Treatment of diabetes by transplantation of drug-inducible insulin-producing gut cells

Abstract

Most patients with type 1 diabetes rely on multiple daily insulin injections to maintain blood glucose control. However, insulin injections carry the risk of inducing hypoglycemia and do not eliminate diabetic complications. We sought to develop and evaluate a regulatable cell-based system for delivery of insulin to treat diabetes. We generated two intestinal cell lines in which human insulin expression is controlled by mifepristone. Insulin mRNA expression was dependent on the mifepristone dose and incubation time and cells displayed insulin and C-peptide immunoreactivity and glucose-induced insulin release following mifepristone treatment. Cell transplantation followed by mifepristone administration reversed streptozotocin (STZ)-induced diabetes in mice, and this effect was dependent on the mifepristone dose delivered. These data support the notion that engineering regulatable insulin expression within a cell already equipped for regulated secretion may be efficacious for the treatment of insulin-dependent diabetes.

Insulin is secreted upon glucose stimulation by both gastrointestinal enteroendocrine K-cells and L-cells engineered with the preproinsulin gene

“…Unfortunately, when transplanted into the peritoneal cavity, diabetic mice developed hypoglycemia (Han et al, 2007, Unniappan et al, 2009. Hypoglycemic states can be potentially fatal and are therefore an unacceptable risk for diabetic patients.…”

The time has come for incretins, a long time coming

“…Excitement about the experimental results presented by Liu et al [10,12] and the clinical results regarding liraglutide [13] involve the potential therapy of obesity without the risk of hypoglycemia (Fig. 2).…”

“…Impetus for this commentary is the report by Liu et al in this issue of the journal [10]. Liu et al investigated whether or not local GLP-1 production in the intestine could differentiate intestinal progenitor cells into insulin-producing cells.…”

Novel cell therapy for type 1 diabetes mellitus

“…The report by Unniappan and colleagues in this issue presents another option [3]. They considered the possibility of using a drug-operated system that could induce target cells to release insulin each and every time the drug stimulus is given.…”

“…When mifepristone is added, the activated regulator dimerizes and binds to the Gal4 DNA binding site that induces the target gene expression. Unniappan et al used exactly this drug-dependent regulatory system [3].…”