Metformin

Metformin (brand name Glucophage) is a member of the class of antidiabetic drugs called biguanides. Unlike the sulfonylureas such as glipizide, metformin does not decrease blood glucose by increasing the plasma concentration of insulin. Instead it works in several other ways to accomplish its purpose.

Metformin exerts its main effect, suppression of gluconeogenesis, by inhibiting the ATP production of the mitochondrial respiratory chain. Mitochondria are little organelles inside most of the cells of our bodies. Their job? To convert the precursor molecule ADP (adenosine diphosphate), into ATP (adenosine triphosphate), a molecule that is used to provide the energy required for many metabolic processes. Our bodies produce a little ATP by breaking down glucose in a process called glycolysis. But most of our ATP is provided when two-carbon units enter the tricarboxylic acid (TCA) cycle and are burned in the mitochondrial respiratory chain to produce carbon dioxide and water. From that link, here is a pictorial representation of the mitochondrial respiratory chain.


When metformin interferes with the conversion of ADP to ATP, the ratio of ATP to ADP decreases. When this ratio decreases, there is a resultant decrease in the activity of pyruvate carboxylase, which is the first enzyme used in the process of gluconeogenesis. The inhibition of pyruvate carboxylase significantly decreases the amount of gluconeogenesis the liver can perform. As we have seen previously, when the liver becomes insulin resistant, it will raise blood glucose by continuing to do gluconeogenesis even when blood sugar levels are normal. Although metformin does nothing directly to reverse insulin resistance in the liver, it is able to use the complex series of events beginning with the inhibition of ATP production in mitochondria to partially block the synthesis of excess glucose by the liver.

(As an aside, the inhibition of gluconeogenesis may cause an increase of lactic acid in the blood, lactic acid being one of the building blocks used for gluconeogenesis. In extreme cases this can lead to lactic acidosis, but the phenomenon is relatively rare with metformin.)

The second major effect of metformin is that it is able to decrease blood glucose by improving glucose uptake in muscle cells. Glucose cannot pass into muscle cells simply by diffusion; it requires specfic transport proteins to carry it into the cell. Studies have shown that metformin increases the number of the glucose transporters GLUT1 and GLUT4 in the plasma membrane of muscle cells. More glucose transport proteins means more glucose can be moved into insulin-resistant muscle cells, which in turn lowers blood glucose.

Although metformin has several other actions that reduce blood glucose, these two are the major ones. Unlike injected insulin, or oral drugs that increase insulin secretion, metformin does not cause an increase in insulin resistance, nor does it cause weight gain. However, it is important to note that metformin does not reverse insulin resistance. It simply acts to lower blood glucose in a non-insulin dependent manner.

Alcohol and the Low-Carb Lifestyle

About six weeks ago, Woodswalker asked me to write a post addressing the role of alcohol in a low-carb diet. This is a huge topic, but I will present a few thoughts for consideration. If you have questions or comments, please remember that I am a biochemist, not a psychiatrist.

Alcohol, also known as ethanol, contains seven calories per gram. That's somewhat less than fat at nine calories per gram, and quite a bit more than carbs and protein at four calories per gram. Pure grain alcohol contains zero carbs. It is not an essential food. The metabolism of ethanol is fairly straightforward.

The first pathway happens mainly in the liver and is constitutive. ADH is the enzyme alcohol dehydrogenase. ALDH is the enzyme acetaldehyde dehydrogenase, and TCA stands for the tricarboxylic acid (Krebs) cycle. The second pathway is also found in the liver and is inducible--that is, it can be upregulated if the body is required to detoxify large amounts of alcohol on a consistent basis. MEOS stands for mitochondrial ethanol oxidizing system.

