Long-term use of metformin and colorectal cancer risk in type II diabetics: a population-based case-control study.

In vitro and animal studies indicate that metformin prevents colorectal cancer (CRC). Epidemiological studies, however, have been equivocal. We undertook this study to assess whether metformin prevents CRC in individuals with type II diabetes. We performed a nested case-control study restricted to Danish citizens with type II diabetes. Data were collected from four Danish nationwide registries. Cases were type II diabetics with a primary CRC between 2000 and 2009, and controls were sampled among subjects with type II diabetes. Long-term exposure to metformin was defined by the redeeming of prescriptions for a cumulative dose of 2000 g within 5 years prior to the index date. To control for potential confounders, we used unconditional logistic regression. We generated adjusted odds ratios (OR) for the association between metformin and CRC and performed subanalyses for selected subgroups and for the dose-response relation. We identified 2088 cases and 9060 controls during the study period. The association between long-term metformin use and CRC gave an adjusted OR at 0.83 (95% CI 0.68-1.00). A protective effect on CRC with long-term use of metformin was only evident for women (OR 0.66 vs. 0.99 for men). There was a significant dose-response association of metformin use >250 defined daily dose (DDD) and for the duration of metformin use >1 year. We found an indication of a protective effect of long-term metformin use against CRC in type II diabetics, although this effect was only seen in women.

Differential effect of T-type voltage-gated Ca2+ channel disruption on renal plasma flow and glomerular filtration rate in vivo.

Voltage-gated Ca(2+) (Cav) channels play an essential role in the regulation of renal blood flow and glomerular filtration rate (GFR). Because T-type Cav channels are differentially expressed in pre- and postglomerular vessels, it was hypothesized that they impact renal blood flow and GFR differentially. The question was addressed with the use of two T-type Cav knockout (Cav3.1(-/-) and Cav3.2(-/-)) mouse strains. Continuous recordings of blood pressure and heart rate, para-aminohippurate clearance (renal plasma flow), and inulin clearance (GFR) were performed in conscious, chronically catheterized, wild-type (WT) and Cav3.1(-/-) and Cav3.2(-/-) mice. The contractility of afferent and efferent arterioles was determined in isolated perfused blood vessels. Efferent arterioles from Cav3.2(-/-) mice constricted significantly more in response to a depolarization compared with WT mice. GFR was increased in Cav3.2(-/-) mice with no significant changes in renal plasma flow, heart rate, and blood pressure. Cav3.1(-/-) mice had a higher renal plasma flow compared with WT mice, whereas GFR was indistinguishable from WT mice. No difference in the concentration response to K(+) was observed in isolated afferent and efferent arterioles from Cav3.1(-/-) mice compared with WT mice. Heart rate was significantly lower in Cav3.1(-/-) mice compared with WT mice with no difference in blood pressure. T-type antagonists significantly inhibited the constriction of human intrarenal arteries in response to a small depolarization. In conclusion, Cav3.2 channels support dilatation of efferent arterioles and affect GFR, whereas Cav3.1 channels in vivo contribute to renal vascular resistance. It is suggested that endothelial and nerve localization of Cav3.2 and Cav3.1, respectively, may account for the observed effects.