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

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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 failureand 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 (KATP) channels to affect membrane potential and the intracellular calcium concentration [Ca2+]i. Other membrane bound receptors and ion channels and intracellular targets that modulate [Ca2+]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 KATP channel openers diazoxide and NN414 and the somatostatin receptor agonist octreotide.

Keywords: beta cell; diabetes; diazoxide; insulin secretion; katp channel; n414; somatostatin

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867043365026

Affiliations: Medicinal Chemistry, Novo Nordisk A / S, Novo Nordisk Park, DK2760 Malov, Denmark

Publication date: June 1, 2004

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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