Inhibition of Insulin Secretion as a New Drug Target in the Treatment of Metabolic Disorders

Abstract

The pattern of insulin release is crucial for regulation of glucose and lipid haemostasis. Deficient insulin release causes hyperglycemia and diabetes, whereas excessive insulin release can give rise to serious metabolic disorders, such as nesidioblastosis (Persistent Hyperinsulinemic Hypoglycemia of Infancy, PHHI) and might also be closely associated with development of type 2 diabetes and obesity. Type 2 diabetes is characterized by fasting hyperinsulinemia, insulin resistance and impaired insulin release, i.e. reduced first phase insulin release and decreased insulin pulse mass. The beta cell function of patients with type 2 diabetes slowly declines and will ultimately result in beta cell failure and increasing degrees of hyperglycemia. Type 2 diabetes, in combination with obesity and cardiovascular disorders, forms the metabolic syndrome. It has been possible to improve beta cell function and viability in preclinical models of type 1 and type 2 diabetes by reducing insulin secretion to induce beta cell rest. Clinical studies have furthermore indicated that inhibitors of insulin release will be of benefit in treatment or prevention of diabetes and obesity. Pancreatic beta cells secrete insulin in response to increased metabolism and by stimulation of different receptors. The energy status of the beta cell controls insulin release via regulation of open probability of the ATP sensitive potassium (K(ATP)) channels to affect membrane potential and the intracellular calcium concentration [Ca(2+)](i). Other membrane bound receptors and ion channels and intracellular targets that modulate [Ca(2+)](i)will affect insulin release. Thus, insulin release is regulated by e.g. somatostatin receptors, GLP-1 receptors, muscarinic receptors, cholecystokinin receptors and adrenergic receptors. Although the relationship between hyperinsulinemia and certain metabolic diseases has been known for decades, only a few inhibitors of insulin release have been characterized in vitro and in vivo. These include the K(ATP) channel openers diazoxide and NN414 and the somatostatin receptor agonist octreotide.

Improved insulin sensitivity and islet function after PPARδ activation in diabetic db/db mice

“…In this method, mice are treated with diazoxide prior to injection of glucose and insulin is used for direct estimation of insulin sensitivity in diabetes models (Ahren and Pacini, 2006). Diazoxide blocks the endogenous insulin secretion by opening of K ATP -channels, thereby inhibiting the depolarization of the plasma membrane and blocking the influx of Ca 2+ (Hansen et al, 2004;Henquin, 2000). This method was recently validated in comparison with insulin sensitivity estimated from IVGTT data using minimal modeling (Ahren and Pacini, 2006;Pacini et al, 2001).…”

Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice

“…Type 2 diabetes is characterised by pancreatic beta cell destruction, which results in an increased insulin-secretory demand on remaining beta cells [1,2]. This results in further Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3653-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.…”

Resveratrol-induced inhibition of insulin secretion from rat pancreatic islets: evidence for pivotal role of metabolic disturbances

“…The restriction of exaggerated insulin secretion is considered to be an important factor in prevention of insulin resistance, type 1 and type 2 diabetes mellitus, and some other metabolic disorders (reviewed in Refs. 16,36). In the present study, the effects of resveratrol on insulin secretion from isolated pancreatic islets were investigated under different stimulatory conditions.…”