GLP-1 Receptor Agonists and DPP-4 Inhibitors in the Treatment of Type 2 Diabetes

Department of Medicine, Lund University, SE-221 84 Lund, Sweden.
Hormone and Metabolic Research (Impact Factor: 2.12). 11/2004; 36(11-12):867-76. DOI: 10.1055/s-2004-826178
Source: PubMed


Glucagon-like peptide-1 (GLP-1) is an incretin hormone with antidiabetic action through its ability to stimulate insulin secretion, increase beta cell neogenesis, inhibit beta cell apoptosis, inhibit glucagon secretion, delay gastric emptying and induce satiety. It has therefore been explored as a novel treatment of type 2 diabetes. A problem is, however, that GLP-1 is rapidly inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme, which results in a short circulating half-life of the active form of GLP-1 (< 2 min). Two strategies have been employed to overcome this obstacle as a treatment of diabetes. One is to use GLP-1 receptor agonists that have a prolonged half-life due to reduced degradation by DPP-4. These GLP-1 mimetics include exenatide and liraglutide. Another strategy is to inhibit the enzyme DPP-4, which prolongs the half-life of endogenously released active GLP-1. Both these strategies have been successful in animal studies and in clinical studies of up to one year's treatment. This review will summarize the background and the current (mid 2004) clinical experience with these two strategies.

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    • "GLP-1 by dipeptidyl peptidase-IV or administrating GLP-1 mimetics [2]. The benefits of increasing endogenous GLP-1 secretion are currently under evaluation, supported by evidence that gastric bypass surgery improves glucose tolerance, at least in part by increased GLP-1 secretion [3]. "
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from proglucagon, which is released from intestinal L-cells and increases insulin secretion in a glucose dependent manner. GPR119 is a lipid derivative receptor present in L-cells, believed to play a role in the detection of dietary fat. This study aimed to characterize the responses of primary murine L-cells to GPR119 agonism and assess the importance of GPR119 for the detection of ingested lipid. GLP-1 secretion was measured from murine primary cell cultures stimulated with a panel of GPR119 ligands. Plasma GLP-1 levels were measured in mice lacking GPR119 in proglucagon-expressing cells and controls after lipid gavage. Intracellular cAMP responses to GPR119 agonists were measured in single primary L-cells using transgenic mice expressing a cAMP FRET sensor driven by the proglucagon promoter. L-cells specific knockout of GPR119 dramatically decreased plasma GLP-1 levels after a lipid gavage. GPR119 ligands triggered GLP-1 secretion in a GPR119 dependent manner in primary epithelial cultures from the colon, but were less effective in the upper small intestine. GPR119 agonists elevated cAMP in ∼70% of colonic L-cells and 50% of small intestinal L-cells. GPR119 ligands strongly enhanced GLP-1 release from colonic cultures, reflecting the high proportion of colonic L-cells that exhibited cAMP responses to GPR119 agonists. Less GPR119-dependence could be demonstrated in the upper small intestine. In vivo, GPR119 in L-cells plays a key role in oral lipid-triggered GLP-1 secretion. Copyright © 2015. Published by Elsevier Inc.
    Peptides 07/2015; 132. DOI:10.1016/j.peptides.2015.06.012 · 2.62 Impact Factor
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    • "However, our study demonstrated that multiple brain regions showed cortical expansion, and we speculate that this expansion pattern implies the involvement of different mechanisms than those seen in obesity and the main cause may be associated with insulin therapy. The surface-based cortical thickness analysis was an objective and quantitative method for investigating subtle cortical structural changes; the longitudinal surface-based cortical thickness analysis could sensitively reveal the dynamic structural changes after insulin therapy and assess the therapeutic effect on the brain when using insulin or glucagon-like peptide-1 [24] [25] [26]. All of the patients involved in this study received diabetes education and nutritional counseling, and the BMI, FPG and HbA1c showed no significant differences between the baseline and follow-up time points. "
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    ABSTRACT: The purpose of this study was to explore the brain structural changes in type 2 diabetes and the effect of insulin on the brain using a surface-based cortical thickness analysis. High-resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MRI were obtained from 11 patients with type 2 diabetes before and after insulin therapy. The cortical thickness over the entire brain was calculated, and cross-sectional and longitudinal surface-based cortical thickness analyses were also performed. Regional cortical thinning was demonstrated in the middle temporal gyrus, posterior cingulate gyrus, precuneus, right lateral occipital gyrus and entorhinal cortex bilaterally for patients with type 2 diabetes mellitus compared with normal controls. Cortical thickening was seen in the middle temporal gyrus, entorhinal cortex and left inferior temporal gyrus bilaterally after patients underwent 1 year of insulin therapy. These findings suggest that insulin therapy may have recovering effects on the brain cortex in type 2 diabetes mellitus. The precise mechanism should be investigated further.
    Journal of Clinical Neuroscience 10/2014; 22(2). DOI:10.1016/j.jocn.2014.07.014 · 1.38 Impact Factor
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    • "GLP-1 receptor agonists work by mimicking the action of the endogenous incretin GLP-1, which acts to control glycemia via several pathways, including stimulation of insulin secretion, inhibition of glucagon secretion, delay of gastric emptying and induction of satiety [12]. DPP-4 inhibitors work by inhibiting the DPP-4 enzyme that breaks down GLP- 1, thus prolonging the half-life of endogenous GLP-1; DPP-4 inhibitors also augment gastric inhibitory polypeptide (GIP) signaling, which like GLP-1 signaling, stimulates insulin release in the presence of elevated glucose levels [12]. GLP-1 receptor agonists and DPP-4 inhibitors have been demonstrated to reduce glycated hemoglobin (HbA 1c ). "
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    ABSTRACT: Objective To compare the efficacy and safety of the once-daily prandial glucagon-like peptide-1 receptor agonist lixisenatide with the dipeptidyl peptidase-4 inhibitor sitagliptin in patients aged <50 years affected by obesity and type 2 diabetes mellitus (T2DM). Materials and methods This was a 24-week, double-blind, randomized, parallel-group study. Obese patients with T2DM inadequately controlled on metformin were randomized to lixisenatide 20 μg once-daily injection (n = 158) or once-daily oral sitagliptin 100 mg (n = 161). The primary endpoint was the proportion of patients with a glycated hemoglobin (HbA1c) <7% and ≥5% weight loss at 24 weeks. Results The proportion of patients that achieved the primary endpoint was 12.0% for lixisenatide versus 7.5% for sitagliptin; weighted average of proportion difference: 4.6%, p = 0.1696). A total of 40.7% of patients achieved HbA1c <7% with lixisenatide versus 40.0% with sitagliptin. Lixisenatide produced greater reductions in body weight (LS mean difference: −1.3 kg, p = 0.0006) and postprandial plasma glucose after a standardized meal test (LS mean difference: −34.4 mg/dL [−1.9 mmol/L], p = 0.0001) versus sitagliptin. There was a similar incidence of treatment-emergent adverse events (63.9% vs. 60.9%) and serious treatment-emergent adverse events (1.9% vs. 1.9%), with low rates of symptomatic hypoglycemia (0.6% vs. 1.9%) for lixisenatide and sitagliptin, respectively, and no cases of severe hypoglycemia. Conclusion In obese patients aged <50 years with T2DM, the proportion of patients with an HbA1c <7% with weight loss ≥5% was similar between groups. Lixisenatide, however, resulted in significantly greater reductions in body weight and postprandial plasma glucose excursions than sitagliptin. Tolerability was similar between groups.
    Journal of Clinical and Translational Endocrinology 06/2014; 1(2):31–37. DOI:10.1016/j.jcte.2014.03.001
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