Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate

Kim, Jung‐Guk; Baggio, Laurie L.; Bridon, Dominique; Castaigne, Jean‐Paul; Robitaille, Martin; Jetté, Lucie; Benquet, Corinne; Drucker, Daniel J.

doi:10.2337/diabetes.52.3.751

Cited by 206 publications

(120 citation statements)

References 53 publications

(54 reference statements)

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“…However, in vitro studies have shown that the fusion protein displays a lower potency than Ex-4. 28,30 These shortcomings continue to foster complementary efforts to generate more potent longer-acting agents with sustained efficacy in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Albumin protein-conjugated GLP-1 molecules (Albugon and CJC-1131) display many anti-diabetic and other beneficial features of GLP-1 along with a substantially prolonged half-life. 28,30 Although DPP-IV-resistant GLP-1R agonists appear to be promising therapeutic drug candidates for the treatment of diabetes, these peptides require once-or twice-daily injections and/or combination therapies with oral diabetic medications. The substantially prolonged half-life of GLP-1-albumin fusion proteins is likely due to reduced renal clearance as a result of its larger size.…”

Section: Introductionmentioning

confidence: 99%

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Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

et al. 2006

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Glucagon-like peptide (GLP-1), a major physiological incretin, plays numerous important roles in modulating blood glucose homeostasis and has been proposed for the treatment of type 2 diabetes. The major obstacles for using native GLP-1 as a therapeutic agent are that it must be delivered by a parenteral route and has a short half-life. In an attempt to develop a strategy to prolong the physiological t 1/2 and enhance the potency of GLP-1, a fusion protein consisting of active human GLP-1 and mouse IgG 1 heavy chain constant regions (GLP-1/Fc) was generated. A plasmid encoding an IgK leader peptide-driven secretable fusion protein of the active GLP-1 and IgG 1 -Fc was constructed for mammalian expression. This plasmid allows for expression of bivalent GLP-1 peptide ligands as a result of IgG-Fc homodimerization. In vitro studies employing purified GLP-1/ Fc indicate that the fusion protein is functional and elevates cAMP levels in insulin-secreting INS-1 cells. In addition, it stimulates insulin secretion in a glucose concentrationdependent manner. Intramuscular gene transfer of the plasmid in db/db mice demonstrated that expression of the GLP-1/Fc peptide normalizes glucose tolerance by enhancing insulin secretion and suppressing glucagon release. This strategy of using a bivalent GLP-1/Fc fusion protein as a therapeutic agent is a novel approach for the treatment of diabetes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

et al. 2006

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“…The proliferative effect of GLP-1 has been shown in previous studies where GLP-1 treatment increased b-cell mass by twofold in normal and diabetic mice. [49][50][51] Chitosan 92-10-5 delivery of pVax1-GLP-1 showed the most elevated plasma GLP-1 and insulin levels and glucose tolerance when compared with other formulations consistent with the greatest expression in HepG2 cells in vitro and without any apparent toxicity both in vitro and in vivo. We have previously investigated the coupling effect of chitosan DDA and MW for plasmid delivery and found that maximum transgene expression occurs for DDA:MW values that run along a diagonal from high DDA/low MW to low DDA/high MW.…”

Section: Discussionmentioning

confidence: 88%

“…40 However, several reports indicate an absence of anoretic effects for several GLP-1 analogs in spite of a clear insulinotropic glucose-lowering effects. 51 For example, treatment with Ex-4, a long lasting GLP-1R agonist in db/db mice, did not induce any change in body weight nor in peripheral insulin sensitivity. 62 Here we show the ability of specific chitosan formulation to deliver a native recombinant GLP-1 by the plasmid rather than a modified peptide sequence in vivo in a diabetic model, thus restoring quasi normoglycemic levels as well additional biological functions regulated by GLP-1 in a pleiotropic manner.…”

Section: Discussionmentioning

confidence: 93%

“…Taken together, the above results indicate that the approach of chitosan/plasmid-DNA GLP-1 delivery permits GLP-1 expression, thereby increasing insulin production and probably b-cell proliferation as indicated by previous studies. [49][50][51] Moreover, the proliferative/antiapoptotic effect of GLP-1 was characterized at the molecular level, where the binding of GLP-1 to its receptor activates the PI3-K pathway leading to the activation of Akt and p44MAPK cell survival/proliferation pathways. 57 It has been previously shown that the i.m.…”

