Effects of different doses of metformin treatment for 6 months on aberrant crypt foci in Chinese patients with impaired glucose tolerance.

This research was carried out to evaluate the chemopreventive effects of different doses of metformin treatment for 6 months on rectal aberrant crypt foci (ACF) in patients with impaired glucose tolerance (IGT). A total of 120 Chinese patients with IGT were enrolled and assigned randomly to a low-dose metformin group (n=30, metformin at 250 mg/day), a middle-dose metformin group (n=30, metformin at 500 mg/day), a high-dose metformin group (n=30, metformin at 1500 mg/day), and a control (untreated with metformin) group (n=30). Each participant was followed for 6 months by protocol, and the number of ACF per patient in the above four groups was examined by magnifying colonoscopy before, and after 3 and 6 months of, treatment. The mean ACF numbers in both the middle-dose and the high-dose metformin groups were significantly decreased at 3 as well as 6 months of treatment, whereas they did not change in the low-dose metformin and the untreated groups. In the high-dose metformin group, BMI, waist circumference, fasting plasma glucose, homeostatic model assessment of insulin resistance index, and 2-h plasma glucose were significantly decreased. However, no such change was observed in the middle-dose metformin group. Changes in the ACF number correlated positively with changes in the homeostatic model assessment of insulin resistance (r=0.273, P=0.013), BMI (r=0.241, P=0.042), and 2-h plasma glucose (r=0.252, P=0.037), respectively, in the high-dose metformin group, but no such correlation was observed in the middle-dose metformin group. Metformin suppressed ACF formation in IGT patients in a dose-dependent manner, possibly through direct and indirect (attenuating insulin resistance) mechanisms.

Colon epithelial proliferation and carcinogenesis in diet-induced obesity.

Colorectal cancer is the third leading cause of cancer death in Japan and the United States and is strongly associated with obesity, especially visceral obesity. Several metabolic mediators, such as adiponectin, have been suspected to play a role in obesity-related carcinogenesis. In a previous human study, the existence of a significant correlation between the number of human dysplastic aberrant crypt foci (ACF) and the visceral fat area was demonstrated, and also that of a significant inverse correlation between the number of dysplastic ACF and the plasma adiponectin level. Other studies have investigated the effect of adiponectin under the normal and high-fat diet conditions in a mouse model of azoxymethane-induced colon cancer. Enhanced formation of both ACF and tumors was observed in the adiponectin-deficient mice, as compared with that in the wild-type, under the high-fat diet condition but not under the normal diet condition. Furthermore, that the 5'-AMP-activated kinase/mammalian target of rapamycin pathway is involved in the promotion of colorectal carcinogenesis in adiponectin-deficient mice under the high-fat diet condition was shown. Therefore, that the 5'-AMP-activated kinase/mammalian target of rapamycin signaling pathway may play an important role in colorectal carcinogenesis was speculated. Metformin, a biguanide derivative widely used in the treatment of diabetes mellitus, has been shown to exert a suppressive effect on ACF formation in both mouse models and humans. Therefore, metformin might be a promising candidate as a safe drug for chemoprevention of colorectal carcinogenesis. Further studies with high evidence levels, such as randomized, controlled studies, are needed to clarify these relationships.

Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial.

The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 +/- 6.45 before treatment versus 5.11 +/- 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 +/- 6.65 versus 7.56 +/- 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer.