Hypoglycaemic effect of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine

Abstract

The insulin-resistant obese fa/fa rat is a convenient model in which to study a potential effect of metformin, a biguanide used in the treatment of non-insulin-dependent diabetes, on insulin-mediated glucose utilization. Female fa/fa rats were given metformin orally for 8 days. Studies were performed on anaesthetized post-absorptive rats 5 h after the last dose of metformin. Glucose production and utilization were enhanced 1.5-fold in metformin-treated rats. The enhanced glucose production was almost entirely due to increased glucose recycling. The digestive tract was the only tissue responsible for the enhanced glucose utilization.

Importance of the intestine as a site of metformin‐stimulated glucose utilization

“…Recent studies have indicated that the intestine is also an important site of metformin-stimulated glucose utilization (Penicaud et al, 1989;Wilcock & Bailey, 1990;Bailey et al, 1992). However, a quantitative determination of the effect of metformin on glucose utilization by the intestine in vivo has not been reported.…”

“…There is also an adjustment of lactate metabolism after a glucose challenge which results in net lactate utilization by the periphery (Jackson et al, 1987;Bailey et al, 1992). Thus it is likely that metforminstimulated glucose utilization by the intestine makes an important contribution to increased glucose recycling (Penicaud et al, 1989). This is envisaged to include an intrasplanchnic substrate cycle in which glucose is converted to lactate in the intestine, released into the portal circulation and extracted by the liver to form glucose (Bailey, 1993).…”

“…Recent studies have shown that metformin increases glucose utilization by the intestine (Penicaud et al, 1989;Bailey et al, 1992). This occurs in the fasted state as well as in the fed state, indicating that the drug can increase the intestinal' extraction of glucose from the vascular compartment.…”

Understanding of Dose-Response of Metformin by Using Continuous Glucose Monitoring

“…Metformin is known to reduce hepatic gluconeogenesis which is considered to be the main mechanism of glucose-lowering of metformin [1]. Metformin has been also reported to increase intestinal glucose utilization and reduce food intake, inducing weight reduction and resulting amelioration of insulin resistance [2,3]. The activation of AMP-activated protein kinase (AMPK) which is a major cellular regulator of glucose metabolism was reported to be a main mechanism for metformin-mediated beneficial effects on diabetes [4], which was challenged by a recent report [5].…”

Insulin requirement for the antihyperglycaemic effect of metformin

“…Indeed the intestine, which has a very different glucose transporter complement from muscle and fat, shows increased glucose utilization in response to metformin in both the basal and postprandial states . Increased glucose recycling, for example via lactate, could then contribute to the maintenance of blood glucose concentrations in the basal state (Penicaud et al, 1989).…”