General Information:

Id: 3,656
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Newsholme P et al.(2007) Amino acid metabolism, insulin secretion and diabetes Biochem. Soc. Trans. 35: 1180-1186 [PMID: 17956307]

Interaction Information:

Comment Amino acids can, under appropriate conditions, enhance insulin secretion from primary islet beta-cells and beta-cell lines.
Formal Description
Interaction-ID: 34765

drug/chemical compound

Amino acid

affects_activity of

process

insulin secretion

in pancreas
Comment In periods of fasting or starvation, amino acid release from skeletal muscle (primarily L-glutamine and L-alanine) may modulate glucagon release from pancreatic alpha-cells, which subsequently may influence insulin secretion from beta-cells.
Formal Description
Interaction-ID: 34797

environment

fasting

increases_quantity of

drug/chemical compound

Glutamine

Comment In periods of fasting or starvation, amino acid release from skeletal muscle (primarily L-glutamine and L-alanine) may modulate glucagon release from pancreatic alpha-cells, which subsequently may influence insulin secretion from beta-cells.
Formal Description
Interaction-ID: 34800

environment

fasting

increases_quantity of

drug/chemical compound

Alanine

Comment In periods of fasting or starvation, amino acid release from skeletal muscle (primarily L-glutamine and L-alanine) may modulate glucagon release from pancreatic alpha-cells, which subsequently may influence insulin secretion from beta-cells.
Formal Description
Interaction-ID: 34802

drug/chemical compound

Amino acid

affects_activity of

process

glucagon secretion

in pancreas, in pancreatic alpha cells
Comment In periods of fasting or starvation, amino acid release from skeletal muscle (primarily L-glutamine and L-alanine) may modulate glucagon release from pancreatic alpha-cells, which subsequently may influence insulin secretion from beta-cells.
Formal Description
Interaction-ID: 34803

process

glucagon secretion

affects_activity of

process

insulin secretion

in pancreas
Comment Dietary amino acids may also stimulate incretin release, e.g. GLP-1 (glucagon-like peptide 1), from intestinal L-cells and therefore may stimulate insulin secretion via incretin-dependent mechanisms.
Formal Description
Interaction-ID: 34804

drug/chemical compound

Amino acid

increases_activity of

process

incretin secretion

in intestine
Comment Dietary amino acids may also stimulate incretin release, e.g. GLP-1 (glucagon-like peptide 1), from intestinal L-cells and therefore may stimulate insulin secretion via incretin-dependent mechanisms.
Formal Description
Interaction-ID: 34806

process

incretin release

increases_quantity of

gene/protein

Glucagon-like peptide 1

in intestine
Comment Dietary amino acids may also stimulate incretin release, e.g. GLP-1 (glucagon-like peptide 1), from intestinal L-cells and therefore may stimulate insulin secretion via incretin-dependent mechanisms.
Formal Description
Interaction-ID: 34807

gene/protein

Glucagon-like peptide 1

affects_activity of

process

insulin secretion

in pancreas
Comment Amino acids may modulate lipid metabolism. ACC, responsible for malonyl-CoA synthesis, is activated by glutamate-sensitive protein phosphatase type 2A, an effect demonstrated in islet beta-cells. ACC is also regulated by phosphorylation via AMP-regulated kinase, an enzyme sensitive to amino acid concentration.
Formal Description
Interaction-ID: 34809

drug/chemical compound

Glutamate

affects_activity of

complex/PPI

Protein phosphatase 2A

Comment Amino acids may modulate lipid metabolism. ACC, responsible for malonyl-CoA synthesis, is activated by glutamate-sensitive protein phosphatase type 2A, an effect demonstrated in islet beta-cells. ACC is also regulated by phosphorylation via AMP-regulated kinase, an enzyme sensitive to amino acid concentration.
Formal Description
Interaction-ID: 34810

complex/PPI

Protein phosphatase 2A

increases_activity of

gene/protein

ACAC

Comment Amino acids may modulate lipid metabolism. ACC, responsible for malonyl-CoA synthesis, is activated by glutamate-sensitive protein phosphatase type 2A, an effect demonstrated in islet beta-cells. ACC is also regulated by phosphorylation via AMP-regulated kinase, an enzyme sensitive to amino acid concentration.
Formal Description
Interaction-ID: 34814

