GLP-1-derived nonapeptide GLP-1(28–36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes

Tomàs, Eva; Stanojević, V; Habener, Joel F.

doi:10.1016/j.regpep.2011.01.003

Cited by 89 publications

(90 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with the in vivo observations, recently demonstrated that GLP-1(9-36)amide suppressed glucose production in isolated mouse hepatocytes by 30% over a dose range of 0.1-100 mM independently of the GLP-1 receptor. Furthermore, in a follow-up study by the same authors (Tomas et al, 2011b), dosedependent (0.01-10 mM) suppression of mitochondrial glucose production and oxidative stress by ;50% was also demonstrated in mouse hepatocytes with GLP-1(28-36)amide. In the case of GLP-1(28-36)amide, cytoprotective action was enhanced (0.1-100 nM) when a "solubilizing" formulation was used (Liu et al, 2012).…”

Section: Introductionmentioning

confidence: 81%

“…It is therefore likely that hepatic proteases (including DPP-IV and NEP) can metabolize native GLP-1(7-36)amide and its downstream metabolites GLP-1(9-36)amide and GLP-1(28-36)amide, generating structurally distinct N-terminustruncated peptides with potentially unique pharmacology. Against the backdrop of the recent data on the cytoprotective gluconeogenesis effects of GLP-1(9-36)amide and GLP-1(28-36)amide derivatives, respectively, in mouse hepatocytes (Tomas et al, , 2011b, we decided to examine their in vitro metabolic stability with an emphasis on characterizing novel downstream metabolites, as such an endeavor had not been undertaken in the primary literature.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Metabolism of the Glucagon-Like Peptide-1 (GLP-1)–Derived Metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in Mouse and Human Hepatocytes

et al. 2013

View full text Add to dashboard Cite

Previous studies have revealed that the glucoincretin hormone glucagon-like peptide-1 (GLP-1)(7-36)amide is metabolized by dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase 24.11 (NEP) to yield GLP-1(9-36)amide and GLP-1(28-36)amide, respectively, as the principal metabolites. Contrary to the previous notion that GLP-1(7-36)amide metabolites are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with both GLP-1(9-36)amide and GLP-1(28-36)amide in animals and humans. In the present work, we examined the metabolic stability of the two GLP-1(7-36)amide metabolites in cryopreserved hepatocytes, which have been used to demonstrate the in vitro insulin-like effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis. To examine the metabolic stability of the GLP-1(7-36)amide metabolites, a liquid chromatography-tandem mass spectrometry assay was developed for the quantitation of the intact peptides in hepatocyte incubations. GLP-1(9-36)amide and GLP-1(28-36)amide were rapidly metabolized in mouse [GLP-1(9-36)amide: t 1/2 = 52 minutes; GLP-1(28-36)amide: t 1/2 = 13 minutes] and human hepatocytes [GLP-1(9-36)amide: t 1/2 = 180 minutes; GLP-1(28-36)amide: t 1/2 = 24 minutes), yielding a variety of N-terminal cleavage products that were characterized using mass spectrometry. Metabolism at the C terminus was not observed for either peptides. The DPP-IV and NEP inhibitors diprotin A and phosphoramidon, respectively, did not induce resistance in the two peptides toward proteolytic cleavage. Overall, our in vitro findings raise the intriguing possibility that the insulinomimetic effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis and oxidative stress might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from the enzymatic cleavage of the peptide backbone in the parent compounds. IntroductionThe glucoincretin hormone glucagon-like peptide-1 (GLP-1) is derived from a proglucagon precursor and secreted by intestinal enteroendocrine L cells in response to oral nutrient ingestion (Kieffer and Habener, 1999;Holst, 2007;Lovshin and Drucker, 2009;Mundil et al., 2012). The majority of circulating GLP-1 levels comprise the 30-amino acid peptide GLP-1(7-36)amide, which acts through a seventransmembrane-spanning, heterotrimeric class B G protein-coupled receptor on pancreatic b cells to exert glucoregulatory and insulinotropic actions (Thorens, 1992). However, after its secretion from the intestine, native GLP-1(7-36)amide is rapidly degraded [half-life (t 1/2 ) = 1-2 minutes) on its N and C termini by the ubiquitously expressed enzymes dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase 24.11 (NEP) (Hansen et al., 1999;Holst, 2007), respectively, to yield GLP-1(9-36)amide and nonapeptide GLP-1(28-36)amide as metabolites (Deacon et al., 1995a,b;Hupe-Sodmann et al., 1995;Mentlein, 1999). In patients with type 2 diabetes mellitus, secretion of GLP-1 is diminished, and administration of e...

