Characteristic of GLP-1 effects on glucose metabolism in human skeletal muscle from obese patients

Villanueva-Peñacarrillo, María Luisa; Martín‐Duce, Antonio; Ramos-Álvarez, Irene; Gutiérrez‐Rojas, Irene; Moreno, Paola; Nuche-Berenguer, Bernardo; Acitores, Alicia; Sancho, Verónica; Valverde, Isabel; González, Nieves

doi:10.1016/j.regpep.2011.03.002

Cited by 18 publications

(13 citation statements)

References 37 publications

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“…However, in myocytes from patients with OB/T2D, although the presence of the ligand at the same concentration exerted a significant stimulatory effect on PKB and p70s6K phosphorylation, this effect did not differ to that previously observed in myocytes from patients with T2D (18). The basal phosphorylation levels of PKB, p70s6K, p42/p44 MAPKs and p90RSK1 were significantly lower in the cells from patients with OB/T2D compared to those from normal subjects, as previously observed in patients with obesity, apart from p90RSK-1, where no modification was reported (18,26). However, in cells from patients with T2D, no decrease in basal kinase activity was detected (18,27), which seems to reflect a major influence of obesity on the reduced basal level detected in patients with OB/T2D.…”

Section: Discussionsupporting

confidence: 81%

“…Specifically, treatment of the cells from patients with OB/T2D with 10 −12 M of the compound induced a significant increment in glucose transport, with maximal effects observed at 10 −11 M. This finding suggests a relevant sensitivity of cells from patients with OB/T2D to the BRS-3 ligand. Although no effects of insulin on glucose uptake in adipocytes in BRS-3-KO mice (possibly due to an impaired GLUT-4 translocation) has been observed (11), in our study, in myocytes from patients with OB/T2D, both the BRS-3 agonist and insulin affected glucose transport, as has been previously reported in myocytes from patients with either OB or T2D (5,26,27). …”

Section: Discussionsupporting

confidence: 71%

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Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

González

Martín‐Duce

Martínez-Arrieta

et al. 2015

International Journal of Molecular Medicine

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Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein-coupled receptor (GPCR) member of the bombesin receptor family. Several studies have suggested an association between obesity, alterations in glucose metabolism, diabetes and the BRS-3 receptor. In this study, we focused on patients simultaneously diagnosed with obesity and type 2 diabetes (OB/T2D). The analysis of BRS-3 expression in the skeletal muscle of these patients revealed a marked decrease in the expression of BRS-3 at the mRNA (23.6±1.3-fold downregulation, p<0.0001) and protein level (49±7% decrease, p<0.05) compared to the normal patients (no obesity and diabetes). Moreover, in cultured primary myocytes from patients with OB/T2D, the synthetic BRS-3 agonist, [D-Try6,β-Ala11,Phe13,Nle14]bombesin6–14, significantly increased the phosphorylation levels of mitogen-activated protein kinase (MAPK), p90RSK1, protein kinase B (PKB) and p70s6K. Specifically, the ligand at 10−11 M induced the maximal phosphorylation of MAPKs (p42, 159±15% of the control; p44, 166±11% of the control; p<0.0001) and p90RSK1 (148±2% of the control, p<0.0001). The basal phosphorylation levels of all kinases were reduced (p<0.05) in the patients with OB/T2D compared to the normal patients. Furthermore, the BRS-3 agonist stimulated glucose transport, which was already detected at 10−12 M (133±9% of the control), reached maximal levels at 10−11 M (160±9%, p<0.0001) and was maintained at up to 10−8 M (overall mean, 153±7%; p<0.007). This effect was less promiment than that attained with 10−8 M insulin (202±9%, p=0.009). The effect of the agonist on glycogen synthase a activity achieved the maximum effect at 10−11 M (165±16% of the control; p<0.0001), which did not differ from that observed with higher concentrations of the agonist. These results suggest that muscle cells isolated from patients with OB/T2D have extremely high sensitivity to the synthetic ligand, and the effects are particularly observed on MAPK and p90RSK1 phosphorylation, as well as glucose uptake. Moreover, our data indicate that BRS-3 may prove to be useful as a potential therapeutic target for the treatment of patients with OB/T2D.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 71%

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

González

Martín‐Duce

Martínez-Arrieta

et al. 2015

International Journal of Molecular Medicine

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“…However, the results of more recent in vitro studies are compatible with the presence of GLP-1 receptors in human hepatocytes [3,4]. Additionally, GLP-1 has been reported to increase glucose transporter levels and insulin-mediated glucose uptake in 3T3-L1 adipocytes [5], and glucose transport in cultured human myocytes [6]. GLP-1 receptor mRNA has also been described in neurons in the hepatic portal region [7].…”

Section: Introductionmentioning

confidence: 70%

Direct effect of GLP-1 infusion on endogenous glucose production in humans

et al. 2012

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Aims/hypothesis Glucagon-like peptide-1 (GLP-1) lowers glucose levels by potentiating glucose-induced insulin secretion and inhibiting glucagon release. The question of whether GLP-1 exerts direct effects on the liver, independently of the hormonal changes, is controversial. We tested whether an exogenous GLP-1 infusion, designed to achieve physiological postprandial levels, directly affects endogenous glucose production (EGP) under conditions mimicking the fasting state in diabetes. Methods In 14 healthy volunteers, we applied the pancreatic clamp technique, whereby plasma insulin and glucagon levels are clamped using somatostatin and hormone replacement. The clamp was applied in paired, 4 h experiments, during which saline (control) or GLP-1(7-37)amide (0.4 pmolmin −1 kg −1 ) was infused. Results During the control study, plasma insulin and glucagon were maintained at basal levels and plasma C-peptide was suppressed, such that plasma glucose rose to a plateau of ∼10.5 mmol/l and tracer-determined EGP increased by ∼60%. During GLP-1 infusion at matched plasma glucose levels, the rise of EGP from baseline was fully prevented. Lipolysis (as indexed by NEFA concentrations and tracerdetermined glycerol rate of appearance) and substrate utilisation (by indirect calorimetry) were similar between control and GLP-1 infusion. Conclusions/interpretation GLP-1 inhibits EGP under conditions where plasma insulin and glucagon are not allowed to change and glucose concentrations are matched, indicating either a direct effect on hepatocytes or neurally mediated inhibition.

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“…Glucagon-like peptide-1 (GLP-1) has been the most well studied of these gut hormones. The effect of GLP-1 on peripheral tissue has demonstrated some effect on glucose uptake in adipocytes and skeletal muscle cells [42][43]. However, the authors feel the effect of GLP-1 has more clinically significant effects on pancreatic function.…”

Section: Effects Of Gastric Bypass Surgery On Insulin Resistancementioning

confidence: 99%

Understanding the Effects of Roux-en-Y Gastric Bypass (RYGB) Surgery on Type 2 Diabetes Mellitus

Lau¹,

Radin²,

Brathwaite³

et al. 2013

Type 2 Diabetes

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Characteristic of GLP-1 effects on glucose metabolism in human skeletal muscle from obese patients

Cited by 18 publications

References 37 publications

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

Direct effect of GLP-1 infusion on endogenous glucose production in humans

Understanding the Effects of Roux-en-Y Gastric Bypass (RYGB) Surgery on Type 2 Diabetes Mellitus

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