Engineering physiologically regulated insulin secretion in non-β cells by expressing glucagon-like peptide 1 receptor

Wu, Lan; Nicholson, Wendell E.; Wu, Chuan‐Yu; McGaha, A; Shiota, Masakazu; Ac, Powers

doi:10.1038/sj.gt.3302055

Cited by 13 publications

(7 citation statements)

References 54 publications

(57 reference statements)

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“…Neuroendocrine cells have been proposed as candidates for glucoseresponsive insulin secretion because, like b-cells, they have active constitutive and regulated secretory pathways and express proprotein convertases PC2 and PC1/3 that are required for proinsulin processing. 6 A major drawback of neuroendocrine cells is that other hormones that are co-secreted with insulin may have adverse side effects. 7 The common ancestry of liver and pancreas-both arise from the gut endoderm during embryogenesis-and the biochemical functions of hepatocytes in glucose homeostasis and ketogenesis have spurred interest in redirecting the fate of cells in the adult liver to function as insulin-secreting pancreatic b-cells.…”

Section: Introductionmentioning

confidence: 99%

Efficient Production of Bioactive Insulin from Human Epidermal Keratinocytes and Tissue-Engineered Skin Substitutes: Implications for Treatment of Diabetes

Lei¹,

Ogunade²,

Kirkwood³

et al. 2007

Tissue Engineering

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Despite many years of research, daily insulin injections remain the gold standard for diabetes treatment. Gene therapy may provide an alternative strategy by imparting the ability to secrete insulin from an ectopic site. The epidermis is a self-renewing tissue that is easily accessible and can provide large numbers of autologous cells to generate insulin-secreting skin substitutes. Here we used a recombinant retrovirus to modify human epidermal keratinocytes with a gene encoding for human proinsulin containing the furin recognition sequences at the A-C and B-C junctions. Keratinocytes were able to process proinsulin and secrete active insulin that promoted glucose uptake. Primary epidermal cells produced higher amounts of insulin than cell lines, suggesting that insulin secretion may depend on the physiological state of the producer cells. Modified cells maintained the ability to stratify into 3-dimensional skin equivalents that expressed insulin at the basal and suprabasal layers. Modifications at the furin recognition sites did not improve proinsulin processing, but a single amino acid substitution in the proinsulin B chain enhanced Cpeptide secretion from cultured cells and bioengineered skin substitutes 10-and 28-fold, respectively. These results suggest that gene-modified bioengineered skin may provide an alternative means of insulin delivery for treatment of diabetes.

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Section: Introductionmentioning

confidence: 99%

Efficient Production of Bioactive Insulin from Human Epidermal Keratinocytes and Tissue-Engineered Skin Substitutes: Implications for Treatment of Diabetes

Lei¹,

Ogunade²,

Kirkwood³

et al. 2007

Tissue Engineering

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show abstract

“…Similarly, insulin secretion sufficient to protect mice from diabetes when their native β cells were destroyed was achieved by adding the insulin gene to intestinal K cells; these cells normally secrete glucose-dependent insulinotropic polypeptide (GIP) in response to glucose in the lumen of the gut [66]. Another class of professional secretory cells, in the pituitary, was engineered to secrete insulin in response to GLP-1 by supplying them with the genes for insulin and the GLP-1 receptor [67]. In vitro, the cells secreted insulin in response to GLP-1 but not glucose.…”

Section: Robustnessmentioning

confidence: 99%

Lessons from models of pancreatic β cells for engineering glucose-sensing cells

Sherman

2010

Mathematical Biosciences

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Mathematical models of pancreatic β cells suggest design principles that can be applied to engineering cells to sense glucose and secrete insulin. Engineering cells can potentially both contribute to future diabetes therapies and generate new insights into β cell function. The focus is on ion channels, Ca2+ handling, and elements of metabolism that combine to produce the varied oscillatory patterns exhibited by β cells.

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“…A variety of cell types have been engineered to produce insulin, including fibroblasts [1], hepatic cells [2][3][4][5], muscle cells [6,7] and endocrine cells of different origins [8][9][10]. While developing recombinant β-cell surrogates, the advantages of targeting intestinal enteroendocrine cells have received notable attention [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Differential rAAV2 transduction efficiencies and insulin secretion profiles in pure and co‐culture models of human enteroendocrine L‐cells and enterocytes

Tang

Sambanis

2004

The Journal of Gene Medicine

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Engineering physiologically regulated insulin secretion in non-β cells by expressing glucagon-like peptide 1 receptor

Cited by 13 publications

References 54 publications

Efficient Production of Bioactive Insulin from Human Epidermal Keratinocytes and Tissue-Engineered Skin Substitutes: Implications for Treatment of Diabetes

Efficient Production of Bioactive Insulin from Human Epidermal Keratinocytes and Tissue-Engineered Skin Substitutes: Implications for Treatment of Diabetes

Lessons from models of pancreatic β cells for engineering glucose-sensing cells

Differential rAAV2 transduction efficiencies and insulin secretion profiles in pure and co‐culture models of human enteroendocrine L‐cells and enterocytes

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