Diabetes in Pregnancy - 2 - Glucose Metabolism and Insulin Action
Saturday, August 04, 2007
Kenneth F. Trofatter, Jr., MD, PhD
Glucose is one of the primary substrates for the production of energy in cells throughout our body, especially, in the brain, muscles, and kidneys. The two main sources of glucose are dietary carbohydrates, primarily, starches (large “sugar” polymers, or complex carbohydrates) from fruits, vegetables, and grains, and disaccharides (made up of only two “sugar” molecules), such as lactose from milk and sucrose from refined sugars. Through the digestion of these carbohydrates in the gut, they are first broken down to monosaccharides (single “sugar” molecules) before they can be absorbed. Once they cross the gut wall, these monosaccharides are transported via the blood to the liver where they are all converted into glucose molecules (also a monosaccharide). The other monosaccharides cannot be used for ‘fuel’ until they are converted into glucose, therefore, the liver’s role is pivotal in the distribution of this primary source of energy to other body tissues.
Once glucose has gotten into cells, several things can happen to it. First, if the cell needs ‘energy’, glucose can be broken down by a series of enzymes that ultimately results in the production of two molecules of pyruvate. (Pyruvate is the substrate for many important reactions that are not necessary for our discussion herein). As a consequence of the production of pyruvate from glucose, there is also the concomitant net production of two molecules of ATP (adenosine triphosphate) which is the common source of ‘fuel’ for most of the metabolic processes in the cell. Secondly, if there is more glucose than the cell needs, glucose can be converted to glycogen (a polymer of glucose) and stored in that form. Only the liver and muscles have the capability to make and store glycogen (interestingly, the brain does not!) but they are limited in how much they can store. Glycogen can rapidly be converted back to glucose when the need arises. Thirdly, if there is an excess beyond the capacity of the liver and muscles to store glycogen, glucose can be converted into ‘fatty acids.’ Fatty acids are stored in fat (adipose) tissues as triglycerides.
So, where does insulin fit into this picture? Well, none of the events above can occur unless glucose can actually get into the cell in the first place. Among insulin’s many functions, its primary role for sake of our discussion is to enhance the ability of cells to get glucose from the blood into the cell. Under normal circumstances, insulin secretion by the pancreatic β-cells in the islets of Langerhans is proportional to the amount of glucose in the blood within a very tight ‘normal’ range for blood glucose levels. (Actual production of insulin within the β-cells is under the influence of many different hormones, including several pregnancy-related hormones). Once insulin is secreted, it is transported in the blood and binds to specific receptors on the cell membrane. Binding of insulin to the cell membrane results in signals that activate several different metabolic processes (specific to the cell type to which the insulin has bound).
One of the messages that insulin sends to the cell by binding to it is to increase the number of plasma membrane glucose transporters, or GLUTs. GLUTs are stored in the cell and are ‘recruited’ to move to the cell membrane by the action of insulin. Once there, they facilitate the transport of glucose from the blood into the cell. GLUTs are continuously being ‘turned over’ and they only hang around in the cell membrane as long as enough insulin is bound to the cell to keep them there. Different GLUTs with different affinities for glucose, characteristically, reside in different tissues: GLUT1 is present in most tissues, GLUT2 is present in liver and pancreatic β-cells, GLUT3 is found in the brain, and GLUT4 is found in the heart, adipose tissue and skeletal muscle. In addition to enhancing glucose transport, insulin stimulates glycogen and fat production, increases amino acid transport into cells, promotes the transcription of specific gene products, and stimulates growth, DNA synthesis, and cell replication.
In our next post, we will discuss how pregnancy alters the ‘normal’ state of affairs with regard to insulin production and action…
5 Comments:
At Mon Aug 20, 05:38:00 PM 2007,
Izzi R. said…
Hi Dr. Trofatter,
Back in June, I responded with a question about the connection of PAI 1 and recurrent early pregnancy loss (Recurrent Early Pregnancy Loss Immunologic and Hematologic Causes #&). You mentioned that you would dedicate an article about this in the near future. If you've done this article, then I've not been able to find it and would love if you could guide me to it! If you've not had time to respond just yet, then I have yet another question. My last miscarriage was in February. I am a teacher trying to take advantage of a relaxing summer and have been trying to get pregnant all summer- since the beginning of June...using ovulation sticks. Does PAI 1 have anything to do with me not being able to conceive? I've mentioned to two of my doctors the connection of pcos and pai 1 and they all agree that I do not fit any of the symptoms of pcos; however, after asking for a glucose/insulin test, I am now scheduled to get a glucose/insulin test (fasting and blood work, then 1 and 2 hour blood test after sugar mixture water). Do you think this is a good step? I know that PAI 1 has something to do with insulin which has to do with the endocrine system which can affect ovulation. I've never had issues in the past getting pregnant (just maintaining my pregnancy- 3 miscarriages)as I have this time. I do not have diabetes. Any advice would be greatly appreciated! No matter how much I try to research PAI 1 and RPL, I can’t seem to understand it. Thanks so much for your time! I.R.
