Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

Cervera, Antonio; Wajcberg, Estela; Sriwijitkamol, Apiradee; Fernandez, M.; Zuo, Pingping; Triplitt, Curtis; Musi, Nicolas; DeFronzo, Ralph A.; Cersósimo, Eugênio

doi:10.1152/ajpendo.00030.2008

Cited by 147 publications

(111 citation statements)

References 31 publications

(37 reference statements)

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“…The profile is characterised by low postprandial glucose concentrations with concomitantly reduced insulin or C-peptide levels. The reduction in postprandial glucose levels, as was only seen in the breakfast meal in this study, in addition to improvement in β-cell function, is caused by reduced gastric emptying (22), glucagon secretion (6) and EGP (12). Due to the short duration of action of EXE, none of its effects was observed following the second meal.…”

Section: Discussionmentioning

confidence: 55%

“…in the postprandial state. In this state, the GLP1 receptor agonist EXE also induces effects beyond the β-cell, including inhibition of gastric emptying, reduction of glucagon levels and endogenous glucose production (EGP) (12). In this study, in contrast to the previous publication, the patients were undergoing treatment during the β-cell function analyses.…”

Section: Introductionmentioning

confidence: 94%

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Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

Raalte

Bunck

Hoekstra

et al. 2016

European Journal of Endocrinology

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Objective: Glucagon-like peptide (GLP)-1 receptor agonist treatment improves β-cell function. In this study, we investigated whether the improvements are sustained during a 3-year treatment period. Research design and methods: Sixty-nine metformin-treated type 2 diabetes patients were randomised to the GLP1 receptor agonist, exenatide (EXE) twice daily (BID) or to insulin glargine (GLAR). β-cell function parameters were derived using the Mari model from standardised breakfast and lunch meals that were administered before treatment, and after 1 and 3 years of treatment. EXE was administered before breakfast. Results: Fifty-nine (EXE: n = 30; GLAR: n = 29) and thirty-six (EXE: n = 16; GLAR: n = 20) patients completed the meal at 1-and 3-year treatment respectively. After 3 years, groups had comparable glycaemic control (HbA1c: EXE 6.6 ± 0.2% and GLAR 6.9 ± 0.2%; P = 0.216). Compared with GLAR, at 1 and 3 years, EXE induced a stronger reduction in post-breakfast glucose concentrations (P < 0.001), with lower C-peptide levels (P < 0.001). Compared with GLAR, EXE increased insulin secretion at 8 mmol/L glucose throughout the study period (P < 0.01). Both treatments improved β-cell glucose sensitivity after 1-year treatment. However, only EXE treatment sustained this improvement for 3 years. No consistent changes in other β-cell parameters including rate sensitivity and potentiation were observed. Conclusions: Compared with GLAR, EXE improved the parameters of β-cell function, especially insulin secretion at 8 mmol/L glucose and β-cell glucose sensitivity, which was sustained during the 3-year treatment period.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 94%

Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

Raalte

Bunck

Hoekstra

et al. 2016

European Journal of Endocrinology

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“…The principal effects of GLP‐1 receptor agonists are to induce pancreatic insulin secretion, slow gastric emptying, and suppress postprandial glucagon secretion 15, 34, 35, 36, 37. Since increases in t max and t 1/2b of the gastric emptying rate were observed in the lixisenatide group vs the sitagliptin group, it is likely that slowing of gastric emptying was the driver for PPG reduction in this study, rather than insulinotropic effects.…”

Section: Discussionmentioning

confidence: 83%

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study)

Yamada

Senda

Naito

et al. 2017

Diabetes Obesity Metabolism

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AimTo evaluate the pharmacodynamics of lixisenatide once daily vs sitagliptin once daily in Japanese patients with type 2 diabetes receiving insulin glargine U100.Materials and methodsThis multicentre, open‐label, phase IV study (NEXTAGE Study; ClinicalTrials.gov number, NCT02200991) randomly assigned 136 patients to either lixisenatide once daily via subcutaneous injection (10 µg initially increased weekly by 5 up to 20 µg) or once‐daily oral sitagliptin 50 mg. The primary endpoint was the change in postprandial glucose (PPG) exposure 4 hours after a standardized breakfast (PPG area under the plasma glucose concentration–time curve [AUC0 :00‐4:00h]) from baseline to day 29.ResultsLixisenatide reduced PPG exposure to a statistically significantly greater extent than sitagliptin: least squares (LS) mean change from baseline in PPG AUC0 :00‐4:00h was −347.3 h·mg/dL (−19.3 h·mmol/L) in the lixisenatide group and −113.3 h·mg/dL (−6.3 h·mmol/L) in the sitagliptin group (LS mean between‐group difference −234.0 h·mg/dL [−13.0 h·mmol/L], 95% confidence interval −285.02 to −183.00 h·mg/dL [−15.8 to −10.2 h·mmol/L]; P < .0001). Lixisenatide led to significantly greater LS mean reductions in maximum PPG excursion than sitagliptin (−122.4 vs −46.6 mg/dL [−6.8 vs −2.6 h·mmol/L]; P < .0001). Change‐from‐baseline reductions in exposure to C‐peptide, fasting glycoalbumin levels, and the gastric emptying rate were greater in the lixisenatide than in the sitagliptin group. The incidence of treatment‐emergent adverse events was higher with lixisenatide (60.9%) than with sitagliptin (16.4%), with no serious events or severe hypoglycaemia reported.ConclusionLixisenatide reduced PPG significantly more than sitagliptin, when these agents were added to basal insulin glargine U100, and was well tolerated.

