Metformin (07) glargine 50iu/kg causes diabetes

The group which demonstrated that exogenous insulin induces insulin resistance in T1DM NOD mice went on to demonstrate that exogenous insulin induces T2DM in normal* mice on a normal chow diet.

*If you can describe Bl/6 mice as normal, with their failure to assemble mitochondrial super complexes and all of the potential implications that has on all sorts of metabolic effects. But I digress, as always.

Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet

So you can imagine that I quite like this group. But they are naughty and the naughtiness is very annoying.

If you read about insulin administration in the current paper you will be presented with this bollocks:

"The dose of glargine was determined according to our previous experiments (Liu et al. 2009a )..."

What they did in Liu et al 2009a was to titrate the dose of insulin determir upwards to just achieve normoglycaemia. Different doses were needed in individual mice because that's what diabetes is like in NOD mice. That is NOT what they did in this current paper to the Bl/6 mice. Here they used glargine and they went straight in at a massive supraphysiological dose:

"C57BL/6 (B6) mice (male, 6–9-week old) from Charles River were treated with either saline or a long- and slow-acting insulin reagent, glargine (50 Unit/kg body weight, s.c. injection, once a day), for 8 weeks".

Even allowing for metabolic scaling from humans down to mice this is a massive dose of glargine. It's not remotely what they did with the NOD mice.

EDIT: Going back through the first paper the NOD T1 mice did actually end up with the average group dose of detemir being 25iu/kg twice daily. The difference in protocol is that the group is assuming that glargine 50iu/kg once daily is equivalent to detemir 25iu/kg twice daily. A big assumption. And that this would be fine for all mice. And that going in at the full dose rate on day one rather than titrating up over two weeks would also be equivalent. But the dose rate is more reasonable than I expected. END EDIT.

So there are fibs in the methods. Can you really trust these folks? Not much choice really...

None of the mice died on the glargine 50iu/kg dose, so I think we can assume that they developed a marked and rapid onset insulin-induced insulin resistance.

When you wade through the IRS1 serine phosphorylation, IRS1 tyrosine phosphorylation, Akt phosphorylation, total Akt etc etc etc in the results section the end conclusion is that the liver became insulin resistant but the gastrocnemius muscle (representing what I called "systemic" tissues) did not. Bummer for my nice, plausible and apparently incorrect ideas.

So to ease my cognitative dissonance I went back to our initial paper and waded through the IRS1 serine phosphorylation, IRS1 tyrosine phosphorylation, Akt phosphorylation, total Akt etc etc etc and discoved that, lo and behold, that under a clinical protocol the gastrocnemius did become insulin resistant. So did the liver but I can live with that, after all the liver does have a (bloody enormous) arterial blood supply in addition to receiving flow from the portal vein.

Phew, biases in-tact.

It's interesting to see in the paper that exogenous glargine actually destroys the pancreas. Beta cell mass falls, their mitochondria undergo marked oxidative stress and this allows the failure to deal with the hepatic insulin resistance induced by glargine 50iu/kg, hence the induction of diabetes.

I think the take home message is that taking glargine 50iu/kg won't help your own clinical diabetes, should you be so affected. It's also too high a dose if you are attempting to do harm!

Anyhow. Growth hormone and insulin resistance next, probably.

Peter