Metformin and Systemic Metabolism

Abstract

Metformin can improve patients' hyperglycemia through significant suppression of hepatic glucose production. However, up to 300 times higher concentrations of metformin accumulate in the intestine than in the circulation, where it alters nutrient metabolism in intestinal epithelial cells and microbiome, leading to increased lactate production. Hepatocytes use lactate to make glucose at the cost of energy expenditure, creating a futile intestine-liver cycle. Furthermore, metformin reduces blood lipopolysaccharides and its initiated low-grade inflammation and increased oxidative phosphorylation in liver and adipose tissues. These metformin effects result in the improvement of insulin sensitivity and glucose utilization in extrahepatic tissues. In this review, I discuss the current understanding of the impact of metformin on systemic metabolism and its molecular mechanisms of action in various tissues.

Keywords: Metformin; insulin resistance; mitochondria; nutrient metabolism.

Figure 1.. Metformin modulates glucose metabolism in the intestine and liver.

(Upper) In the intestine, metformin alters the composition and function of microbiota, leading to increased production of lactate from glycolysis; high metformin concentrations can inhibit oxidative phosphorylation in mitochondria of intestinal epithelial cells and increase glucose utilization through glycolysis and overproduction of lactate; high metformin concentration may inhibit gluconeogenesis by inactivating AMP deaminase in intestinal epithelial cells. (Lower) In the liver, pharmacological metformin concentration promotes the formation of the AMPKαβγ heterotrimeric complex and increases AMPKα phosphorylation at T172 and suppression of mG3PDH to reduce HGP. Supra-pharmacological metformin can inhibit the gluconeogenesis by increasing AMP, and AMP inhibits adenylate cyclase or FBP-1 to suppresses the HGP. Lactate generated from the intestine is used to make glucose in the liver through gluconeogenesis at the cost of cellular energy, generating a futile intestine-liver cycle. The black arrows indicate the direct effects, and the shaded arrows indicate the indirect effects. CRTC2, creb-regulated transcriptional coactivator 2; FBP-1, fructose 1,6-bisphosphatase 1; mG3PDH, mitochondrial glycerol 3-phosphate dehydrogenase. L, lactate; M, metformin.

Figure 2.. Metformin modulates lipid metabolism in the intestine, liver, and adipose tissue.

(Left) In the intestine, metformin stimulates GLP-1 expression and secretion through AMPK-dependent and -independent pathway in L cells. Metformin inhibits chylomicron assembly and secretion in enterocytes by reducing the levels of Apo-48, Apo-IV, and triglyceride synthesis. (Middle) In the liver, metformin-mediated activation of AMPK phosphorylates SREBP-1 and ACC to inhibit the de novo lipogenesis (DNL), disinhibits the activity of CPT-1; metformin also promotes the mitochondrial fission to increase mitochondria number; these metformin’s effects lead to elevated fatty acid oxidation. (Right) In brown adipocytes, metformin stimulates fatty acid uptake and activates HSL to increase lipolysis. Metformin increases mitochondrial biogenesis by activating PGC-1 signaling. Activated AMPK also drives mitochondrial fission. Collectively, metformin augments fatty acid oxidation in brown adipose tissue. The black arrows indicate the direct effects, and the shaded arrows indicate the indirect effects. ACC1/2, acetyl-coenzyme A carboxylase 1/2; CAMKII, calcium/calmodulin-activated protein kinase II; CPT1, carnitine palmitoyltransferase 1; DAG, diacylglycerols; DGAT, diacylglycerol acyltransferase; FAS, fatty acid synthase; HSL, hormone-sensitive lipase; MAG, monoacylglycerols; MGAT, monoacylglycerol acyltransferase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α; PKA, protein kinase A; SREBP1, sterol regulatory element binding protein 1; TG. triglycerides.

Figure 3.. Metformin improves insulin sensitivity.

(Upper) In the intestine, metformin changes the composition of microbiota, resulting in decreased LPS production and increased SCFAs. SCFAs and metformin-mediated activation of AMPK strengths the intestinal barrier, along with decreased chylomicron generation, leading to reduction of LPS levels in the circulation. (Lower) In extra-intestinal cells, reduced LPS levels and its initiated low-grade of inflammation improves insulin signaling by reducing IRS acetylation and serine and threonine phosphorylation and by increasing PIP3 levels. The black arrows indicate the direct effects, and the shaded arrows indicate the indirect effects. ER stress, endoplasmic reticulum stress; IKKβ, IκB kinase β; JNK, c-jun N-terminal kinases; NF-κB, nuclear factor-kappa B; P300, E1A binding protein P300; PTEN, phosphatase and tensin homolog; TJ, tight junction; TLR4, toll like receptor 4; SHIP2, Src homology 2 domain containing inositol-5-phosphatase 2.