Pharmacological interventions that directly stimulate or modulate insulin secretion from pancreatic β‐cell: implications for the treatment of type 2 diabetes

Abstract

Blood glucose concentration is controlled by a number of hormone and neurotransmitter signals, either increasing or reducing glucose levels in the case of hypoglycemia or hyperglycemia, respectively. The pancreatic beta-cell responds to an increase in circulating glucose levels by a cascade of metabolic and electrophysiological events leading to the secretion of insulin. Type 2 diabetes is a metabolic disorder characterized by chronic hyperglycemia; the progressive pancreatic beta-cell dysfunction, with altered insulin production and secretion, is a major pathophysiological determinant of the disease together with the resistance of insulin-sensitive tissues to the action of the hormone. Hence, drugs which stimulate or enhance insulin secretion will reduce plasma glucose concentrations; this lowering of hyperglycemia will, in turn, reduce the occurrence of long-term complications. K(ATP) channels play a critical role in insulin secretion and can be considered as transducers of glucose-induced metabolic changes into biophysical events leading to the exocytosis of insulin granules. All currently marketed insulin secretagogues, sulfonylureas and glinides, target the beta-cell K(ATP) channels and reduce their opening probability. They induce insulin release regardless of the plasma glucose concentration, thus favoring the occurrence of hypoglycemia in the fasting state. Despite the intensive use of current drugs, many patients suffering from type 2 diabetes still exhibit poor glycemic control, others fail to respond to the treatment, and some develop serious complications. Therefore, there is a real need for innovative compounds, either enhancing insulin secretion from the pancreas or improving insulin action on the hormone-sensitive tissues. Here, we overview the existing and novel approaches targeting the beta-cell to enhance the release of insulin, with special emphasis on new ways of amplifying insulin secretion in a glucose-dependent manner.

Sulfonylureas and Glinides Exhibit Peroxisome Proliferator-Activated Receptor γ Activity: A Combined Virtual Screening and Biological Assay Approach

“…So far, members of these classes were presumed to act by a mechanism independent of PPAR␥. According to this mechanism, they bind to the sulfonylurea receptor SUR1 in pancreatic islet ␤ cells, closing K ϩ channels and leading to increased insulin production (Farret et al, 2005). In contrast, here we provide evidence that binding to and activating PPAR␥ may be a new mode of action for at least some of these drugs, resulting in enhanced insulin sensitivity in peripheral tissue.…”

“…These compounds bind to the sulfonylurea receptor SUR1 on the membrane of ␤-cells, triggering the closure of the nearby potassium channel, which in turns leads the ␤-cell to increase insulin secretion (Farret et al, 2005). Our discovery that some insulin secretagogue drugs activate PPAR␥ has attractive implications for the pharmacological treatment of type 2 diabetes.…”

Purinergic receptors in the endocrine and exocrine pancreas

“…The graph shows the theoretical oscillations in insulin and glucagon levels in the presence of high glucose concentrations Therapeutic potentials for improving insulin secretion Many drugs can increase insulin secretion in vitro, but only some have a therapeutic potential for treatment of noninsulin-dependent diabetes. The most frequently used drugs to date are sulphonylureas and glinides, which decrease the open probability of K ATP channels, and result in depolarization of the cell membrane, and the increase in cell Ca 2+ leads to insulin release [61,[65][66][67]. The action of these drugs is independent of plasma glucose concentrations and therefore it may be difficult to achieve glycaemic control, i.e.…”

System Engineering Approach of Diabetes Treatment

“…Although DM is still incurable, the therapy of DM presented considerable progression in the recent years, for instance the appearance of different cell stimulating drugs [7,15], partial immunosuppressant drug applications in order to reduce the autoimmune effect [16], transplantation of Langerhansislets [17] or pancreas [18] and stem cell experiments [17] are just some of the achieved results.…”