Just a short post on this paper:
Lethal Hypoglycemic Ketosis and Glyceroluria in Mice Lacking Both the Mitochondrial and the Cytosolic Glycerol Phosphate Dehydrogenases
The glycerol-3-phosphate shuttle is composed of a cytosolic G3Pdh which actually hydrogenates dihydroxy acetone phosphate to glycerol-3-phosphate, using NADH, and a second, mitochondrial version, which does the actual dehydrogenating reconversion back to dihydroxy acetone phosphate. Assuming things are going in the most usual direction.
Lab models of mice with knockout of either part of the glycerol-3-phosphate shuttle are very interesting and are long term survivors, to be discussed another day. Today I’d just like to think about those mice with a complete knockout, deleting both components. They die at a few days of age with an array of problems, lethal hypoglycaemia being the end crisis.
At this stage of life they are being fed a very high fat, low carbohydrate diet (mouse milk, it's mostly palmitic acid. That should tell you something!) and they are very heavily reliant on gluconeogensis to maintain adequate glucose levels using glycerol from the milk's triglycerides as the necessary glucose precursor. As the paper says:
“Glyceride-glycerol is an especially important gluconeogenic precursor in the neonatal mouse, because 80% of calories from mouse milk are derived from fat, 16–17% from protein, and only 2–5% from lactose (20, 22–24). Thus total calories available from dietary glycerol ( 4%) equal calories from lactose.”
Now, if you are a lab mouse drinking a low carbohydrate diet, should you be insulin sensitive or insulin resistant? If you are insulin sensitive, how much glucose would you like to waste in your muscles, when you only have a limited supply of the stuff in the first place? I would like to suggest that, even in mice, burning glucose for fuel when there is a very limited supply, might not be a survival trait. So insulin resistance, physiological, might be essential for survival. If physiological resistance is essential this is why they have evolved to produce palmitic acid as the main fat in the maternal milk supply. What is needed is a decent input at ETFdh plus and some input at mtG3Pdh to drive enough electrons backwards through complex I to achieve full physiological insulin resistance.
These mice have zero input at mtG3Pdh so are reliant on ETFdh working under palmitic acid to try and achieve this. This clearly doesn't hack it.
The electron transport chain has an ad libitum supply of palmitic acid. The question is:
Without the glycerophosphate shuttle, can the ETC generate reverse electron flow using ETFdh alone to trigger enough superoxide to adequately resist insulin's wasteful usage of precious glucose?
Obviously not. So the second question has to be:
Can pamitic acid at levels in excess of 900micromol/l generate just enough superoxide to allow insulin signalling to commence, without assistance from mtG3Pdh?
I suspect the answer is yes. This generates just enough superoxide (hence H2O2) to allow insulin signalling to commence. Active but inappropriate insulin signalling then triggers a fatal fall in blood glucose as GLUT4s translocate to cell surfaces and glucose drops through them to be squandered irreplaceably. Glucose crashes, the mice die.
It's an extreme model but it makes us think about what might be happening in addition the malonyl-CoA and CPT1 level of signalling and the limited gluconeogenesis discussed so very nicely in the paper.