives.
You can increase delta psi, of course, to get insulin working. Increasing delta psi requires increased electrons in to the respiratory chain through complex I. In the blunted insulin signalling situation of low delta psi we can't use GLUT4 transporters but we can, given high enough plasma glucose levels, get sufficient glucose in to the cell to generate enough of a delta psi to allow the pulse of H2O2 and its downstream effects to occur. So overcome the inability of insulin to signal in the presence of FFAs.
The cost is that an elevated blood glucose level is needed. This is what we look at with the ratio of fasting glucose to fasting insulin, the HOMA score. An elevated HOMA score is a marker of UNCOUPLING at the delta psi level in mitochondria. It should be associated with an increased metabolic rate in proportion to the degree of fatty acid induced uncoupling.
Does this happen in real life? These data are from the Pima but the pattern is generic in insulin resistant states:
Note first that the changes in FFA concentrations are statistically non significant, but that the trend is nicely upwards with insulin levels
The authors comment:
"Alternatively, FFA may contribute to increased RMR via stimulation of mitochondrial uncoupling proteins (UCPs) (53,54). As early as 1976, Himms-Hagen (53) suggested that FFAs stimulate UCP-1. More recently, elevated FFA concentrations were reported to stimulate UCP-3 expression in rats (54)"
Bear in mind that as people progress from NGT through IGT to diabetes there are not only progressive changes in blood lipid and glucose levels but also progressive damage to mitochondria per se, which makes comparing a healthy rat to a metabolically challenged human being slightly dubious.
But the changes make sense.
If we look at the post prandial situation we have, after a carbohydrate containing meal, the combination of chronically elevated FFAs with acutely elevated glucose. There will be a high delta psi as soon as blood glucose rises high enough (supra physiological) to allow non-GLUT4 uptake to elevate delta psi high enough for insulin signalling. At this time point the mitochondria allow insulin to function. We can now translocate GLUT4s to the cell surface and start to lower postprandial hyperglycaemia by pouring metabolites through glycolysis or in to glycogen stores.
At the same time, among insulin's many diverse functions, the activation of free fatty acids to their CoA form increases, with a view to anabolic or storage functions. I would presume a different CoA ligase directs the activated fatty acids to oxidation. There is quite a group of LCFA CoA ligases.
At this point we lose the freedom of free fatty acids, they are ligated to CoA and suddenly become effective inhibitors of uncoupling rather than facilitators. We are now set up for the post prandial state. As soon as we have access to glycolysis combined with beta oxidation we have the possibility to generate marked reverse electron flow through complex I and re-inhibit the action of insulin using much greater generation of H2O2 than is needed for insulin's initial activation.
Metabolically, the mitochondria do this at this time to stop caloric overload in any individual cell, by diverting excess calories to storage in adipocytes. From the NADH:FADH2 ratio, long chain saturated fats do this best. Monounsaturates appear to be designed to allow a normal combination of glucose and fatty acid oxidation and PUFA fail to generate adequate insulin resistance to protect an individual cell (including adipocytes) from an overload of metabolic substrate. In the immediate post prandial state saturated fats can best protect cells from an absorptive excess of metabolites. These fatty acids are already present in supraphysiological levels, whatever has been eaten.
The elevated insulin needed to maintain post prandial normoglycaemia will, if the adipocytes are able to respond at all, divert fat from the circulation and into those adipocytes. This is the simple ability of insulin, and cellular resistance to insulin, to limit metabolic injury when calories are present in excess of immediate needs.
Under inappropriately elevated FFAs there is an initial failure of insulin's action due to depressed delta psi during fasting and a subsequent post-meal failure of insulin's action due to inappropriately elevated fatty acid metabolism through electron transport flavoprotein dehydrogenase's FADH2 when combined with high delta psi.
To me, this looks very much like impaired metabolic flexibility, reduced to the level of delta psi and superoxide. I like it.