Liver Function Impacts Health in Diabetes:
Are you loving your liver?
In naturopathic medicine, we take the concept of “you are what you eat” very seriously and extend it further into “you are what you eat, absorb and can’t eliminate”; digestive health and liver function are critical to optimal health. The liver is a very important organ for all of us, as it is responsible for regulating our metabolism, including our blood sugar, as well as for detoxifying toxic substances. This article will describe some markers of a burdened liver and relate this to diabetes and the risk for cardiovascular disease. In addition, I will outline some choices you can make to love your liver through food choices and behaviors. Finally, I will discuss some data available on “treating” the liver using botanical medicines and nutrients in the context of diabetes.
Where is My Liver and What Does it Do?
The liver is a large organ tucked up under the right hand side of your rib cage. The liver has many functions including processing food, regulating our blood sugar and blood fat levels, and detoxifying our bodies. The liver detoxifies substances that we produce inside of our own bodies as well as toxic substances that we ingest or absorb from the outside world. In some cases, substances that we absorb from our food have biological actions. For example, dairy products can contain extra amounts of hormones, like estrogens, if the dairy cows are treated with these hormones while they are raised. The extra estrogen-like compounds in cow’s milk have biologic activity inside of our bodies, unless they are eliminated via our detox pathways. Compounds like hormones in dairy are called xenobiotics.
In general, human detox pathways are broken down into two phases, Phase I and Phase II. Phase I makes compounds more reactive, or sticky, so that they can combine with other materials in Phase II in order to eliminate them from the body; for example a fat may be made more soluble (or dissolvable) in water so that we are able to eliminate the fat in our urine. This description is an oversimplification of a convoluted, overlapping series of reactions that has some duplication and redundancy; usually a single chemical can be detoxed via several separate pathways. This overlap in function is a protective mechanism to avoid toxic accumulations of toxins that cause damage.
Although there is overlap in detox pathways within the liver, every process in the body can be overburdened by being given too much to do. In the case of the detoxification in the liver, if too much or too many substances require elimination, the liver can reach its capacity and the concentrations of these compounds can build or accumulate. This bioaccumulation leads to a toxic liver or “liver congestion” as it is referred to in naturopathic medicine.
To illustrate this idea, I’ll continue with the estrogen example. Imagine you were a young woman producing estrogens normally, but you also took a birth control pill, drank non-organic dairy daily and used plastic wrap on all your food at home (plastic wrap leeches estrogen-like compounds into the foods we eat and should be avoided in my opinion). Your body would do fine keeping up with metabolizing and detoxing the estrogens you produce on your own, and your body would probably respond to the extra hormones in the birth control pill okay too, by increasing the activity of the enzymes needed in this pathway. However, what about the estrogen-like compounds in dairy? Or the estrogen-like compounds in plastic? Imagine these do not get broken down and eliminated all in one day, and then the next day you drink more dairy, take your pill, etc. You can see how relatively quickly, these compounds could build up in your body - and for substances like hormones - begin to alter function in your body.
In the clinic, we see patients with “liver congestion” frequently. They are typically tired, feel generally ill, have generalized soreness, headaches, poor digestion and have impaired blood sugar regulation.
How Can I Tell if My Liver is “Congested”?
The liver is an exceptionally tolerant organ, and therefore the situation inside the body needs to get very bad before signs show up. However, there are liver function tests available from your doctor that provide information about your liver. One test in particular seems to be important in diabetes as well as risk for cardiovascular disease. This test is called gamma-glutamyl transferase, or GGT for short.
GGT has several roles in liver function, and both are very important. The first role of GGT is it helps to recycle nutrients and amino acids in order to increase antioxidants in the liver, specifically GGT increases glutathione production. Glutathione is a keystone to our antioxidant defenses! In addition to increasing glutathione, GGT also is a detox enzyme that combines, or conjugates, substances to glutathione in order for them to be eliminated from the body.
What Does GGT Have to Do with Diabetes?
Even slight increases in blood levels of GGT appear to
- Increase risk for developing diabetes,
- Increase risk for developing the metabolic syndrome,
- Increase risk for having a cardiovascular problem like a heart attack and
- Increase risk for high blood pressure [2-5].
It is important to point out that the increases that seem to increase risk of all of these things are not “elevations” on your labs like you would see for your cholesterol being too high, but are technically within the normal range because most people are somewhat toxic and the “normal” range represents this baseline toxicity!
Wait a Minute, I’m Lost. How Does GGT Impact my Diabetes?
