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Abstract

Despite the fact that insulin injection can protect diabetic patients from developing diabetes-related complications, recent meta-analyses indicate that rapid and long-acting insulin analogues only provide a limited benefit compared with conventional insulin regarding glycemic control. As insulin deficiency is the main sequel of type-1 diabetes (T1D), transfer of the insulin gene-by-gene therapy is becoming an attractive treatment modality even though T1D is not caused by a single genetic defect. In contrast to human insulin and insulin analogues, insulin gene therapy targets to supplement patients not only with insulin but also with C-peptide. So far, insulin gene therapy has had limited success because of delayed and/or transient gene expression. Sustained insulin gene expression is now feasible using current gene-therapy vectors providing patients with basal insulin coverage, but management of postprandial hyperglycaemia is still difficult to accomplish because of the inability to properly control insulin secretion. Enteroendocrine cells of the gastrointestinal track (K cells and L cells) may be ideal targets for insulin gene therapy, but cell-targeting difficulties have limited practical implementation of insulin gene therapy for diabetes treatment. Therefore, recent gene transfer technologies developed to generate authentic beta cells through transdifferentiation are also highlighted in this review.

Figure 1 Human proinsulin encoding peptides. The top peptide is the wild-type human proinsulin sequence cleavable by prohormone convertases (PC1/3 or PC2), which are only expressed in beta cells, K cells, L cells and some endocrine cells. The bottom peptide is the modified human proinsulin with tetrabasic furin endopeptidase processing sites.

Figure 2 Pharmacological regulation of insulin gene expression. The model proposes the initial expression of two recombinant transcription factors carrying a DNA-binding domain (DB) or a transcription activation domain (TA). The administration of rapamycin then leads to the two transcription factors forming a heterodimer resulting in the activation of RNA polymerase II, thereby inducing insulin gene expression.

Figure 3 Regulated insulin secretion through controlled aggregation in the endoplasmic reticulum (ER) as a response to postprandial hyperglycemia. Modified insulin peptides accumulate within the ER as protein aggregates. Administration of a synthetic drug causes disaggregation of the insulin peptides, facilitating their passage to Golgi. Insulin is released via the constitutive secretory pathway. This system was originally designed for direct pharmacological control of protein secretion to generate fast and transient delivery of therapeutic proteins. Nu, Nucleus.

Figure 4 Schematic view of an ideal pancreatic beta cell surrogate. Glucose transporter 2 (GLUT2) and glucokinase (GK) act as cellular glucose sensors. Prohormone convertase (PC1/3 and PC2) converts proinsulin to insulin. In addition, a beta cell substitute should possess a regulated secretory pathway allowing insulin storage in the cytoplasm and release upon stimulation. G protein coupled receptor (GPCR) expression is also desired to respond to glucagon-like peptide 1 (GLP-1), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Key players of glucose-mediated insulin secretion are depicted. In brief, when blood glucose level rises above 5.5 mM, glucose enters into the cell through GLUT2 and gets phosphorylated by GK. Glycolysis increases the ATP/ADP ratio activating K channels (K Ch) leading to membrane depolarisation. Opening of Ca2+ Channels (Ca Ch) results in Ca2+ influx and fusion of insulin containing vesicles with the plasma membrane. Molecules with incretin effect (GLP-1, VIP and PACAP) also stimulate insulin release through GPCR.