My Nortorous and Evil Liver

[Ronin]

Fellow Pre-D's, et al.,

I've been reading through a lot of research papers on both Diabetes and the "Metabolic Syndrome." Considering the complexity of organs, hormones, and enzymes involved it is a miracle that the process works at all.

I did have a blinding-flash of understanding of why the powers-at-be (the ADA, et al) have come up with our diagnosis of Pre-Diabetic. The reason is that we're probably actually in the early stages of the "Metabolic Syndrome." While Type-1 and 1.5 diabetics have a non-functioning pancreas (or at least non-functioning beta-cells) our Pancreatic functions don't seem to be triggering the system in quite the way it should be working, or perhaps it is really the Liver that is the crux of the problem.

My first indication of the "Metabolic Syndrome" was actually with my Lipid Levels which were quite high almost 20 years ago and I managed through diet, exercise, and Statin drugs (currently Zocor) I managed to get cholesterol into the good-to-excellent range. I thought that carbohydrates were the best thing in the world and could eat them with abandon. I have all kinds of fat-free recipies that have moderate to huge doses of carbs. Little did I know that I was falling into "The Metabolic Trap."

I can say that, from what I have read to date, the real culprit seems to be the regulatory mechanism that sets and maintains the BG levels.

A lowered carbohydrate diet tends to pull the setting down when combined with lots of exercise. But, if I stray or don't exercise my Liver builds up a large store of glycogen and gives me a wham in the morning.

I guess that I have to deal with the fact that I am the owner of a Notorious and Evil Liver. :eek:

[BlueSky]

.... I guess that I have to deal with the fact that I am the owner of a Notorious and Evil Liver. :eek:
Lets be fair here :D . Your liver is doing what it has alwyas done, which is exactly what it is supposed to do. It releases stored glycogen into the blood stream in response to well defined triggers. Everything would be fine if it wasn't for insulin resistance. It is the inability to efficiently metabolise this glucose that makes your blood sugar go up. And it really isn't your livers fault. The raised level of blood glucose means that the liver turns more of it into triglycerides, increasing lipid levels. Once again, the liver is only doing wjhat it is supposed to do. Insulin resistance is the root cause of these problems.

[Ronin]

Hi BlueSky!

I've been hearing the "Insulin Resistance" argument for some time. While it is the common knowledge, I'm having more and more questions. Why? Largely because the chemical mechanisim that triggers the liver and pancreas is extremely complex.

Ever since Type-2 Diabetes was identified the term Insulin Resistance was put into use. (I know because my father was a Type-2 and I heard the term spoken back then.) When I read about IR all I hear is: lose weight (I did and am now a bit below what is normal for my height), exercise (I do 90+ minutes per day at a very high intesity), curb your carb intake (I have dropped the intake by over 50%). I'll admit that I haven't had the C-Peptide test yet so I'm not sure of my insulin output.

I'm raising a question because there is just too much "common knowledge" in the area that does not seem to be supported by scientific research.

I found the same thing in the area of cholesterol management until statin drugs were introduced. It was all about diet and exercise (which do contribute to the condition). However, statins are directed at the trigger mechanisim in the liver that sets what levels of lipids are maintained. (Oh yes, there is a glucose connection here.)

While you are a Type-1, and pretty well informed, I still have questions. What about the liver issue, and the Metabolic Syndrome? It seems that there is something going on that goes beyond simple diet and exercise. Perhaps, like lipids the seat of the problem is a liver that is not functioning as planned.

The one surprise I have had in my research is that, like lipid production, the liver will make glucose when signaled by the alpa-cells from the pancreas. I've even read Bernstein on this aspect of glucose management so aparently even a Type-1 has working alpha-cells directing the liver to make glucose from other sources.

There are still questions to be answered.

[Ronin]

Everyone:

I've been thinking more-and-more about this whole issue and BlueSky's response citing "Insulin Resistance" as "The Cause."

At the crux of the IR argument is that something in the body is resistant to the signal that insulin sends out, and perhaps even the other signaling hormones and enzymes. What organ is the "master control?" Well, it is that chemical factory we call the Liver.

Muscle cells, brain cells, all the cells, for that matter, use glucose for energy in that process called the "Krebbs Citric Acid Cycle" that converts ADP back into ATP for the cells to use for energy and are returned to the mitochondria for re-processing. Are these cells unable to use glucose in the presence of insulin? Given the effect of exercise on BG levels that would not seem to be the case, and if they were not able general loss of energy and eventual death would be the result. So, what is not responding to the presence of Insulin? The Liver comes to mind again. Insulin is supposed to cause the liver to take glucose out of the blood stream and convert it into glycogen for storage and later use. This is to be stored first in the liver and then in the fat cells when the storage capacity of the liver is exceeded. Converseley, when the Pancreas secretes glucagon (or the adrenal glands secrete adrenelin, or the muscles secrete Lactic Acid, or Cortisol increases) the liver is to release glucose into the blood stream to provide additional energy.

