Expression of CTB-10&amp;#215;rolGLP-1 in E.coli and Its Therapeutic Effect on Type 2 Diabetes

Tu, Peipei; Ma, Zhiyi; Wang, Haisong; Ma, Bo; Li, Xiaodan; Duan, Huikun; Jiang, Peng; Li, Miao; Wu, Ri; Zhu, Jian-Hong; Li, Minggang

doi:10.2174/138920101606150407114815

Cited by 7 publications

(3 citation statements)

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“…Lys residues are susceptible to serine protease cleavage. In previous studies, when Lys 26, 34 was replaced with Gln 26 and Asp 34 , the modified GLP-1 also exhibited greater resistance to proteolytic digestion than the native peptide [ 14 , 21 ]. In order to eliminate the DPP-IV target in GLP-1 and increase protease resistance, Ala 8 was replaced with Gly 8 , and Lys 26, 34 was replaced with Gln 26 and Asp 34 to synthesize a modified human GLP-1 (mGLP-1).…”

Section: Resultsmentioning

confidence: 99%

Bioactivity of a modified human Glucagon-like peptide-1

Wang

et al. 2017

PLoS ONE

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Diabetes has become the third largest cause of death in humans worldwide. Therefore, effective treatment for this disease remains a critical issue. Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis, and therefore represents a promising candidate to use for the treatment of diabetes. Native GLP-1, however, is quickly degraded in in the circulatory system; which limits its clinical application. In the present study, a chemically-synthesized, modified analogue of human GLP-1 (mGLP-1) was designed. Our analyses indicated that, relative to native GLP-1, mGLP-1 is more resistant to trypsin and pancreatin degradation. mGLP-1 promotes mouse pancreatic β-cell proliferation by up-regulating the expression level of cyclin E, CDK2, Bcl-2 and down-regulating Bax, p21, and stimulates insulin secretion. An oral glucose tolerance test indicated that mGLP-1 significantly improved glucose tolerance in mice. Intraperitoneal injections of mGLP-1 into streptozotocin (STZ)-induced type 2 diabetic mice significantly reduced blood sugar levels and stimulated insulin secretion. Oral gavages of mGLP-1 in diabetic mice did not result in significant hypoglycemic activity.

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Section: Resultsmentioning

confidence: 99%

Bioactivity of a modified human Glucagon-like peptide-1

Wang

et al. 2017

PLoS ONE

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“…However, the active forms of GLP-1, GLP-1(7-36) amide, and GLP-1(7-37), have a very short physiological half-life of less than 2 minutes. Different forms of human GLP-1 are expressed in different hosts but are still used as peptides and applied after protein purification [57][58][59]. Many groups have already investigated GLP-1 gene therapy for T2DM.…”

Section: Gene Therapy With Glp-1 and Its Analogsmentioning

confidence: 99%

Advances and potential of gene therapy for type 2 diabetes mellitus

Yue

Zhang

et al. 2019

Biotechnology & Biotechnological Equipment

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Gene therapy of type 2 diabetes mellitus (T2DM) and its complications has attracted intensive interest in recent years. In this paper, we critically review literature reports on gene therapy of T2DM published over the last five years. By reviewing these advances, three questions were addressed. First, which genes and how do they exert anti-diabetic effects? Target genes including that regulating glucose homeostasis, improving insulin secretion or sensitivity, and ameliorating diabetic induced complications are summarized. Second, how to deliver and which route is advantageous? All main methods that have been used for delivery of target genes into diabetic subjects are outlined and discussed regarding their pros and cons. Last, what are the future directions and how do these advances promote the study of T2DM gene therapy? Testing of novel targets in a parallel way and especially, using combinational approaches may be the main directions. In conclusion, there are a large number of genes playing important roles during the incidence and development of T2DM, and many of them hold great promise as potential targets for gene therapy. Oral delivery of target genes by probiotics may be a nice route with priority to develop, due to its high efficiency and safety for future gene therapy of T2DM. ARTICLE HISTORY

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“…Recombinant DNA biotechnology has the potential to overcome the disadvantages associated with chemical synthesis and produces these high-yields of peptides at a low cost. Currently, bacteria, yeast, and transgenic plants have been used as bioreactors to produce recombinant human GLP-1 [ 16 – 18 ]. It is worth noting that small peptides, such as GLP-1, are difficult to obtain when conventional expression and purification systems are used, due to the low molecular weight of the synthesized peptide and the susceptibility of the small peptides to degradation.…”

Section: Introductionmentioning

confidence: 99%

Modified human glucagon-like peptide-1 (GLP-1) produced in E. coli has a long-acting therapeutic effect in type 2 diabetic mice

Wang

et al. 2017

PLoS ONE

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Glucagon-like peptide 1 (GLP-1) is a very potent insulinotropic hormone secreted into the blood stream after eating. Thus, it has potential to be used in therapeutic treatment of diabetes. The half-life of GLP-1, however, is very short due to its rapid cleavage by dipeptidyl peptidase IV (DPP-IV). This presents a great challenge if it is to be used as a therapeutic drug. GLP-1, like many other small peptides, is commonly produced through chemical synthesis, but is limited by cost and product quantity. In order to overcome these problems, a sequence encoding a six codon-optimized tandem repeats of modified GLP-1 was constructed and expressed in the E. coli to produce a protease-resistant protein, 6×mGLP-1. The purified recombinant 6×mGLP-1, with a yield of approximately 20 mg/L, could be digested with trypsin to obtain single peptides. The single mGLP-1 peptides significantly stimulated the proliferation of a mouse pancreatic β cell line, MIN6. The recombinant peptide also greatly improved the oral glucose tolerance test of mice, exerted a positive glucoregulatory effect, and most notably had a glucose lowering effect for as long as 16.7 hours in mice altered to create a type 2 diabetic condition and exerted a positive glucoregulatory effect in db/db mice. These results indicate that recombinant 6×mGLP-1 has great potential to be used as an effective and cost-efficient drug for the treatment of type 2 diabetes.

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Expression of CTB-10×rolGLP-1 in E.coli and Its Therapeutic Effect on Type 2 Diabetes

Cited by 7 publications

References 0 publications

Bioactivity of a modified human Glucagon-like peptide-1

Bioactivity of a modified human Glucagon-like peptide-1

Advances and potential of gene therapy for type 2 diabetes mellitus

Modified human glucagon-like peptide-1 (GLP-1) produced in E. coli has a long-acting therapeutic effect in type 2 diabetic mice

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