drug/chemical compound

Amino acid

affects_activity of

complex/PPI

AMPK

Comment Amino acids may modulate lipid metabolism. ACC, responsible for malonyl-CoA synthesis, is activated by glutamate-sensitive protein phosphatase type 2A, an effect demonstrated in islet beta-cells. ACC is also regulated by phosphorylation via AMP-regulated kinase, an enzyme sensitive to amino acid concentration.
Formal Description
Interaction-ID: 34815

complex/PPI

AMPK

affects_activity of

complex/PPI

Protein phosphatase 2A

Comment Addition of L-alanine to the BRIN-BD11 beta-cell line increased expression of ATP citrate lyase by 2.0-fold. ATP citrate lyase will convert citrate into acetyl-CoA in the cytosol, thus providing the key step in fatty acid synthesis, ACC, with substrate.
Formal Description
Interaction-ID: 34816

drug/chemical compound

Alanine

increases_expression of

gene/protein

ACLY

Comment Addition of L-alanine to the BRIN-BD11 beta-cell line increased expression of ATP citrate lyase by 2.0-fold. ATP citrate lyase will convert citrate into acetyl-CoA in the cytosol, thus providing the key step in fatty acid synthesis, ACC, with substrate.
Formal Description
Interaction-ID: 34818

gene/protein

ACLY

increases_quantity of

drug/chemical compound

Acetyl-CoA

Comment Addition of L-glutamine to BRIN-BD11 beta-cells up-regulated ACC expression at the mRNA and protein level, thus stimulating fatty acid synthesis.
Formal Description
Interaction-ID: 34819

drug/chemical compound

Glutamine

increases_expression of

gene/protein

ACAC

Comment Amino acids may exert an influence via mTOR (mammalian target of rapamycin)-dependent stimulation of protein synthesis and, indirectly, gene expression.
Formal Description
Interaction-ID: 34820

drug/chemical compound

Amino acid

affects_activity of

process

TOR signaling

Comment Expression of genes related to beta-cell signal transduction, metabolism and apoptosis are chronically regulated by L-alanine.
Formal Description
Interaction-ID: 34823

drug/chemical compound

Alanine

affects_activity of

process

signal transduction

in pancreatic beta cells
Comment Expression of genes related to beta-cell signal transduction, metabolism and apoptosis are chronically regulated by L-alanine.
Formal Description
Interaction-ID: 34824

drug/chemical compound

Alanine

affects_activity of

process

metabolic process

in pancreatic beta cells
Comment Expression of genes related to beta-cell signal transduction, metabolism and apoptosis are chronically regulated by L-alanine.
Formal Description
Interaction-ID: 34825

drug/chemical compound

Alanine

affects_activity of

process

type B pancreatic cell apoptotic process

in pancreatic beta cells
Comment L-Glutamine increased the chronic 24 h insulin secretion rate of a beta-cell line by 30%.
Formal Description
Interaction-ID: 34828

drug/chemical compound

Glutamine

increases_activity of

process

insulin secretion

in pancreatic beta cells; via leucine-activated GLUD1
Comment L-Glutamine strongly up-regulated both the calcineurin catalytic and regulatory subunit mRNA expression in BRIN-BD11 beta-cells. Calcineurin, or protein phosphatase 2B, is a calcium-binding protein that has been shown to contribute to the mechanism of somatostatin-induced inhibition of exocytosis in mouse pancreatic beta-cells. However, calcineurin has been identified as a key activator of NFAT (nuclear factor of activated T-cells) signalling in pancreatic beta-cells. NFAT dephosphorylation and activation promotes the expression of cell cycle regulators and increases beta-cell proliferation and mass. Additionally, NFAT activation induces the expression of genes, including metabolic enzymes, critical for beta-cell endocrine function. Indeed, mutation of these calcineurin/NFAT dependent genes results in hereditary forms of monogenic Type 2 diabetes.
Formal Description
Interaction-ID: 34829

