Monday, April 28, 2008

The Liver: Your Metabolic Gatekeeper

As I've been learning more about the different blood markers of metabolic dysfunction, something suddenly occurred to me. Most of them reflect liver function! Elevated fasting glucose, low HDL cholesterol, high LDL cholesterol, high triglycerides and high fasting insulin all reflect (at least in part) liver function. The liver is the "Grand Central Station" of cholesterol and fatty acid metabolism, to quote Philip A. Wood from How Fat Works. It's also critical for insulin and glucose control, as I'll explain shortly. When we look at our blood lipid profile, fasting glucose, or insulin, what we're seeing is largely a snapshot of our liver function. Does no one talk about this or am I just late to the party here?!

I read a paper today from the lab of C. Ronald Kahn that really drove home the point. They created a liver-specific insulin receptor knockout (LIRKO) mouse, which is a model of severe insulin resistance in the liver. The mouse ends up developing severe whole-body insulin resistance, dramatically elevated post-meal insulin levels (20-fold!), impaired glucose tolerance, and elevated post-meal and fasting glucose. Keep in mind that this all resulted from nothing more than an insulin resistant liver.

LIRKO mice had elevated post-meal blood glucose due to the liver's unresponsiveness to insulin's command to take up sugar. Apparently the liver can dispose of one third of the glucose from a meal, turning it into glycogen and triglycerides. The elevated fasting glucose was caused by insulin not suppressing gluconeogenesis (glucose synthesis) by the liver. In other words, the liver has no way to know that there's already enough glucose in the blood so it keeps on pumping it out. This is highly relevant to diabetics because fasting hyperglycemia comes mostly from increased glucose output by the liver. This can be due to liver insulin resistance or insufficient insulin production by the pancreas.

One of the interesting things about LIRKO mice is their dramatically elevated insulin level. Their pancreases are enlarged and swollen with insulin. It's as if the pancreas is screaming at the body to pick up the slack and take up the post-meal glucose the liver isn't disposing of. The elevated insulin isn't just due to increased output by the pancreas, however. It's also due to decreased disposal by the liver. According to the paper, the liver is responsible for 75% of insulin clearance from the blood in mice. The hyperinsulinemia they observed was both due to increased secretion and decreased clearance. Interestingly, they noted no decline in beta cell (the cells that secrete insulin) function even under such a high load.

Something that's interesting to note about these mice is they have very low blood triglyceride. It makes sense since insulin is what tells the liver to produce it. Could this have something to do with their lack of beta cell dysfunction?

The really strange thing about LIRKO mice is that their blood glucose becomes more normal with age. Strange until you see the reason: their livers are degenerating so they can't keep up glucose production!

LIRKO mice reproduce many of the characteristics of type II diabetes, without degenerating completely into beta cell death. So insulin resistance in the liver appears to reproduce some elements of diabetes and the metabolic syndrome, but the full-blown disorders require other tissues as well. As a side note, this group also has a skeletal muscle-specific insulin receptor knockout which is basically normal. Interesting considering muscle tissue seems to be one of the first tissues to become insulin resistant during diabetes onset.

So if you want to end up like your good pal LIRKO, remember to drink high-fructose corn syrup with every meal! You'll have fatty liver and insulin resistance in no time!

I have a lot more to say about the liver, but I'll continue it in another post.

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