Finally, unprocessed glucose at extreme levels for extended periods of time is proven to be toxic and lead to the diabetic complications we already know about.

From my perspective I draw two conclusions:

1. We live in an energy rich world and we tend to over-eat, usually out consuming our total daily requirements in a single meal, and sometimes in a single sports drink.

2. Something goes screwy in the singaling mechanism between the liver and other organs in the body that causes the body not to properly respond to the signals sent by the body for the liver to make the conversions and withdraw glucose from the blood stream when BG levels are too high.

What do we need to do? Well, restrict caloric intake to equal to or less than requirements while trying to match ingestion of high glucose/glycemic foods to immediately pre or during exercise/exertion. [Note: I tend to have anerobic periods while bicycling so I release lactic acid which causes my liver to dump glucose hence my post-exercise BG levels tend to be higher than pre-exercise/exertion. Any anerobic exercise (where you feel the burn) will do the same thing.] Post exercise/exertion meals should be high in protien and still keeping the daily intake of calories to equal to/less than requirements.

I still say the the liver is the key for us Pre-D's and Type-2's something more than just glucose processing is going wrong and the signaling system is broken. I don't know how to restore it, but that would be "the cure" and if I had it I'd be rich.

[REDLAN]

Are these cells unable to use glucose in the presence of insulin?

Actually they are unable to absorb glucose without the presence of insulin. Insulin turns on GLUT4 receptors - and glut4 receptors are found on muscle and fat cells. I'm pretty sure insulin isn't required to metabolise glucose once it is inside the cell.

GLUT4 - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/GLUT4)

I believe that about 75% of your body's supply of glucose is used by muscles - and I believe I'm right in saying that it is poor glucose uptake by muscles is the main cause of insulin resistance.

there are multiple protein cytokines that alter the way that the body responds to insulin - and I would suggest that many of them are poorly understood.

Anything that affects glut4 expression or glut4 activation by insulin will increase insulin resistance.

and now we have a simple model for why exercise benefits type 2 diabetes and helps lower insulin resistance.

and it's all down to this baby AMP-activated protein kinase - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/AMP-activated_protein_kinase)

AMPK as it is known is very sensitive to AMP to ATP concentrations. When the muscles are stimulated the AMP concentration rises, ATP concentration decreases and AMPK stimulates the cell to produce more GLUT4 - more GLUT4 lowers your insulin resistance, with the bonus that it lasts for several hours.

I also personally believe that adiponectin (produced by fat cells), may be important in determining the body's long term insulin resistance, and is important in the body's regulation of total fat

Adiponectin - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Adiponectin)

there is however very little concrete research into this hormone and it's regulatory function, but adiponectin is known to stimulate AMPK, and plasma levels of adiponectin are low in type 2 diabetes and people who are obese.

Adiponectin levels are known to rise rapidly during calorie restriction - and here the potential for another simple model explaining why dieting works for type 2 diabetes.

calorie restriction stimulate fat cells to produce adiponectin. adiponectin mobilises fat stores and stimulates AMPK, which in turn causes increased oxidation of fatty acids, and lowers insulin resistance - this however is purely a theory and requires independent experimental verification.

Also the body has multiple intertwined regulatory systems which push the body towards anabolism (energy storage) or catabolism (energy burning) - any defect or change in any one of these systems can alter the body's response to regulatory hormones such as insulin.

for instance there is a fairly recent study about the regulatory effects of bone tissue on adiponectin production by fat cells.

I personally believe that type 2 is primarily a metabolic condition, and that the factors that are said to cause type 2, in particular obesity, are in fact a symptom of an underlying medical condition.

[BlueSky]

... Muscle cells, brain cells, all the cells, for that matter, use glucose for energy .... Are these cells unable to use glucose in the presence of insulin? ....
Hey Ronin,

Perhaps a more pertinent question would be : "Why are these cells not able to use glucose in the presence of insulin". And maybe the answer is simply because there is nothing they can do with this glucose. Glucose can't be stored in these cells. And too much glucose in the cell would be toxic. So cells will only admit glucose they can use pretty much straight away. And, in the presence of abundant glucose they use a clever mechanism to protect themselves. The number of insulin receptors on the cell surface is down-regulated. And glucose sloshing around in the blood stream can't get in. The wellbeing of the cell is protected, albeit at the expense of increased insulin resistance and maybe even raised blood glucose.