show abstract

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

In Vitro Metabolism of the Glucagon-Like Peptide-1 (GLP-1)–Derived Metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in Mouse and Human Hepatocytes

et al. 2013

View full text Add to dashboard Cite

show abstract

“…GLP-1 has been shown to protect against mitochondrial dysfunction in several cell types. For example, i) it has been shown that GLP-1 is involved in the mobilization of intracellular Ca 2C and the stimulation of mitochondrial ATP synthesis in cultured b-cells (Tsuboi et al 2003), and ii) the study of isolated mouse hepatocytes found that GLP-1 entered cells and acted on hepatocyte mitochondria to modulate oxidative phosphorylation and to suppress oxidative stress and ROS production in ND-fed mice and diet-induced obese mice (Tomas et al 2011). Furthermore, a recent study demonstrated that sitagliptin administration can increase active GLP-1 levels in the brain and improve memory behaviors in Alzheimer's disease mice models (D'Amico et al 2010).…”

Section: Discussionmentioning

confidence: 99%

DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats

Pintana

Apaijai²,

Chattipakorn³

2013

Journal of Endocrinology

169

View full text Add to dashboard Cite

Recent evidence has demonstrated that insulin resistance is related to the development of type 2 diabetes mellitus. Our previous study found that high-fat diet (HFD) consumption caused not only peripheral and brain insulin resistance but also brain mitochondrial dysfunction and cognitive impairment. Vildagliptin and sitagliptin, dipeptidyl-peptidase-4 inhibitors, are recently developed anti-diabetic drugs. However, the effects of both drugs on cognitive behaviors and brain mitochondrial function in HFD-induced insulin-resistant rats have not yet been investigated. Sixty male Wistar rats were divided into two groups to receive either normal diet or HFD for 12 weeks. Rats in each group were then further divided into three treatment groups to receive either vehicle, vildagliptin (3 mg/kg per day), or sitagliptin (30 mg/kg per day) for 21 days. The cognitive behaviors of the rats were tested using the Morris Water Maze test. Blood samples were collected to determine metabolic parameters and plasma oxidative stress levels. Upon completion of the study, the animals were killed and the brains were removed to investigate brain and hippocampal mitochondrial function as well as to determine oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD. Our findings suggest that the inhibition of dipeptidyl-peptidase-4 enzymes with vildagliptin or sitagliptin in insulinresistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction. Key Words" insulin resistance " high-fat diet " DDP-4 inhibitors " memory decline " brain mitochondrial dysfunction

show abstract

“…GLP-1 induces facilitation of neural afferents when injected intraportal, but this effect is not changed by Ex9-39 [282]. However, comparable to the effects of the nonapeptide GLP-1(28-36)amide, cleavage product of the enzyme NEP24.11, Ex9-39 weakly inhibits gluconeogenesis [283]. GLP-1(9-36)amide, which has been considered to be biologically inactive, shows insulin-like action in cultured hepatocytes and men [284,285].…”

Section: Per2 Induction Both In Vitro and In Vivomentioning

confidence: 97%

Metabolic Synchronization of the Liver Circadian Clock

Landgraf¹

2011

The Endocrine Society's 93rd Annual Meeting &Amp; Expo, June 4–7, 2011 - Boston

View full text Add to dashboard Cite

GLP-1-derived nonapeptide GLP-1(28–36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes

Cited by 89 publications

References 35 publications

In Vitro Metabolism of the Glucagon-Like Peptide-1 (GLP-1)–Derived Metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in Mouse and Human Hepatocytes

In Vitro Metabolism of the Glucagon-Like Peptide-1 (GLP-1)–Derived Metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in Mouse and Human Hepatocytes

DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats

Metabolic Synchronization of the Liver Circadian Clock

Contact Info

Product

Resources

About