Sulfonylurea and glinide reduce insulin content, functional expression of KATP channels, and accelerate apoptotic β-cell death in the chronic phase

Abstract

We previously found that chronic exposure to glibenclamide inhibits acute glibenclamide-induced insulin secretion by reducing the number of functional ATP-sensitive K(+) (K(ATP)) channels on the plasma membrane of pancreatic beta-cells. In the present study, we compared sulfonylurea-induced and glinide-induced insulin secretion in pancreatic beta-cells chronically exposed to these widely used oral hypoglycemic agents. Chronic exposure of pancreatic beta-cells to sulfonylureas (glibenclamide or tolbutamide) and glinide (nateglinide) similarly impaired their acute effectiveness by reducing the insulin content and the number of functional K(ATP) channels on the plasma membrane. Functional expression of the voltage-dependent Ca(2+) channels (VDCCs), ion channels that play a critical role in the K(ATP) channel dependent insulin secretory pathway, was similar to that in drug-untreated cells. Chronic exposure to each of the three agents similarly accelerated apoptotic beta-cell death. Thus, reduction of the insulin content, reduction of the number of functional K(ATP) channels on the plasma membrane, and acceleration of apoptotic beta-cell death all are involved in impaired insulinotropic agent-induced acute insulin secretion in the chronic phase of sulfonylurea and glinide treatment. These findings help to clarify the mechanism of secondary failure after long-term therapy by these hypoglycemic agents, and should have important clinical implications regarding pharmacotherapy for type 2 diabetes.

Short duration of diabetes and disuse of sulfonylurea have any association with insulin cessation of the patients with type 2 diabetes in a clinical setting in Japan (JDDM 30)

“…Although we had these study limitations, these results, together with previous reports, suggest that remission may associate with disuse of sulfonylurea prior to insulin therapy in outpatients with T2DM. The findings are also compatible with reports indicating that long-term overstimulation of β-cells by sulfonylureas may exhaust β-cell function [7,8].…”

“…Sulfonylureas may reduce insulin secretion, resulting in desensitization from long-term overstimulation [7,8]. One study reported that most T2DM patients who stopped insulin after intensive insulin therapy had not been treated with sulfonylureas, whereas most of those who continued with insulin had [14].…”

“…These studies suggest that elimination of glucotoxicity by intensive insulin therapy may improve β-cell function and achieve remission [5,6]. Conversely, sulfonylureas may exert negative effects on β-cells by overstimulation and the induction of desensitization, which is known as "secondary failure" [7,8]. However, patients with T2DM are often treated with sulfonylureas and these drugs remain central in the treatment of diabetes treatment in Japan [9].…”

Docking and molecular dynamics studies on the interaction of four imidazoline derivatives with potassium ion channel (Kir6.2)

“…Studies performed over the past few years have suggested that some imidazoline derivatives may stimulate insulin secretion in a more glucose-dependent fashion than sulphonylureas [10,11]. Thus, the inherent risk of hypoglycaemias caused by the therapeutic use of sulphonylureas may be avoided.…”

Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

“…In addition, while the effects of GLP1 on pancreatic hormone secretion are glucose dependent, which virtually eliminates the risk of hypoglycaemia, the actions of insulin and SUs are not dependent on elevated glucose levels, and thus therapies with these agents lead to much higher rates of hypoglycaemia. Furthermore, while non-glucose-dependent insulin secretagogues, such as SUs, may place excessive stress on pancreatic b-cells and potentially promote b-cell apoptosis (Maedler et al 2005, Takahashi et al 2007, Aston-Mourney et al 2008, incretins activate signalling pathways that provide protection against apoptosis (Trumper et al 2002, Hui et al 2003, Wang et al 2004. Preclinical studies in rodents have provided hope that enhancing GLP1R signalling may be able to halt the progressive decline in b-cell mass and perhaps even promote the growth of new b-cells in vivo (Xu et al 1999, Stoffers et al 2003).…”