The role of the liver in all this is to turn excess glucose into triglycerides so it can be stored as fat. Mmmm ... both very high triglycerides and excess weight are symptoms of the Metabolic Syndrome that you were talking about. And high insulin levels are thought to be a cause of high blood pressure, too. :D

[Tropo]

I guess that I have to deal with the fact that I am the owner of a Notorious and Evil Liver. :eek:

Hello everyone, this is my first post on this forum, and Ronin's post really caught my attention because I've had a problem with BG that was a direct result of a liver condition.

Back in June 2005 I came down with a serious case of drug-induced cholestasis (liver). I was living in the Philippines at the time (I'm Australian) and visited my doctor several times for severe systemic pruritus. He didn't know what it was, but about 5 days later when my girlfriend remarked that I was very yellow I knew I had jaundice and told my doctor who immediately scheduled some liver tests.

My bilirubin levels were through the roof and I was glowing a bright yellow and couldn't sleep due to my severe pruritus. It was **** on earth and persisted for over 2 months.

Anyway, to cut a very long story shorter, I visited a specialist (Internal Medicine) who scheduled a routine blood glucose test (fasting) along with the standard liver tests.

My fasting BG was through the roof at 212 (11.78) . 2 weeks later it was up to 255 (14.17)!

Stangely I was the one who had to bring the high BG levels to my doctor's attention. I later found out he was a diabetic himself, yet he didn't seem concerned about the readings (wonderful doctors in the Philippines). Perhaps he was too distracted by my liver condition or hoped that the BG would return to normal once my liver did.

Up until that day (age 45) I had never had a BG test, so I knew very little about diabetes and had absolutely no idea of what my usual readings were before I became ill.

I searched high and low on the Internet to find some connection between my high BG and my liver condition hoping all the while that I didn't have diabetes and that my BG would return to normal once my liver did (I had confidence that it would).

I came up empty handed until I read Ronin's post here.

To continue, I started taking diabetic medication to lower my BG. I used a combination of Metformin and Daonil. I was feeling far too ill at the time to exercise so I had to rely solely on the medication.

Here's a brief chronology of events:

Diagnosis of liver condition (cholestasis) about June 10

First BG reading: 28 June 05: 212 (fasting 12 hours)
Second BG reading: 11 July 05: 255 (fasting)

After those I bought my own glucose meter and started testing myself daily.

12 July 05: PP (2 hour) = 251

13 July: 224 (fasting)
14 July: 202
15 July: 229

After that it started to decrease quickly with medication.

16 July: 177
17 July: 165
18 July: 159

(skipping ahead)

21 July: 130
22 July: 124
23 July: 143

Over the following week there was little change but I started to exercise then, and on the 31st July I reduced my medication by half.

My liver metabolism was not good, but improving. My jaundice was improving and bilirubin levels were dropping fast. My stools were returning to normal (getting darker). Due to my liver condition, I still found it difficult to digest fat.

2 August: 130
4 August: 111

I reduced my medication again, and at this stage I started taking only 1 metformin in the evening before bed.

9 August: 114
11 August: 122

At this stage I was doing a lot more exercise (gym, swimming, walking), so I decided to experiment and dropped the diabetic medicine completely.

Over the next month without medication my fasting BG ranged from 118 to 132.

Another month later my readings were always in the 115-120 range.

At that stage I was feeling healthy again, and my liver readings were normal. I became preoccupied with other things and stopped testing my BG for a while.

At the end of 2005 I was getting readings consistently in the 110 - 115 range and post prandial readings were always normal.

That was the end of my BG testing until June this year.

The last 3 months of testing have yielded fasting levels as low as 106, and up to a high of 124 (once)...averaging around the 115 mark.

For example, today my fasting level was 110.

My 1-hour PP after a big meal heavy in carbohydrates (rice) was 135, and my 2-hour PP was 108.

In the last 3 months I've never had a 1-hour PP above 140, or a 2-hour PP above 120 no matter what I eat...even with a decent serving of ice cream.

I can only conclude that my liver had an enormous affect on my BG levels when I was suffering from cholestasis, and there must be some truth to Ronin's theories.

Sorry for the long post. :)

[BlueSky]

Wecome to the forums. That is an interesting story. Have you actually been diagnosed as diabetic or pre-diabetic?

[Tropo]

Hi BlueSky.

I have now diagnosed myself as being pre-diabetic on the basis that my FBG is always over 100. I've never done a formal GTT, but I keep an eye on how I respond to food. So far I've been lucky in that my PP levels are in the normal range.

Previous to my illness I'd never had a Blood Glucose test. On hindsight I wish I'd had an AC1 test as I have no idea how long my BG had been elevated. In the hospital in the Philippines where I had my tests I'm not sure if they even had that one on their list...but to be honest, at the time I was suffering so much from my liver condition that my BG was only a secondary concern.

My eyesight definitely deteriorated at that time (and hasn't recovered) so maybe my BG had been elevated for quite a while....I'll never know.