Hepatic glucose sensing is required to preserve β cell glucose competence

Abstract

Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr -/-mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link. IntroductionHepatic glucose metabolism is highly regulated during the fed-tofast transition by changes in plasma levels of insulin and glucagon, but also by the changes in blood glucose concentrations. In the fed state, the presence of high insulin concentrations in the portal circulation favors storage of glucose in the form of glycogen and the use of glucose through the glycolytic pathway for its conversion into fatty acids. Important regulatory events activated during the absorptive phase include the transcriptional induction of glucokinase by insulin and of L-pyruvate kinase by the carbohydrate-responsive element-binding protein (ChREBP), which translocates to the nucleus following its dephosphorylation by a glucose metabolite-activated phosphatase (1). At the same time, glucose inhibits glycogen phosphorylase through inhibition of glycogen phosphorylase phosphatase, whereas glucose-6-phosphate activates glycogen synthase (2), thus favoring glycogen biosynthesis. The combination of insulin-dependent Srebp-1c and glucose-dependent ChREBP activation then induces the expression of lipogenic genes, including Acc, Fas, and Scd1 (1, 3).In the fasted state, the decrease in glycemia reduces the intracellular levels of glucose and glucose-6-phosphate, thereby favoring glycogen degradation and reducing the activation of ChREBP and the expression of L-pyruvate kinase and lipogenic genes. Higher glucagon levels favor the gluconeogenic pathway by inducing the expression of PEPCK and G6Pase that catalyzes the hydrolysis of glucose-6-phosphate into glucose, a reaction that takes place in the lumen of the ER. The last steps of glucose output

GLUT2, glucose sensing and glucose homeostasis

“…First, Glut2 inactivation in hepatocytes of adult mice using a tamoxifen-dependent recombination system (LG2KO mice) [52] suppressed hepatic glucose uptake but did not modify glucose homeostasis in the fed, fasted, or fasted and refed states. Measurement of tissue glucose uptake in LG2KO mice showed increased uptake in the tibialis anterior and extensor digitorum longus muscles.…”

“…Indeed, since part of the glucose generated from glucose 6-phosphate in the endoplasmic reticulum can be transported back into the cytoplasm, it needs to be equilibrated with the extracellular glucose. Preventing this equilibration in LG2KO hepatocytes leads to the accumulation of glucose and glucose 6-phosphate in the cytoplasm, which causes a permanent increase in nuclear ChREBP and a paradoxical upregulation of the gene encoding L-pyruvate kinase and the lipogenic genes in the fasted state [52,53]. The presence of GLUT2 in hepatocytes is therefore required for the normal control by glucose of gene expression under physiological conditions.…”

“…The third surprise was that, even though Glut2 gene inactivation in adult mouse liver had no immediate impact on whole body glucose homeostasis, LG2KO mice progressively developed glucose intolerance as a result of a defect in GSIS [52]. Thus, altered glucose metabolism in hepatocytes induced progressive beta cell dysfunction.…”

Apigenin Causes Biochemical Modulation, Glut4 and Cd38 Alterations to Improve Diabetes and to Protect Damages of Some Vital Organs in Experimental Diabetes

“…STZ causes destruction of β-cells of the islets and reduction in insulin release (Ning et al, 2011). The structural and biochemical functions of liver and kidneys may also be affected by alteration of insulin concentration which inhibits rapid glucose uptake and storage as glycogen in liver (Seyer et al, 2013). It is well recognized that flavonoids are able to improve diabetic subject by decreasing blood glucose levels (Rauter et al, 2010).…”

Role of nutrient transporters in lifestyle-related diseases

“…GLUT2 is also expressed in the liver and regulates glucose uptake/efflux, and this transport activity is important to maintain the blood glucose level. Recent studies demonstrated that GLUT2 also plays a key role in the preservation of beta-cell glucose competence 12) , and that a genetic variant of GLUT2 is associated with the higher intake of sugars 13) . Interestingly, the Finnish Diabetes Prevention Study showed that moderate-tovigorous physical activity could modify the risk of developing T2D associated with the genetic variant of GLUT2 in persons with impaired glucose tolerance 14) .…”