At Tue Aug 21, 06:07:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Hi I.R.: No I haven't forgotten you. Just have been so busy lately and your situation requires more thought than the average one. You have figured that out yourself because of the trouble you've had sorting out the literature! I will try to put something together just for you in the next couple of weeks. Thanks for being so patient! P.S. Let me know the results of your test. You may be grasping at straws, but then again, you may be on to something! Dr T
At Tue Sep 11, 02:46:00 PM 2007,
Anonymous said…
Hi Dr. Trofatter,
Low and behold, after a few months of asking for an insulin/glucose test, my wish was granted last week. I received my results yesterday and both fasting tests were normal and my two hour glucose was normal as well; however, my two hour insulin levels were elevated which is evidence of insulin resistance. I have to say that I am frustrated simply because I have mentioned the correlation of PAI 1 and insulin to my doctors a couple of times before but was essentially dismissed because I don't fit the "criteria" of a person who has insulin resistance. I'm not overweight at all and I'm not inactive. I just wish that my RE understood more about PAI 1, especially since he has a patient with PAI 1! I start glucophage with hopes of increasing the quality of my ovulation. I do ovulate "regularly" on CD 15. What are your thoughts of taking glucophage/ metformin while pregnant? ...I know that it is controversial either way. I would appreciate any insight about the connection of PAI 1 and early trimester pregnancy loss as well as its connection to insulin.
Hope you're doing well! IR
At Wed Sep 12, 04:44:00 PM 2007,
Kenneth F. Trofatter, Jr., MD, PhD said…
Hi IR: I respect your persistence. Since I keep getting sidetracked from answering your questions related to PAI 1, let me at least summarize my thoughts. I would continue the metformin at least through first trimester. There indeed appears to be a need to increase insulin sensitivity in first trimester to aid in proper implantation and placentation. I bet you will be home free from the baby's standpoint if you can get past twelve weeks. You will still be at increased risk for gestational diabetes. Why you're at it, why don't you throw the progesterone support, baby aspirin, extra folic acid, and heparin or Lovenox into the mix as well. The latter I would not begin until a pregnancy is confirmed chemically (just about the time you miss a period). I promise, again, to tell you what I know about PAI 1 whenever I can get a long enough break at work to collect my thoughts on the literature. Hang in there girl. I wish you the best on this and think you are going to be a great MOM! Dr T
At Wed Sep 19, 03:32:00 PM 2007,
Anonymous said…
Hi Dr. Trofatter,
I'm a little confused right now and would appreciate some guidance. I am on CD 31 and received a positive this month on CD 27. :) I started Lovenox and am continuing low dose aspirin, my prenatal and because of the insulin resistance diagnosis, I began glucophage on CD 23. I talked with my nurse today about a calcium supplement and also mentioned the glucophage. She talked with my doctor and she said that he wants me to stop taking glucophage. According to him, since I never made it to the maintenance dose (the 3 pills each day), then it isn't doing anything to help me. I've read elsewhere though that it can help prevent MC. She said that they only wanted me on it to regulate my ovulatory pattern, which does make sense to me, even though I do ovulate regularly just at a later day than 14. My question/concern is that my doctor isn't giving any thought to his decision of stopping glucophage and my diagnosis with PAI 1. This is such a big deal to me. I feel like I'm always calling the office and asking about insulin, ovulation, needing extra calcium, etc. To be honest, I think they should have told me to take the calcium, not me having to call and requesting it because of the lovenox and everything I've read. Why isn't my doctor being an advocate for me and my personal situation? I want to call again tomorrow, but would like a second opinion about my feelings as to whether they're rational or not! I really do like my RE and know that he's performed miracles for many women, but I don't think he's done anything to learn about my situation. Thoughts??!!
Thanks again for your insight and time! It means so much! Izzi
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