Metformin, the Liver, and Diabetes

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Most people think diabetes comes from pancreas damage, due to autoimmune problems or insulin resistance. But for many people diagnosed “Type 2,” the big problems are in the liver. What are these problems, and what can we do about them?

First, some basic physiology you may already know. The liver is one of the most complicated organs in the body, and possibly the least understood. It plays a huge role in handling sugars and starches, making sure our bodies have enough fuel to function. When there’s a lot of sugar in the system, it stores some of the excess in a storage form of carbohydrate called glycogen. When blood sugar levels get low, as in times of hunger or at night, it converts some of the glycogen to glucose and makes it available for the body to use.

Easy to say, but how does the liver know what to do and when to do it? Scientists have found a “molecular switch” called CRTC2 that controls this process. When the CRTC2 switch is on, the liver pours sugar into the system. When there’s enough sugar circulating, CRTC2 should be turned off. The turnoff signal is thought to be insulin. This may be an oversimplification, though.

According to Salk Institute researchers quoted on RxPG news, “In many patients with type II diabetes, CRTC2 no longer responds to rising insulin levels, and as a result, the liver acts like a sugar factory on overtime, churning out glucose [day and night], even when blood sugar levels are high.” Because of this, the “average” person with Type 2 diabetes has three times the normal rate of glucose production by the liver, according to a Diabetes Care article.

Diabetes Self-Management reader Jim Snell brought the whole “leaky liver” phenomenon to my attention. He has frequently posted here about his own struggles with soaring blood sugars that were not controlled by 75/25 insulin, pioglitazone (brand name Actos), nateglinide (Starlix), and glyburide (Micronase, Diabeta, Glynase, Prestab). All the medicines were overwhelmed by his liver’s dumping glucose.

The best tool medicine has found for controlling the liver is metformin. Metformin has been known for decades; it has been the first-line oral diabetes medicine in the United States since the 90’s. But until recently, we really haven’t understood how it works, so it has usually not been used to best advantage.

Metformin prevents the liver from dumping more glucose into the blood. Scientists used to think it worked by telling CRTC2 to cooperate with insulin (in other words, reducing insulin resistance.) But new studies have found that metformin actually works by bypassing CRTC2 and directly telling the liver cells to hold the sugar.

So if your CRTC2 switch is busted, you need some metformin in your blood at most times, to prevent the liver’s dumping glucose. Jim discovered this one night when he forgot his dinnertime metformin and took it at bedtime instead. In the morning, he had very little dawn effect; his morning sugars were much better. Working with his doctor, he figured out that taking 500 milligrams of metformin at 10 PM and another 500 milligrams at midnight kept his sugars down until 5:30 AM.

It seems that for people whose leaky livers are the main factor in their sugar levels, taking 500 milligrams of metformin four or five times a day might be optimum. But everyone’s different, and it takes some work (with your doctor) to find what pattern works best for you.

Metformin takes a couple of hours to fully absorb, and lasts about five hours in most people. (Half-life in the body is about six hours.) There is also an extended release form that can be taken once or twice a day.

What causes leaky livers in the first place is not really known. It seems that people with fatty livers may be up to five times as likely to develop diabetes, so liver fat, which is loosely associated with abdominal fat, may be part of the story. But thin people can have leaky livers, too, so there’s more to it.

It might help to learn when your liver tends to dump sugars. This might require frequent monitoring for a while. Jim has a continuous glucose monitor, which enabled him to get his regime right. According to him, if his sugar goes low, or his metformin level goes low, or sometimes after eating (for some unknown reason), his liver will dump glucose into his bloodstream, as he can see on his monitor. The only thing that stops it is having enough metformin in his system. (I’m sure Jim will correct any mistakes I’ve made in the comments section.)

People without diabetes sometimes take metformin for weight loss or for conditions like polycystic ovary syndrome (PCOS). It’s one of the best, most affordable and most successful chemical medicines ever invented.

When the dose is too low, however, it may not seem to work at all. Bottom line is that many people with diabetes may not be getting enough metformin or not getting it at the right times. You might be one of them, especially if you have a dawn effect, especially if you’re already on a basal insulin.

There is a lot more to learn and say about these topics, but I want to hear from you first. Does any of this ring a bell for you? What have been your experiences?

Want to learn more about this popular diabetes drug? Read “Diabetes Medicine: Metformin,” “Metformin: The Unauthorized Biography,” and “Metformin Smelling Fishy? What You Can Do,” then take our quiz, “How Much Do You Know About Metformin?”

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