Section: Discussionmentioning

confidence: 99%

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Effective and safe gene-based delivery of GLP-1 using chitosan/plasmid-DNA therapeutic nanocomplexes in an animal model of type 2 diabetes

et al. 2011

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates blood glucose level post-prandially. It has been proposed that GLP-1 can be used in type 2 diabetes (T2D) mellitus treatment because of its insulinotropic action. Despite its remarkable advantages, GLP-1 suffers the disadvantage of an extremely short half-life owing to its degradation by the dipeptidyl peptidase IV protease. One way of overcoming this drawback is GLP-1 gene delivery. Here we show effective and safe gene-based delivery of GLP-1 using chitosan/plasmid-DNA therapeutic nanocomplexes (TNCs) in Zucker diabetic fatty (ZDF) animal model of T2D. The expression plasmid fused the GLP-1 gene to a Furin cleavage site was driven by a cytomegalovirus promoter/enhancer. TNCs were prepared by mixing this plasmid with chitosans of specific molecular weight (MW), degree of deacetylation (DDA) and ratio of chitosan amine to DNA phosphate (N:P ratio). Animals injected with the TNC chitosan 92-10-5 (DDA-MW-N:P) showed GLP-1 plasma levels of about fivefold higher than that in non-treated animals and the insulinotropic effect of recombinant GLP-1 was shown by a threefold increase in plasma insulin concentration when compared with untreated animals. Intraperitoneal glucose tolerance tests revealed an efficacious decrease of blood glucose compared with controls for up to 24 days after treatment, where injections of this formulation allowed near-normalization of blood glucose level. TNCs composed of specific chitosans and GLP-1-expressing plasmid constructs showed an impressive ability to harness the profound therapeutic potential of GLP-1 for the treatment of T2D mellitus.

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New Drugs for the Treatment of Diabetes Mellitus

Bailey

2004

International Textbook of Diabetes Mellitus

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This chapter reviews agents other than insulin that are being considered or recently introduced for the treatment of hyperglycemia. These include agents that lower blood glucose by delaying the intestinal digestion and absorption of carbohydrates, increase insulin concentrations, or potentiate insulin action. Other agents under investigation act independently of insulin to enhance glucose utilization, reduce glucose production, decrease obesity, or increase glucose elimination. Intestinal carbohydrate digestion is delayed by fiber supplements and by agents that competitively inhibit α‐glucosidase enzymes (e.g., miglitol and voglibose), thereby decreasing postprandial glucose excursions. Several insulin secretagogues have been designed to rapidly and transiently close ATP‐sensitive potassium channels in the pancreatic B‐cells (e.g., novel meglitinides and imidazolines). Analogues of the intestinal incretin glucagon‐like peptide 1 (GLP‐1) (7‐36 amide), which are more stable and longer acting than the native peptide, act predominantly via the cAMP pathway within the B‐cells to potentiate nutrient‐induced insulin secretion, and enhance insulin biosynthesis. Additionally these agents delay gastric emptying, promote satiety, and, most interestingly, appear to increase formation of new B‐cells. Inhibitors of the circulating enzyme dipeptidyl peptidase 4 augment the effects of GLP‐1 by slowing the degradation of GLP‐1. Non‐peptide compounds have been identified that can activate insulin receptor signaling and prevent normal deactivation of insulin receptor signaling (e.g., inhibitors of certain protein tyrosine phosphatases). Several new thiazolidinedione and non‐thiazolidinedione peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists are in development, along with dual PPAR‐γ and ‐α agonists to address both hyperglycemia and dyslipidemia. Various anti‐obesity agents have been shown to benefit glycemic control, including new β 3 ‐adrenoceptor agonists to stimulate thermogenesis. The amylin analogue pramlintide, which acts centrally to reduce appetite, suppress glucagon secretion, and slow gastric emptying offers an adjunct to insulin therapy, without causing weight gain. Further agents are being considered to antagonize glucagon receptors, reduce the metabolic effects of glucocorticoids, and directly stimulate glucose uptake and metabolism by muscle. Approaches to reduce hepatic glucose output include compounds that inhibit glycogen phosphorylase, glucose‐6‐phosphatase, or other enzymes of gluconeogenesis. Increased glucose elimination is being considered by inhibiting renal glucose reabsorption.

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Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate

Cited by 206 publications

References 53 publications

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

Effective and safe gene-based delivery of GLP-1 using chitosan/plasmid-DNA therapeutic nanocomplexes in an animal model of type 2 diabetes

New Drugs for the Treatment of Diabetes Mellitus

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