Lessons from LIRKO

The LIRKO mouse has no insulin receptors in its liver.  It's one pretty sickly mouse.  In most studies it becomes hyperglycemic and hyperinsulinemic very early in life, but by six months or so of age is either normoglycemic or hypoglycemic.  Despite the concurrent hyperglycemia and hyperinsulinemia, the LIRKO remains normal weight, it is even a bit underweight if anything.  This is despite the fact that  circulating free fatty acids (FFA, or my preferred acronym, NEFA)  are suppressed by 40%.  {Here are the two papers I've discussed in previous blog posts: Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction , High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice both links are to free full texts}

LIRKO presents two problems for the TWICHOOB:

1.  Chronic hyperinsulinemia does not cause rampant fat accumulation 

2.  Insulin "locking away" fats does not lead to hyperphagia (overeating)

The real gossip mongers on the outskirts of the IHC have been buzzing about various of us bloggers having been "schooled" by Dr. Jim Johnson, whom I will call Jim because that is the way he signed his comments here on this blog.  I hope that Jim will continue to engage this discussion, but for my part I have to beg off the Twitter part of it.  Twitter, with its character limits and difficulty following anything more than a short back and forth, just is not the appropriate venue for productive conversation on these topics.   I have offered in email to do a Todd Becker style thing (search on Insulin Wars and Todd Becker here to see what I mean) if that might work better and Jim has mine so if he's reading this and comments are too cumbersome b/c of length and formatting limits, just email me and I'll post it up!

In any case, as I understand it, Jim has written off the *IRKO mice as complicated beings that are not representative of realistic physiological scenarios that occur in nature.  I would remind that his "half insulin" KO mouse is not either ... especially in humans as the insulin deficient invariably exhibit some manner of disturbed glucose and lipid metabolism.  The other argument Jim has put forth is that the LIRKO is irrelevant b/c it wasn't created to study obesity.  I find that an odd argument for any scientist to make given the prevalence of great scientific discoveries that were the product of experiments or even accidents while investigating often wholly unrelated phenomena.  But I find it additionally troubling in light of the fact that Jim's own mouse and experiments led to the "surprising" discovery of obesity prevention.  According to their own press release, this mouse was not designed for obesity research either!  {see Does Hyperinsulinemia Drive Diet-Induced Obesity?}

To conclude that hyperinsulinemia "drives" obesity from just his work, requires ignoring considerable data -- both observational and experimental -- that is inconsistent with that hypothesis.  It is not sufficient to me to disregard this data, in a manner that appears flippant but I think that's the Twitter-factor ... or at least I hope so.

If hyperinsulinemia drives diet induced obesity, then a complete hypothesis must include at least a hypothesis as to how.  A mechanism.  In the low carb community, that mechanism has always been an imbalance of fatty acid sequestration (esterification/acylation) as compared to mobilization (lipolysis).  As Taubes put it, anything that works to put fat into adipocytes (e.g. insulin, but not ASP oddly enough) is "fattening" and anything that works to mobilize fats (e.g. less insulin, but more oddly enough not exercise) is "unfattening".

So with the LIRKO mouse the hyperinsulinemia should "trap" fatty acids in the adipocytes and this mouse should be fat.  But it is not.  The next thing that must be looked at then, is if this "violates" the mechanism of the hypothesis.  IOW, is there something about hepatic insulin signaling that interferes with the adipocyte signalling?  Not according to the studies.  Insulin is doing its job and NEFA (circulating free fatty acids) are considerably depressed (40%) in the LIRKO mouse.  So why is it not fat?  A reasonable explanation has not been provided.

But leaving obesity aside for another day (feel free to discuss now), LIRKO holds a few more "lessons" for us.

Pancreatic Exhaustion is countered by LIRKO:  This is a common meme.  Eat a lot of carbs, use your pancreas, which leads to abusing your pancreas as it needs to secrete more and more as your cells become deaf to the signaling.  Eventually you wear your poor pancreas out and you become diabetic.  If this were the case, LIRKO should eventually become hypoinsulinemic with evermore out of control hyperglycemia.  But exactly the opposite occurs as LIRKO ages.  The LIRKO at 6 months is still pumping out crazy amounts of insulin (9X fasting, almost 25X fed) compared to controls, while it's fasting hyperglycemia has turned to hypoglycemia and postprandial hyperglycemia is significantly muted compared to the young LIRKO (though still hyperglycemic vs. controls).   The livers of these mice are giving out, no longer able to keep up with the unchecked gluconeogenesis the liver thinks it's supposed to generate.

LIRKO counters Hyperinsulinemia causing Insulin Resistance:  If we define IR as skeletal muscle IR measured or ascertained by postprandial glucose clearance, this, too is countered by LIRKO.  In the glucose tolerance test administered to the LIRKO, the same amount is administered.  If chronic hyperinsulinemia led to diminishing insulin receptor action, reduction in glucose transporters or anything of the sort that reduced glucose "clearance", we would expect worsening postprandial hyperglycemia over time.  But we don't.  This is not to say that HI cannot precede and/or cause IR, but not by this mechanism analogous to building up a tolerance.

LIRKO counters Glucotoxicity Killing Beta-Cells:   One of the mechanisms by which hyperglycemia is thought to accelerate the progression of diabetes is that of glucotoxicity damaging beta cells.  Although LIRKO's hyperglycemia subsides with age, it certainly does not appear to damage the pancreas.

LIRKO counters Chronic Hyperinsulinemia interfering with acute GSIS by depleting insulin stores:   This isn't something we hear often, but it's a corollary of the exhausted pancreas theory.  I blogged on a study about exactly this Chronic Exposure to Free Fatty Acid Reduces Pancreatic β-Cell Insulin Content by Increasing Basal Insulin Secretion That Is Not Compensated For by a Corresponding Increase in Proinsulin Biosynthesis Translation almost two years ago.  That study, on which renowned diabetologist JD McGarry was a contributing author, boils down to chronic insulin production by stimulation by elevated NEFA doesn't stimulate replenishing of the stores so that glucose stimulated insulin secretion, GSIS, is impaired.  Given the chronic hyperinsulinemia, merely producing a lot of insulin chronically can't be the cause of impaired GSIS.  LIRKO still mounts an impressive GSIS despite pumping out a lot of basal insulin.  What is different here?  Well,

LIRKO supports "It's all about the NEFA"  The LIRKO mouse is a sick mouse alright and doesn't fare well as it ages.  But the one thing LIRKO is not lacking is pancreatic function.  They have super pancreata!!  They produce both basal and glucose stimulated insulin admirably, something Type 2's don't do from earlier on than is often recognized.  The basal hyperinsulinemia in T2 is often accompanied by impaired GSIS.  Why?  Well, the study in the previous paragraph holds the clue.  It is the elevated NEFA that leads to interfering with the insulin production machinery.   This may be due to excessive buildup of fatty acids in pancreatic cells as well (recall the "crash diet" study? Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol )   But LIRKO has no such problem because if anything, NEFA are suppressed and properly tucked away where they are supposed to be stored when insulin is functioning properly at the adipocyte level.