I agree, this is a pretty complicated topic, but hang in there and it may make more sense (I hope!) Not everything about GGT and how it represents abnormal function is fully known. However, it has been proposed that GGT is a marker of oxidative stress in the liver . GGT has been shown to be inversely related to concentrations of antioxidants in the blood in a very large study, i.e. GGT was increased when antioxidants were decreased. If the body is under oxidative stress, it makes sense that it would try to compensate by increasing its antioxidant defenses; this increase may be represented by higher GGT levels in the blood.
Because the liver is so important in regulating blood sugar by sensing blood sugar levels and responding by either increasing or decreasing its production of sugar, it stands to reason (although is not fully known how) that oxidative stress in the liver may impact this regulation of blood sugar.
How Does GGT Get Elevated in the First Place?
Not all factors that elevate GGT are well known, however some are. Certain diet patterns are associated with increased GGT, including consumption of red meat and alcohol, whereas consumption of non-fried or canned vegetables, grains, beans, tree nuts and coffee seem to be associated with lower levels of GGT. Recall, GGT was higher when blood antioxidant levels were lower, therefore it makes sense that consuming an antioxidant rich diet filled with multi-colored vegetables foods is one strategy to prevent elevations in GGT!
Although this has not yet been shown in research, I speculate that Advanced Glycosylation Endproducts (See Complementary Corner December 2006) may also contribute to elevated GGT levels. (If you review the AGE article, you will find meat and fried foods amongst the highest AGE-containing foods). In general, cooked oils or fats produce oxidants, called peroxides, in the body which elevated GGT. In addition some drugs, like acetaminophen in over the counter pain medication, also deplete the antioxidant glutathione and cause elevations in GGT.
What Can I do to Protect My Liver?
The easiest answer is to follow a healthy diet, rich in tree nuts, beans, fruits and vegetables and lean animal proteins like fish and poultry. Limit red meat and avoid fried foods. When using cooking oils, use olive oil and don’t cook at high temperatures.
Some research suggests low amounts of alcohol may actually be good for people with diabetes and may improve glucose control and reduce vascular risk , however alcohol should be limited to no more than one drink per day for women and two drinks per day for men. Many alcoholic beverages, including beer and wine, contain significant amounts of carbohydrates, so all alcohol needs to be included in your daily carbohydrate allotments and your daily calorie requirements.
In naturopathic medicine, we refer to some foods as “liver foods” as these foods have either been shown to be protective for liver function in some way or contain nutrients required for detoxification. Some of these foods include garlic; onions; artichokes; root vegetables like parsnips, carrots and burdock; dandelion greens; and brassica-family vegetables like broccoli, mustard greens, turnips, cabbage and brussel sprouts.
Finally, although not well researched, it makes sense to me to eat organically when ever possible and avoid using plastics and harsh chemicals around the house. Although the exact influence of these household chemicals and food contaminants is not well known, I think your liver has enough to do without adding more substances to detoxify. Frankly, we are exposed to enough chemicals, like diesel exhaust, that we cannot control, so why not reduce our exposures whenever we can?
Are There Herbs or Nutrients that May Protect My Liver?
One of the most widely known “liver herbs” is milk thistle. Milk thistle contains a compound called silymarin which is a powerful antioxidant in the liver. Silymarin has been shown in human clinical research to reduce fasting blood glucose, reduce markers of inflammation in the liver and reduce hemoglobin A1c by 0.8% over a one-year period . In a separate four-month study, Silymarin reduced hemoglobin A1c by 1.0% in four months (this is better than some medications!). Silymarin also reduced other liver enzymes, but unfortunately GGT was not tested in this study.
In addition to milk thistle, tumeric or Curcuma longa, the commonly used cooking spice in curries and Indian fare, has been shown to reduce GGT in animal research by reducing the oxidative stress caused by oxidize oils . Curcuma may have other health benefits, including an anti-inflammatory activity and may improve insulin sensitivity. (See Complementary Corner July 2006 for more information on how some culinary spices may affect diabetes.)
N-acetylcysteine (NAC) is an antioxidant material available as a nutritional supplement; NAC is known to act as a precursor to glutathione in humans. NAC has not been well studies in humans. However in rats, NAC appears to lower GGT when challenged with high doses of alcohol and/or oxidized oils. In addition, genetic experiments in mice where the gene for GGT has been removed results in the mice developing cataracts (a common complication of diabetes) and dying prematurely. If these mice are fed NAC, the animals do not develop cataracts and live a normal lifespan.
