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

Abstract

Transgenic mice carrying the human insulin gene driven by the K-cell glucose-dependent insulinotropic peptide (GIP) promoter secrete insulin and display normal glucose tolerance tests after their pancreatic β-cells have been destroyed. Establishing the existence of other types of cells that can process and secrete transgenic insulin would help the development of new gene therapy strategies to treat patients with diabetes mellitus. It is noted that in addition to GIP secreting K-cells, the glucagon-like peptide 1 (GLP-1) generating L-cells share/ many similarities to pancreatic β-cells, including the peptidases required for proinsulin processing, hormone storage and a glucosestimulated hormone secretion mechanism. In the present study, we demonstrate that not only K-cells, but also L-cells engineered with the human preproinsulin gene are able to synthesize, store and, upon glucose stimulation, release mature insulin. When the mouse enteroendocrine STC-1 cell line was transfected with the human preproinsulin gene, driven either by the K-cell specifi c GIP promoter or by the constitutive cytomegalovirus (CMV) promoter, human insulin co-localizes in vesicles that contain GIP (GIP or CMV promoter) or GLP-1 (CMV promoter). Exposure to glucose of engineered STC-1 cells led to a marked insulin secretion, which was 7-fold greater when the insulin gene was driven by the CMV promoter (expressed both in K-cells and L-cells) than when it was driven by the GIP promoter (expressed only in K-cells). Thus, besides pancreatic β-cells, both gastrointestinal enteroendocrine K-cells and L-cells can be selected as the target cell in a gene therapy strategy to treat patients with type 1 diabetes mellitus.

Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine

“…Ever since, several studies have been published in an attempt to control diabetes through targeting different tissues, such as pancreas [ 250 ], muscle [ 251 , 252 ], liver [ 253 , 254 , 255 ], and K-enteroendocrine cells (K cells) [ 256 ]. For effective hypoglycemic therapy, these tissues should be able to produce or secrete insulin in a glucose-dependent manner [ 257 , 258 ].…”

Molecular Docking and Pharmacokinetic Prediction of Herbal Derivatives as Maltase-Glucoamylase Inhibitor

“…Diabetes syndrome is a metabolic disorder, which causes congenital (type I insulin-dependent) or acquired (type II noninsulin-dependent) diabetes mellitus, and approximately 7% of the world population is suffering from this chronic disorder [1][2][3][4]. This chronic disease not only affects the carbohydrate metabolism but also alters lipid and protein metabolism in advanced stages, leading to complications such as microvascular or macrovascular which are more fatal than the primary diabetic state; thus, all credit goes to regulating postprandial glucose levels [5][6][7].…”