Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment spproaches using vitamin E, magnesium, and betaine - Fatty Liver

Alternative Medicine Review, August, 2002 by Lyn Patrick

Depletion of magnesium from normal cells creates cellular insulin resistance. (58) Magnesium levels are related to insulin resistance in type 1 and 2 diabetics and in nondiabetics. In patients with type 1 diabetes, low serum and plasma magnesium levels have been documented in several trials and are considered a relatively common finding; 25-48 percent of type 2 diabetics have been shown to have low blood magnesium levels. (59-61) Low plasma magnesium is significantly correlated with decreased glucose disposal in both type 1 and type 2 diabetes. (62,63)

Magnesium concentrations also appear to be related to insulin resistance in nondiabetic populations. Eighteen "healthy patients" (nondiabetic) who had lower levels of plasma magnesium (below 0.80 mmol/L) were significantly more likely to have higher fasting insulin levels and insulin resistance than those who had plasma magnesium above 0.80 mmol/L. Insulin resistance was defined by elevated plasma glucose and insulin after an oral glucose challenge. (64) Of note, the magnesium deficiency-related insulin resistance was independent of body mass index or waist-to-hip ratio.

When a nondiabetic group of subjects were fed a low magnesium diet for four weeks, insulin sensitivity decreased by 25 percent. (65) Magnesium supplementation in type 2 diabetics (41.4 mmol) has been shown to lead to a significant lowering of fructosamine levels, indicating an increase in insulin sensitivity. (59)

There is evidence that magnesium may also act as an antioxidant: magnesium increases the rate of production of the free-radical quenching enzyme superoxide dismutase, (66) while magnesium depletion appears to increase cellular sensitivity to oxidative damage (67) and the production of oxygen radicals in cell studies. (68) There are no studies in NASH patients looking at either magnesium levels or magnesium supplementation on liver enzyme levels or liver histology. There is sufficient evidence, however, that reducing insulin resistance in both diabetics and nondiabetics with both NAFLD and NASH improves steatosis. (33) Considering the evidence for magnesium depletion and its effect on insulin resistance, evaluation of magnesium status and repletion in both NAFLD and NASH is warranted.

Vitamin E

Vitamin E has been shown to protect against liver fibrosis in animal models (69,70) and has also been shown to improve insulin sensitivity in type 2 diabetes, nondiabetics, and hypertensives. (71,72) Vitamin E supplementation (600 IU/day for four weeks) has also been able to significantly raise erythrocyte magnesium levels and plasma reduced glutathione levels while increasing insulin sensitivity in hypertensives. (71)

Two small studies using vitamin E revealed some important data in the treatment of NASH. The first study looked at 400-1200 IU of dl-[alpha]-tocopherol in children 8-14 years of age. (73) All children in the study were obese and had a history of elevated AST and ALT levels for over three months with evidence of fatty liver on liver ultrasonography. Median serum ALT was approximately 3.9 times the upper limit of normal, AST was 2.3 times the upper limit of normal, and alkaline phosphatase was 1.5 times the upper limit of normal. All of the children were considered to have NASH even though their diagnoses were not confirmed by liver biopsy. Each participant was started on 400 IU vitamin E and had liver enzyme levels repeated monthly. If AST and ALT values were not within normal limits one month after beginning treatment, the dose of vitamin E was raised by 400 IU per month to a maximum of 1200 IU. The children were followed for 5.2 months. At that time their weight was not demonstrably different but serum ALT and AST had returned to normal by the end of the third month. Alkaline phosphatase was still elevated but had dropped significantly. Four of the children were able to reach normal ALT and AST levels with 400 IU, four needed 800 IU, and two needed 1200 IU. Two children discontinued vitamin E and had a recurrence of elevated ALT and AST levels within two months. An important point made in this study by the authors is that weight loss is difficult in children. These study participants were able to achieve normal ALT and AST levels without losing weight, which they were unable to do although they had been counseled by a physician and had regular meetings with a dietician during the study.