Vitamin E, although controversial in humans, has been shown to reduce GGT levels in diabetic rats and has been shown to reduce markers of lipid peroxides in humans. Of note, the doses used to reduce peroxides in humans are much higher than doses typically used by most people; 1600-3200 IUs per day were required.
Your liver is a vital organ that assists in regulating blood glucose and in detoxifying normal and foreign wastes from the body. If the body is too burdened by outside toxins, these toxins accumulate and appear to alter biological function. GGT is an enzyme in the liver than functions to increase antioxidant status in the liver, as well as combine toxins with glutathione in order to detox harmful substances. Slight increases of GGT within the normal range appear to increase risk for diabetes and many cardiovascular complications associated with diabetes. There are numerous health habits that are associated with lower GGT levels, including eating a low red meat, low alcohol, high whole foods diet. In addition, clinical and animal research is supporting the use of botanical medicines like Tumeric and Milk Thistle in treating liver disease as well as preventing oxidative damage in the liver. In the case of Milk Thistle, this liver protection also appears to be accompanied by improvement in blood glucose control in people with diabetes. Love your liver, it’s yours to protect.
Ryan Bradley, ND, MPH is a naturopathic doctor, clinical researcher and epidemiologist in San Diego, CA. He is an Associate Professor and Assistant Director of Research at the National University of Natural Medicine in Portland, OR and an Assistant Professor in the Department of Family Medicine and Public Health at the University of California, San Diego.
1. Dickinson, D.A. and H.J. Forman, Glutathione in defense and signaling: lessons from a small thiol. Ann N Y Acad Sci, 2002. 973: p. 488-504.
2. Andre, P., et al., Three-year increase of gamma-glutamyltransferase level and development of type 2 diabetes in middle-aged men and women: the D.E.S.I.R. cohort. Diabetologia, 2006. 49(11): p. 2599-603.
3. Andre, P., et al., Gamma-glutamyltransferase activity and development of the metabolic syndrome (International Diabetes Federation Definition) in middle-aged men and women: Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. Diabetes Care, 2007. 30(9): p. 2355-61.
4. Lee, D.H., et al., Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem, 2003. 49(8): p. 1358-66.
5. Lee DH, S.K., Hu G, Jacobs DR Jr, Jousilahti P, Sundvall J, Tuomilehto and J., Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur Heart J., 2006. 27(18): p. 2170-6.
6. Lim, J.S., et al., Is serum gamma-glutamyltransferase inversely associated with serum antioxidants as a marker of oxidative stress? Free Radic Biol Med, 2004. 37(7): p. 1018-23.
7. Lee, D.H., L.M. Steffen, and D.R. Jacobs, Jr., Association between serum gamma-glutamyltransferase and dietary factors: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Clin Nutr, 2004. 79(4): p. 600-5.
8. Shai I, W.J., Harman-Boehm I, Raz I, Fraser D, Rudich A, Stampfer MJ, Glycemic effects of moderate alcohol intake among patients with Type 2 diabetes: a multicenter, randomized clinical intervention trial. Diabetes Care, 2007. 30(12): p. 3011-3016.
9. Velussi, M., et al., Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol, 1997. 26(4): p. 871-9.
10. Hussein HF, L.B., Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M, The Efficacy of Silybum marianum Gaertn. (Silymarin) in the Treatment of Type II Diabetes: A Randomized, Double-blind, PLacebo-controlled, Clinical Trial. Phytotherapy Research, 2006. 20: p. 1036-1039.
11. Rukkumani, R., et al., Comparative effects of curcumin and an analog of curcumin on alcohol and PUFA induced oxidative stress. J Pharm Pharm Sci, 2004. 7(2): p. 274-83.
12. Varma, P.S., et al., Alcohol and thermally oxidized pufa induced oxidative stress: role of N-acetyl cysteine. Ital J Biochem, 2004. 53(1): p. 10-5.
13. Chevez-Barrios, P., et al., Cataract development in gamma-glutamyl transpeptidase-deficient mice. Exp Eye Res, 2000. 71(6): p. 575-82.
14. Al-Shamsi, M., A. Amin, and E. Adeghate, Vitamin e ameliorates some biochemical parameters in normal and diabetic rats. Ann N Y Acad Sci, 2006. 1084: p. 411-31.
15. Roberts, L.J., 2nd, et al., The relationship between dose of vitamin E and suppression of oxidative stress in humans. Free Radic Biol Med, 2007. 43(10): p. 1388-93.