If a meal is consumed that contains alcohol, carbs, protein and fat, the calories from the alcohol will be processed first. This means that fat will not be used for energy until all the calories from the ingested alcohol have been burned. If a signficant number of calories of alcohol are ingested, this will postpone or even prevent fat burning. Drinking hard (i.e., distilled) liquor by itself does not affect insulin secretion, but when hard liquor is consumed with food, it increases insulin resistance and insulin secretion. Hard liquor also contains quite a few calories per ounce. By contrast, an ounce of mixed drinks, wine or beer will have fewer calories from ethanol. However, mixed drinks, wine and beer all contain carbohydrates, and, if they are consumed in quantity, will result in insulin secretion and eventual weight gain.

According to Dr. Michael Eades (see the comment at 31 October 2008, 21:34), a single glass of dry wine per day can improve insulin sensitivity and can assist with weight loss. For those who can stop at one glass of wine, that's great. But remember that alcohol is a psychoactive drug, and as such, it lowers inhibitions. In the low-carb context, it is important to note that alcohol can lower inhibitions against consuming carbs, and inhibitions against consuming a second glass of wine as well.

Alcohol stops gluconeogenesis. Gluconeogenesis is the process used by the liver to keep blood glucose levels within normal limits. If a person consumes lots of carbohydrates, an alcohol-induced cessation of gluconeogenesis will probably not even be noticed. However, if a person consumes alcohol while doing very low-carb, he is likely to experience a fall in blood sugar followed by a compensatory release of adrenaline. This can lead to heart palpitations which will be relieved by drinking orange juice or eating a high-glycemic food. Unfortunately, this regimen is not conducive to longterm success on a low-carb diet. If a low-carber notices that alcohol consumption is followed by the symptoms of low blood sugar, it may be necessary for him to drink less than a full serving to minimize the undesirable side effects.

More on Insulin Control

The previous post discussed a three-legged stool approach to dealing with reactive hypoglycemia. The three legs of the stool are critical for lowering blood insulin and restoring insulin responsiveness. They are:

-Eating low-carb
-Eating moderate protein
-Waiting 5-6 hours between meals

Overall, these three appear to be the most important strategies for lowering blood insulin and restoring insulin responsiveness. However, a scan of low-carb websites suggests some additional ideas for improving insulin control.





-Avoid "sweet"
For 18 days Jimmy Moore did a "Sweet"-Free Challenge. He avoided all artificial sweeteners, including those in diet soda. The taste of sweet, even if it comes in a zero-calorie product, can be enough to trigger an insulin release from the pancreas.

-Be careful with alcohol
Dr. Mike Eades discusses alcohol consumption in the comments section of a recent post at his blog. In response to a commenter, Lowcarb convert, Dr. Mike says Studies have shown that a glass of wine per day helps with weight loss, but if you can’t stop with just one - and I’m one of those who has difficulty in doing so - cold turkey may be the better strategy. In response to that, another poster, Tom, says For me, wine is a gateway drug…to carbs! Alcohol lowers inhibitions, including inhibitions against eating carbs, and eating carbs leads to the release of insulin. A word to the wise is sufficient.

-When you eat carbs, make them low-glycemic carbs
Dr. William Davis discusses Quieting the insulin storm in a recent post at his blog. He points out that some foods, like wheat and cornstarch, have a higher glycemic index than table sugar. The higher the glycemic index, the more rapidly blood sugar will rise, and the more insulin will be released by the pancreas in response.

-Eat healthy fats at every meal
Healthy fats make up the caloric difference between an individual's daily caloric need and the calories provided by low carbs plus moderate protein. Fats provide energy, promote satiety and can be consumed with no insulin required whatsoever.

-Avoid eating a large volume of food at one sitting
In his book The Diabetes Solution, Dr. Richard Bernstein discusses the fact that simply overstretching the stomach causes the release of insulin. This effect happens without reference to what type of food is consumed. It occurs whenever the stomach has been distended--by overeating or by eating large servings of high fiber foods. (According to Dr. Bernstein, it even happens when the stomach is distended with air.) To avoid oversecreting insulin, it is preferable to avoid eating one large meal and two small ones, but instead keep all three meals at a similar volume of food.