Liraglutide, a once‐daily human GLP‐1 analogue, improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Vilsbøll, Tina; Brock, Birgitte; Perrild, Hans; Levin, Klaus; Lervang, Hans-Henrik; Kølendorf, K; Krarup, Thure; Schmitz, O.; Zdravković, Milan; Le-Thi, T.; Madsbad, Sten

doi:10.1111/j.1464-5491.2007.02333.x

Cited by 199 publications

(137 citation statements)

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“…Type 2 diabetes mellitus (T2DM) tends to be progressive and islet β-cell failure is the major contributor to the natural progression of the disease (15). Liraglutide, a human GLP-1 analogue with a long half-life, is a new type of hypoglycaemic agent and may potentially delay the disease progression by improving β-cell function in T2DM and increasing β-cell mass in animal models (16,17). Accumulating evidence has demonstrated that liraglutide stimulates β-cell proliferation, induces islet neogenesis and inhibits β-cell apoptosis, thus leading to the expansion of β-cell mass in vitro (17,18).…”

Section: Discussionmentioning

confidence: 99%

The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide in β cells

et al. 2011

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Abstract. Numerous studies have shown that liraglutide, a modified form of human glucagon-like peptide-1 (GLP-1), increases β-cell mass. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the role of Akt/FoxO1/p27 signaling in liraglutide-induced β-cell proliferation. INS-1 rat insulinoma cells were exposed to two different concentrations of liraglutide. MTT assay was performed to evaluate β-cell proliferation. The expression of Akt/FoxO1/p27 was detected by quantitative real-time PCR and Western blotting. The results revealed that in comparison to the non-treatment group, stimulating INS-1 cells with 10 and 100 nM liraglutide caused β-cell proliferation to be significantly enhanced. The mRNA levels of p27 in INS-1 cells declined upon treatment with liraglutide compared to the non-treatment group. Western blot analysis revealed that the phosphorylation of Akt and FoxO1 was markedly elevated following exposure to liraglutide. Moreover, LY294002, a phosphatidylinositol 3-kinase (PI-3K) inhibitor, significantly abrogated liraglutide-induced effects. Therefore, we conclude that liraglutide increased the β-cell mass by upregulating β-cell proliferation and that the proliferative action of liraglutide in β cells was mediated by activation of PI-3K/Akt, which resulted in inactivation of FoxO1 and decreased p27.

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Section: Discussionmentioning

confidence: 99%

The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide in β cells

et al. 2011

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“…However, presently available meta-analyses include only published studies, without any attempt at retrieving data from completed and publicly disclosed, although not formally published, clinical trials. Since very few studies on liraglutide have been published in extensive form to date (3,(8)(9)(10), presently available meta-analysis do not provide comprehensive information on the clinical profile of this agent.…”

Section: Introductionmentioning

confidence: 99%

“…Other drugs of the same class, such as liraglutide (3), are presently under development, and will soon be available in many countries.…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials

Monami

Marchionni

Mannucci

2009

European Journal of Endocrinology

131

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Objective: The role of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information. Design and methods: All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with GLP-1 receptor agonists (exenatide and liraglutide), with a durationO12 weeks were meta-analysed for HbA1c, body mass index, hypoglycaemia and other adverse events. Results and conclusions: A total of 21 RCTs (six of which unpublished), enrolling 5429 and 3053 patients (with GLP-1 receptor agonists and active comparator or placebo respectively), was retrieved and included in the analysis. GLP-1 receptor agonists determine a significant improvement of HbA1c in comparison with placebo (K1.0 (K1.1, K0.8), P!0.001), with a low risk of hypoglycaemia. There is no evidence of increased cardiovascular risk with the use of GLP-1 receptor agonists. GLP-1 receptor agonists, which induce weight loss, are associated with gastrointestinal side effects. GLP-1 receptor agonists are effective in reducing HbA1c and postprandial glucose. In patients failing to sulphonylureas and/or metformin, GLP-1 receptor agonists are similarly effective as insulin. Available data suggest that the efficacy and tolerability of the novel agent, liraglutide, which is adequate for oncea-day administration, are comparable with those of exenatide bis in die.European Journal of Endocrinology 160 909-917

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“…Liraglutide has also shown favourable effects on several parameters of b-cell function [30][31][32][33][34] and to improve early markers of cardiovascular disease [35].…”

Section: Introductionmentioning

confidence: 99%

Effect of renal impairment on the pharmacokinetics of the GLP‐1 analogue liraglutide

Jacobsen

Hindsberger

Robson

et al. 2009

Brit J Clinical Pharma

196

127

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Patients with Type 2 diabetes are likely to have or to develop renal impairment, which affects the pharmacokinetics of some antidiabetic treatments.• Whether dosing of the once-daily human glucagon-like peptide-1 analogue liraglutide should be modified in patients with renal impairment has not previously been studied. WHAT THIS STUDY ADDS• Renal dysfunction was not found to increase the exposure of liraglutide. • Hence, no dose adjustment is expected to be required in patients with Type 2 diabetes and renal impairment treated with liraglutide. AIMSTo investigate whether dose adjustment of the once-daily human glucagon-like peptide-1 analogue liraglutide is required in patients with varying stages of renal impairment. METHODSA cohort of 30 subjects, of whom 24 had varying degrees of renal impairment and six had normal renal function, were given a single dose of liraglutide, 0.75 mg subcutaneously, and completed serial blood sampling for plasma liraglutide measurements for pharmacokinetic estimation. RESULTSNo clear trend for change in pharmacokinetics was evident across groups with increasing renal dysfunction. While the between-group comparisons of the area under the liraglutide concentrationcurve (AUC) did not demonstrate equivalence [estimated ratio AUCsevere/AUChealthy 0.73, 90% confidence interval (CI) 0.57, 0.94; and AUC (continuous ambulatory peritoneal dialysis)CAPD/AUChealthy 0.74, 90% CI 0.56, 0.97], the regression analysis of log(AUC) for subjects with normal renal function and mild-to-severe renal impairment showed no significant effect of decreasing creatinine clearance on the pharmacokinetics of liraglutide. The expected AUC ratio between the two subjects with the lowest and highest creatinine clearance in the study was estimated to be 0.88 (95% CI 0.58, 1.34) (NS). Degree of renal impairment did not appear to be associated with an increased risk of adverse events. CONCLUSIONSThis study indicated no safety concerns regarding use of liraglutide in patients with renal impairment. Renal dysfunction was not found to increase exposure of liraglutide, and patients with Type 2 diabetes and renal impairment should use standard treatment regimens of liraglutide. There is, however, currently limited experience with liraglutide in patients beyond mild-stage renal disease.

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Liraglutide, a once‐daily human GLP‐1 analogue, improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Cited by 199 publications

References 20 publications

The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide in β cells

The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide in β cells

Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials

Effect of renal impairment on the pharmacokinetics of the GLP‐1 analogue liraglutide

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