Metformin-mechanisms of its glycemia-reducing effect
Abstract
Metformin currently serves as the basis of oral treatment for patients with type 2 diabetes. While metformin's effect on glycemia is well established, its mode of action remains unclear. In clinical studies, long-term metformin treatment improved glucose disposal and reduced hepatic gluconeogenesis. The effects on gluconeogenesis have been confirmed in experimental animals and cell preparations, but mostly at higher doses than those used in humans. Proposed hepatic mechanisms can be grouped into those with and without AMP-activated protein kinase (AMPK) activation; the latter include inhibition of mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase. Experimental studies on the effects of metformin on skeletal muscles suggest that AMPK activation and anti-inflammatory activities are possible mechanisms for increasing glucose disposal. Inhibition of renal gluconeogenesis may contribute to the extraintestinal glycemia-lowering effects of metformin. Following the observation that short-term intravenous metformin lacks glycemia-lowering effects in humans, intestinal mechanisms have been investigated. Suggested mechanisms include inhibition of intestinal glucose absorption owing to increased glycolysis driven by complex I inhibition in the mitochondria of enterocytes, stimulation of glucose transport into the colon, and stimulation of glucagon-like peptide-1 (GLP-1) secretion. Intestinal GLP-1 activates the gut-brain-liver axis, which impairs hepatic…
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