drug/chemical compound

Glutamine

increases_expression of

gene/protein

PPP3C

Comment L-Glutamine strongly up-regulated both the calcineurin catalytic and regulatory subunit mRNA expression in BRIN-BD11 beta-cells. Calcineurin, or protein phosphatase 2B, is a calcium-binding protein that has been shown to contribute to the mechanism of somatostatin-induced inhibition of exocytosis in mouse pancreatic beta-cells. However, calcineurin has been identified as a key activator of NFAT (nuclear factor of activated T-cells) signalling in pancreatic beta-cells. NFAT dephosphorylation and activation promotes the expression of cell cycle regulators and increases beta-cell proliferation and mass. Additionally, NFAT activation induces the expression of genes, including metabolic enzymes, critical for beta-cell endocrine function. Indeed, mutation of these calcineurin/NFAT dependent genes results in hereditary forms of monogenic Type 2 diabetes.
Formal Description
Interaction-ID: 34832

drug/chemical compound

Glutamine

increases_expression of

gene/protein

PPP3R

Comment Although L-glutamine is rapidly taken up and metabolized by islets, it alone does not stimulate insulin secretion or enhance glucose-induced insulin secretion. However, activation of GDH (glutamate dehydrogenase) by addition of leucine enhances insulin secretion by increasing the entry of glutamine carbon into the tricarboxylic acid cycle. It is known that glucose inhibits glutaminolysis in beta-cells, presumably via GTP-dependent allosteric inhibition of GDH, resulting in accumulation of L-glutamate and thus product-dependent inhibition of glutaminase, and as a result blocks leucine-stimulated insulin secretion.
Formal Description
Interaction-ID: 34833

drug/chemical compound

Leucine

increases_activity of

gene/protein

GLUD1

Drugbank entries Show/Hide entries for GLUD1
Comment Although L-glutamine is rapidly taken up and metabolized by islets, it alone does not stimulate insulin secretion or enhance glucose-induced insulin secretion. However, activation of GDH (glutamate dehydrogenase) by addition of leucine enhances insulin secretion by increasing the entry of glutamine carbon into the tricarboxylic acid cycle. It is known that glucose inhibits glutaminolysis in beta-cells, presumably via GTP-dependent allosteric inhibition of GDH, resulting in accumulation of L-glutamate and thus product-dependent inhibition of glutaminase, and as a result blocks leucine-stimulated insulin secretion.
Formal Description
Interaction-ID: 34837

gene/protein

GLUD1

increases_activity of

drug/chemical compound

Glutamine

Drugbank entries Show/Hide entries for GLUD1
Comment Although L-glutamine is rapidly taken up and metabolized by islets, it alone does not stimulate insulin secretion or enhance glucose-induced insulin secretion. However, activation of GDH (glutamate dehydrogenase) by addition of leucine enhances insulin secretion by increasing the entry of glutamine carbon into the tricarboxylic acid cycle. It is known that glucose inhibits glutaminolysis in beta-cells, presumably via GTP-dependent allosteric inhibition of GDH, resulting in accumulation of L-glutamate and thus product-dependent inhibition of glutaminase, and as a result blocks leucine-stimulated insulin secretion.
Formal Description
Interaction-ID: 34838

drug/chemical compound

Glucose

decreases_activity of

process

glutamine catabolic process

in pancreatic beta cells
Comment As glutamate is known to inhibit glucagon secretion from the pancreatic alpha-cell, glutamate release from the beta-cell may additionally represent a novel paracrine mechanism for pancreatic islet hormone release.
Formal Description
Interaction-ID: 34839

drug/chemical compound

Glutamate

decreases_activity of

process

glucagon secretion

in pancreatic alpha cells
Comment Beta-cells overexpressing L-glutamate decarboxylase showed a reduced glutamate content and a reduction in glucose-stimulated insulin secretion.
Formal Description
Interaction-ID: 34847

gene/protein

GAD2

affects_activity of

process

insulin secretion involved in cellular response to glucose stimulus

in pancreas
Drugbank entries Show/Hide entries for GAD2
Comment Elevated plasma homocysteine levels have been reported in hyperinsulinaemic obese subjects and in subjects with Type 2 diabetes with pre-existing coronary vascular disease.
Formal Description
Interaction-ID: 34848

phenotype

increased circulating insulin level

increases_quantity of

drug/chemical compound

Homocysteine

Comment Homocysteine has a negative impact on insulin secretion in pancreatic beta-cells.
Formal Description
Interaction-ID: 34849

drug/chemical compound

Homocysteine

decreases_activity of

process

insulin secretion

in pancreatic beta cells