System-L amino acid transporters play a key role in pancreatic β-cell signalling and function

Cheng, Qi; Beltran, Violeta Diez; Chan, Stanley M H; Brown, Jeremy R. Glissen; Bevington, Alan; Herbert, Terence P.

doi:10.1530/jme-15-0212

Cited by 43 publications

(46 citation statements)

References 52 publications

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“…The neutral amino acid exchanger LAT1-4F2hc (SLC7A5-SLC3A1) LAT1 (SLC7A5) is a major transporter of BCAAs in many non-epithelial cells and is involved in insulin signalling, including insulin secretion directly through its cytosolic accumulation of leucine (217) (Fig. 1E).…”

Section: Slc38 Family Of Neutral Amino Acid Symportersmentioning

confidence: 99%

“…Expression of LAT1 in β-cells facilitates leucine uptake, which acts as an allosteric activator of Glutamate Dehydrogenase (GDH) (229,230), enhancing insulin secretion via increased glutamate mitochondrial production and islet cell proliferation (151,217,231). Activation of mTORC1 signalling is also promoted by LAT1-mediated leucine uptake into β-cells (217).…”

Section: Slc38 Family Of Neutral Amino Acid Symportersmentioning

confidence: 99%

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Amino acid transporters in the regulation of insulin secretion and signalling

Javed

Fairweather

2019

Biochemical Society Transactions

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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.

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Section: Slc38 Family Of Neutral Amino Acid Symportersmentioning

confidence: 99%

Section: Slc38 Family Of Neutral Amino Acid Symportersmentioning

confidence: 99%

Amino acid transporters in the regulation of insulin secretion and signalling

Javed

Fairweather

2019

Biochemical Society Transactions

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“…Amino acids enter the cell via active transporters such as the system-L amino acid transporter 1 (LAT1), which is abundantly expressed in islets. siRNA-mediated LAT1 knockdown in clonal β cells and rat islet cultures inhibits leucine-stimulated mTORC1 activation, insulin secretion and islet cell proliferation [43]. However, whether the effect of leucine on β-cell proliferation is specific or merely reflects the absence of an aminoacid essential for global protein synthesis remains an open question.…”

Section: Amino Acidsmentioning

confidence: 99%

Nutrient regulation of pancreatic β-cell proliferation

2017

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Excess consumption of energy-dense foods combined with a sedentary lifestyle is driving an obesity epidemic. Although obesity is closely associated with insulin resistance, most individuals meet the insulin demand by increasing their functional β-cell mass. Those who eventually develop type 2 diabetes are distinguished by a failure in this compensatory process. Although a causal role of insulin resistance in compensatory β-cell responses has received considerable experimental support, precisely how the β cell senses changes in the metabolic environment is still unknown. As metabolism of glucose, lipids and amino acids is profoundly altered in obesity, it is not surprising that these nutrients are conspicuous among the factors proposed to contribute. In this review we summarise our understanding of the role of nutrients, in particular glucose, fatty acids and amino acids in β-cell compensation with a particular emphasis on their relation to insulin resistance-induced factors and their underlying mechanism of action. Finally, we describe the concept of epigenetic programming and review recent studies illustrating how the status of the β cell epigenome is a product of its nutrient environment, and how metabolic programming of the β cell contributes to diabetes risk.

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“…92 Although the mechanisms for amino acid potentiation of GSIS are not fully understood, several studies have suggested that (1) amino acid mixtures can stimulate cAMP production in isolated islets; 55,93 (2) amino acids can activate the mammalian targets of rapamycin and AMP-activated protein kinase pathways; [94][95][96] (3) amino acids can improve nicotinamide adenine dinucleotide (NADH) mitochondrial shuttle activity; 97,98 and (4) amino acid transporters or receptors may be directly involved in the process of insulin secretion. 99 …”

Section: Amino Acid-potentiated Gsis and Glucose-dependent Amino Acidmentioning

confidence: 99%

Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes

Lü

2017

Annals of the New York Academy of Sciences

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Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose-stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM)). Mutations of beta cell ion channels involved in insulin secretion regulation also alter glucose sensing. Activating or inactivating mutations of ATPdependent potassium (K ATP ) channel genes result in severe but completely opposite clinical phenotypes, including PNDM and CHI. Mutations of the other ion channels, including voltage-gated potassium channels (K v 7.1) and voltage-gated calcium channels, also lead to abnormal glucose sensing and CHI. Furthermore, amino acids can stimulate insulin secretion in a glucose-independent manner in some forms of CHI, including activating mutations of the glutamate dehydrogenase gene, HDAH deficiency, and inactivating mutations of K ATP channel genes. These genetic defects have provided insight into a better understanding of the complicated nature of beta cell fuel-sensing mechanisms.

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System-L amino acid transporters play a key role in pancreatic β-cell signalling and function

Cited by 43 publications

References 52 publications

Amino acid transporters in the regulation of insulin secretion and signalling

Amino acid transporters in the regulation of insulin secretion and signalling

Nutrient regulation of pancreatic β-cell proliferation

Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes

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