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“…Endogenous glucose production by the liver was suppressed by 45% with exenatide treatment, with increased insulin secretion and diminished glucagon release. 31 Exenatide administration also resulted in delayed gastric emptying and retention of glucose within the splanchnic area. 31 Preclinical and clinical studies have sought to evaluate the effects of GLP-1 receptor agonists and DDP-4 inhibitors on β-cell function.…”

Section: Modulating the Incretin System In Type 2 Dmmentioning

confidence: 99%

“…31 Exenatide administration also resulted in delayed gastric emptying and retention of glucose within the splanchnic area. 31 Preclinical and clinical studies have sought to evaluate the effects of GLP-1 receptor agonists and DDP-4 inhibitors on β-cell function. Preclinical work has shown that GLP-1 receptor agonists inhibit β-cell apoptosis and stop or slow the progressive destruction of β cells in animals.…”

Section: Modulating the Incretin System In Type 2 Dmmentioning

confidence: 99%

A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes Mellitus

Freeman

2010

Mayo Clinic Proceedings

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Philadelphia, PA 19131-1626 (jeffreyfreemando@aol.com). © 2010 Mayo Foundation for Medical Education and ResearchT he pathophysiologic defects that characterize type 2 diabetes mellitus (DM) include insulin resistance in liver and skeletal muscle and pancreatic β-cell dysfunction. Initially, β cells are able to increase insulin secretion sufficiently to offset insulin resistance, thus maintaining normoglycemia. When β cells are no longer able to compensate, plasma glucose levels increase. 1 Recent findings indicate that defects in β-cell function and increased insulin resistance occur early in the natural history of type 2 DM and can be present for 3 to 6 years before diagnosis. 2 Also, DM-related complications or tissue damage is evident in approximately 50% of individuals with type 2 DM at the time of diagnosis. 3 Progressive β-cell dysfunction is pathognomonic of the natural history of type 2 DM. Data from the longitudinal United Kingdom Prospective Diabetes Study (UKPDS) 16 showed that, over time, patients experience increasing A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes MellitusJeffrey S. Freeman, DO Progressive deterioration of β-cell function is a hallmark of type 2 diabetes mellitus (DM). Together with increasing insulin resistance in peripheral tissues (in both the liver and the skeletal muscle), the inability of pancreatic insulin secretion to manage fasting and postprandial glucose levels results in hyperglycemia. Currently available oral antidiabetes agents improve glycemic parameters, but no single drug addresses the numerous pathophysiologic defects known to contribute to hyperglycemia in patients with type 2 DM. Dysregulation in the incretin system is another component of the pathophysiologic processes that lead to DM. Agents used to correct defects in the incretin system, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, offer the potential to restore glucose-dependent insulin secretion and improve β-cell function. Glucagon-like peptide 1 receptor agonists also promote weight loss and provide beneficial effects on cardiovascular risk factors. A new approach that promotes the selection of pharmacotherapy for the treatment of patients with DM, with the goal of slowing or reversing the natural history of the disease, may be in order. Clinicians can select agents to address specific pathophysiologic defects to improve glycemia, with the hope of preventing the development of complications. Even patients receiving intensive therapy that improved mean hemoglobin A 1c (HbA 1c ) levels from 6.9% at baseline to 6.1% at 1 year showed deterioration of results over time; after 6 years, the mean HbA 1c level for these patients was 7.1%. 4 In UKPDS 49, the proportion of patients who maintained target glycemic levels decreased markedly during 9 years of follow-up. This decrease is consistent with progressive deterioration in β-cell function, such that only 50% of patients maintained their glycemic goal...

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Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

Cited by 147 publications

References 31 publications

Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study)

A Physiologic and Pharmacological Basis for Implementation of Incretin Hormones in the Treatment of Type 2 Diabetes Mellitus

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