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

Kumar, M. Sunil; Hunag, Y; Glinka, Yelena; Prud’homme, Gérald J.; Wang, Q

doi:10.1038/sj.gt.3302836

Cited by 64 publications

(79 citation statements)

References 70 publications

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“…This sustained increase in insulin correlated with a sustained GLP-1 expression in plasma ( Figure 2) and improved glucose tolerance. It has also been reported that GLP-1 could stabilize insulin mRNA and increase insulin transcription, consistent with recent results where increased serum insulin levels were shown in GLP-1/IgG1-Fc-treated db/db mice 47 and our pVax1-GLP-1-treated ZDF rats. However, there have been several reports showing that serum insulin levels in GLP-1-treated animals decreased because of an improvement in insulin sensitivity.…”

Section: Discussionsupporting

confidence: 93%

“…injection of a plasmid expressing a GLP-1/IgG-Fc fusion construct significantly lowered fasting blood glucose levels in db/db mice and enhanced b-cell mass in streptozocin-induced type 1 diabetes. 47 Adenoviral expression vectors, encoding GLP-1 linked to a leader sequences, have also been developed and have produced a promising re-establishment of homeostatic glucose levels in diabetic animal models such as ZDF, db/db mice and non-obese diabetic/severe combined immunodeficiency mice. 48,58 When compared with these previous studies, chitosan-mediated gene delivery of recombinant GLP-1 showed an enhanced longevity of expression and glucose normoregulation.…”

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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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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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“…Conclusion: Administration of GLP-1 via this method did have long lasting anti-diabetogenic effect on these animals. (Kumar et al, 2006) Table 4 In vitro cell systems used to study the differentiation properties of GLP-1R agonists in various cell types. Monkey Embryonic Stem Cells Ex-4 (1 nM) C-peptide, PDX-1 and NeuroD expressed in treated cells Expanded clonal population of mouse pancreatic neuroendocrineEx-4 (10 nM) Used in the culture medium along with other pancreatic hormone differentiation factors, 130 bFGF, EGF and Activin-A (Seaberg et al, 2004) …”

Section: % Partial Pancreatectomy Balb/c Mice and Glp-1r −/−mentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

583

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…[53][54][55] Others have fused GLP-1 to various proteins such as IgG or albumin to improve circulating half-lives. 18,56 In each of these studies, the therapeutic effects of GLP-1 were achieved following systemic increase in GLP-1 levels. Although continuous infusion of GLP-1 in humans has not been associated with decreased receptor activation, the effects associated with chronic and continuous high levels of circulating GLP-1 are likely not yet fully appreciated.…”

Section: Aav-mediated Expression Of Glp-1 In Beta-cells Mj Riedel Et Almentioning

confidence: 99%

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

et al. 2009

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that performs a wide array of well-characterized antidiabetic actions, including stimulation of glucose-dependent insulin secretion, upregulation of insulin gene expression and improvements in beta-cell survival. GLP-1-receptor agonists have been developed for treatment of diabetes; however, the short biological half-lives of these peptide-based therapeutics requires that frequent injections be administered to maintain sufficient circulating levels. Thus, novel methods of delivering GLP-1 remain an important avenue of active research. It has recently been demonstrated that self-complimentary, double-stranded, adeno-associated virus serotype-8 (DsAAV8) can efficiently transduce pancreatic beta-cells in vivo, resulting in long-term transgene expression. In this study, we engineered a DsAAV8 vector containing a GLP-1 transgene driven by the mouse insulin-II promoter (MIP). Biological activity of the GLP-1 produced from this transgene was assessed using a luciferase-based bioassay. DsAAV8-MIP-GLP-1 was delivered via intraperitoneal injection and beta-cell damage induced by multiple low dose streptozotocin (STZ) administration. Glucose tolerance was assessed following intraperitoneal glucose injections and beta-cell proliferation measured by PCNA expression. Expression of GLP-1 in Min6 beta-cells resulted in glucose-dependent secretion of biologically active GLP-1. Intraperitoneal delivery of DsAAV8-MIP-GLP-1 to mice led to localized GLP-1 expression in beta-cells and protection against development of diabetes induced by multiple low-dose STZ administration. This protection was associated with significant increase in beta-cell proliferation. Results from this study indicate that expression and secretion of GLP-1 from beta-cells in vivo via DsAAV8 represents a novel therapeutic strategy for treatment of diabetes.

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

Cited by 64 publications

References 70 publications

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

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

Mechanisms of action of glucagon-like peptide 1 in the pancreas

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

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