Amino acid transporters in the regulation of insulin secretion and signalling

Abstract

Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid transporters. This review focuses on amino acid transporters linked to the regulation of insulin secretion and signalling with a focus on those of the small intestine, pancreatic β-islet cells and insulin-responsive tissues, liver and skeletal muscle. We summarise the role of the amino acid transporter B0AT1 (SLC6A19) and peptide transporter PEPT1 (SLC15A1) in the modulation of global insulin signalling via the liver-secreted hormone fibroblast growth factor 21 (FGF21). The role of vesicular vGLUT (SLC17) and mitochondrial SLC25 transporters in providing glutamate for the potentiation of insulin secretion is covered. We also survey the roles SNAT (SLC38) family and LAT1 (SLC7A5) amino acid transporters play in the regulation of and by insulin in numerous affective tissues. We hypothesise the small intestine amino acid transporter B0AT1 represents a crucial nexus between insulin, FGF21 and incretin hormone signalling pathways. The aim is to give an integrated overview of the important role amino acid transporters have been found to play in insulin-regulated nutrient signalling.

A GC-MS/Single-Cell Method to Evaluate Membrane Transporter Substrate Specificity and Signaling

“…However, large variations of amino acid concentrations have been noted (Taylor and Smith, 1987;Meier et al, 2002) between oocyte stages, time post-surgery, and ionic incubation conditions. The method developed here can also be used to investigate amino acid signaling, the components of which are highly conserved in multicellular eukaryotes (Panchaud et al, 2013;Saxton and Sabatini, 2017;Tatebe and Shiozaki, 2017;Javed and Fairweather, 2019). Our results support the concept of SNAT2 as a transceptor (Pinilla et al, 2011), because mTORC1 activation was observed at time points where cytosolic leucine was barely increased.…”

Excessive Intake of High-Fructose Corn Syrup Drinks Induces Impaired Glucose Tolerance

“…Their expression in the HFCS group was significantly decreased compared with that in the control group ( Figure 5 A,B). Depending on the metabolic and nutritional status, amino acids, such as glutamine and glutamate, act as modulators of nutrient disposal, and play a role in regulating blood glucose through interaction with insulin signaling [ 28 ]. The mRNA expression of the amino acid transporter SLC38A3, and of the glutaminolysis enzymes glutaminase ( Gls ) and glutamate dehydrogenase 1 ( Glud1 ), did not differ between the two groups ( Figure 5 C,D).…”

“…Both glutamate and glutamine provide reducing equivalents for the production of NADH in the TCA cycle and ultimately for the synthesis of ATP to facilitate glucose-stimulated insulin secretion via the closure of ATP-sensitive potassium channels [ 28 , 58 ]. Glutamine is transported into β-cells by transporters, such as SLC38A3 [ 28 , 59 , 60 ]. Glutamine is converted to glutamate by Gls and then to α-ketoglutarate by Glud.…”

Protein Isolates from Raw and Cooked Foxtail Millet Attenuate Development of Type 2 Diabetes in Streptozotocin‐Induced Diabetic Mice

“…That is, the availability of amino acids or peptides is regulated by transporters, whose enhancement was also beneficial for insulin signaling modulation in various tissues, including the small intestine, pancreatic -islet cells, liver, and skeletal muscle. [47] Diabetes leads to poor permeability of the intestinal epithelial barrier and impairs amino acids or peptides transporter functions, thus resulting in low nutrients bioavailability, including peptides and amino acids. [47,48] Amino acid supplementation was demonstrated to ameliorate the damaged permeability of the intestinal barrier, improve the amino acids or peptides transporter function, and then result in the increased amino acid and peptide bioavailability.…”

“…[47] Diabetes leads to poor permeability of the intestinal epithelial barrier and impairs amino acids or peptides transporter functions, thus resulting in low nutrients bioavailability, including peptides and amino acids. [47,48] Amino acid supplementation was demonstrated to ameliorate the damaged permeability of the intestinal barrier, improve the amino acids or peptides transporter function, and then result in the increased amino acid and peptide bioavailability. [49,50] As such, higher levels of amino acids generated by the protein isolate from the cooked foxtail millet via hydrolysis in vivo may better alleviate the impaired permeability of the intestinal epithelial barrier, enhance the amino acid or peptides transporter function, and then increase the bioavailability of peptides and amino acids, which contributes to glucose metabolism modulation ultimately.…”