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.
Monday, April 28, 2008
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Cari Hartman Loses the Diet
Cari Hartman has lost 123 pounds. She is being featured on the Today Show this morning. She lost the weight, not by going on a diet, and not by counting calories, but by making a complete lifestyle change. She joined a fitness center, quit fast food, quit drinking tons of Diet Cokes each day and started eating real meals and taking her lunch to work. See her inspirational weight loss story here.
The photo of a portable lunch is by moira.
Sunday, April 27, 2008
Book Review: Blood Sugar 101
I just finished reading "Blood Sugar 101" by Jenny Ruhl. It's a quick read, and very informative. Ruhl is a diabetic who has taken treatment into her own hands, using the scientific literature and her blood glucose monitor to understand blood sugar control and its relationship to health. The book challenges some commonly held ideas about diabetes, such as the notion that diabetics always deteriorate.She begins by explaining in detail how blood glucose is controlled by the body. The pancreas releases basal amounts of insulin to make glucose available to tissues between meals. It also releases insulin in response to carbohydrate intake (primarily) in two bursts, phase I and phase II. Phase I is a rapid response that causes tissues to absorb most of the glucose from a meal, and is released in proportion to the amount of carbohydrate in preceding meals. Phase II cleans up what's left.
In a person with a healthy pancreas, insulin secretion will keep blood glucose under about 130 mg/dL even under a heavy carbohydrate load. The implications of this are really interesting. Namely, that blood glucose levels will not be very different between a person who eats little carbohydrate, and one who eats a lot, as long as the latter has a burly pancreas and insulin-sensitive tissues.
Most Americans don't have such good control however, hence the usefulness of low-carbohydrate diets. This begs the question of why we lose blood sugar control. Insulin resistance seems like a good candidate, maybe preceded by leptin resistance. As you may have noticed, I'm starting to think the carbohydrate per se is not the primary insult. It's probably something else about the diet or lifestyle that causes carbohydrate insensitivity. Grain lectins are a good candidate in my opinion, as well as inactivity.
Diabetics can have blood glucose up to 500 mg/dL, that remains elevated long after it would have returned to baseline in a healthy person. Ruhl asserts that elevated blood sugar is toxic, and causes not only diabetic complications but perhaps also cancer and heart disease.
Heart attack incidence is strongly associated with A1C level, which is a rough measure of average blood sugar over the past couple of months. It makes sense, although most of the data she cites is correlative. They might have seen the same relationship if they had compared heart attack risk to fasting insulin level or insulin resistance. It's difficult to nail down blood sugar as the causative agent. More information from animal studies would have been helpful.
Probably the most important thing I took from the book is that the first thing to deteriorate is glucose tolerance, or the ability to pack post-meal glucose into the tissues. It's often a result of insulin resistance, although autoimmune processes seem to be a factor for some people. Doctors often use fasting glucose to diagnose diabetes and pre-diabetes, but typically you are far gone by the time your fasting glucose is elevated!
I like that she advocates a low-carbohydrate diet for diabetics, and lambasts the ADA for its continued support of high-carbohydrate diets.
Overall, a good book. I recommend it!
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