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Pathways in -Cell Stimulus-Secretion Coupling As Targets for Therapeutic Insulin Secretagogues

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Pathways in -Cell Stimulus-Secretion Coupling As Targets for Therapeutic Insulin Secretagogues Pathways in ␤-Cell Stimulus-Secretion Coupling as Targets for Therapeutic Insulin Secretagogues Jean-Claude Henquin Physiologically, insulin secretion is subject to a dual, useful tools to unravel the mechanisms of stimulus-secre- hierarchal control by triggering and amplifying path- tion coupling. Until recently, however, hypoglycemic sul- ؉ ways. By closing ATP-sensitive K channels (KATP chan- fonylureas were the only drugs used to stimulate insulin nels) in the plasma membrane, glucose and other secretion in patients with type 2 diabetes. metabolized nutrients depolarize ␤-cells, stimulate The story of sulfonylureas started in 1942, in Montpellier ؉ Ca2 influx, and increase the cytosolic concentration of (rev. in 3). Marcel Janbon and his colleagues recognized 2؉ 2؉ free Ca ([Ca ]i), which constitutes the indispensable that some patients receiving a sulfonamide (2254RP) for triggering signal to induce exocytosis of insulin gran- the treatment of typhoid fever were experiencing severe ules. The increase in ␤-cell metabolism also generates -؉ hypoglycemia. Auguste Loubatie`res rapidly confirmed ex amplifying signals that augment the efficacy of Ca2 on the exocytotic machinery. Stimulatory hormones and perimentally that the drug was causing hypoglycemia and, neurotransmitters modestly increase the triggering sig- in 1946, at the end of a remarkable series of experiments nal and strongly activate amplifying pathways biochem- for the time, concluded that the underlying mechanism ically distinct from that set into operation by nutrients. was a direct stimulation of insulin secretion by 2254RP. In Many drugs can increase insulin secretion in vitro, but 1955, in Berlin, Franke and Fuchs reported that another only few have a therapeutic potential. This review iden- antibacterial sulfonamide, carbutamide, also caused hypo- tifies six major pathways or sites of stimulus-secretion glycemia. The drug was rapidly used to treat diabetic coupling that could be aimed by potential insulin-secret- patients who did not require insulin, and was followed 1 ing drugs and describes several strategies to reach these year later by tolbutamide (3). The discovery of hypoglyce- targets. It also discusses whether these perspectives are mic sulfonylureas was thus serendipitous. Although many realistic or theoretical only. These six possible ␤-cell targets are 1) stimulation of metabolism, 2) increase of drugs have since been reported to exert hypoglycemic side 2؉ ؉ effects, none has had such a prolific progeny. The reason [Ca ]i by closure of K ATP channels, 3) increase of ,2؉ of the success of sulfonylureas is obvious. They all [Ca ]i by other means, 4) stimulation of amplifying pathways, 5) action on membrane receptors, and 6) including the mother compound 2254RP (3), act on ATP- ϩ action on nuclear receptors. The theoretical risk of sensitive K channels (KATP channels), which play a inappropriate insulin secretion and, hence, of hypogly- central role in the regulation of insulin secretion by cemia linked to these different approaches is also envis- glucose itself. aged. Diabetes 53 (Suppl. 3):S48–S58, 2004 Nowadays, search for novel insulin secretagogues is guided by our knowledge of stimulus-secretion coupling in ␤-cells. In this review, I shall first outline the major mechanisms regulating insulin secretion before discussing ptimal treatment of type 2 diabetes is difficult how distinct pathways or sites of action could serve as because of the complex pathogenesis of the therapeutic targets. disease (1,2). Pharmacological agents improv- Oing the action of insulin on its target tissues and agents correcting the deficient secretion of insulin by THE PHYSIOLOGICAL CONTROL OF INSULIN ␤-cells both have a place in our armamentarium. Many SECRETION chemicals can increase insulin secretion in vitro and are Insulin secretion is subject to tight control by glucose, other nutrients, neurotransmitters, and hormones. Al- From the Unite´ d’Endocrinologie et Me´tabolisme, University of Louvain though numerous and complex, the mechanisms underly- Faculty of Medicine, Brussels, Belgium. ing this multifactorial regulation can be schematized by a Address correspondence and reprint requests to J.C. Henquin, Unite´ hierarchical interaction between triggering and amplifying d’Endocrinologie et Me´tabolisme, UCL 55.30, avenue Hippocrate 55, B-1200 Brussels, Begium. E-mail: [email protected]. pathways (Fig. 1) (4,5). Received for publication 8 April 2004 and accepted in revised form 20 May When the concentration of glucose increases, ␤-cell 2004. metabolism accelerates, leading to closure of K chan- This article is based on a presentation at a symposium. The symposium and ATP the publication of this article were made possible by an unrestricted educa- nels in the plasma membrane. These channels are com- ϩ tional grant from Servier. posed of the pore-forming K IR6.2 and the regulatory [Ca2ϩ] , free cytosolic Ca2ϩ concentration; Epac, exchange protein activated i sulfonylurea receptor 1 (SUR1). Binding of intracellular by cAMP; GEF, guanine nucleotide exchange factor; GIP, glucose-dependent ϩ insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; GTP, guanosine ATP to K IR6.2 closes the channel, whereas binding of ϩ triphosphate; KATP channel, ATP-sensitive K channel; PKA, protein kinase A; MgADP to SUR1 opens the channel. The increase in the PKC, protein kinase C; PPAR, peroxisome proliferator–activated receptor; SUR1, sulfonylurea receptor 1. ATP/ADP ratio resulting from the metabolism of glucose © 2004 by the American Diabetes Association. thus closes the channel (Fig. 1). The consequence is a S48 DIABETES, VOL. 53, SUPPLEMENT 3, DECEMBER 2004 J.-C. HENQUIN FIG. 1. Schematic representation of the triggering and amplifying pathways involved in the control of insulin secretion by glucose and other agents, and identification of potential sites of action (1–6) for pharmacological insulin secretagogues. ؉, stimulation; ؊, inhibition. See also Table 1. depolarization of the plasma membrane, with opening of nisms. They also produce major amplifying signals, mainly voltage-dependent Ca2ϩ channels, acceleration of Ca2ϩ through activation of protein kinases, in particular protein influx, and increase in the concentration of cytosolic free kinase A (PKA) and protein kinase C (PKC) (14–16,18–19). 2ϩ 2ϩ Ca ([Ca ]i) that is necessary and sufficient to trigger In addition to PKA, cAMP-regulated guanine nucleotide insulin secretion (6–10). However, this triggering signal exchange factors (GEFs, or Epac) might mediate part of alone is poorly effective. Its efficacy is augmented by an the effects of cAMP on insulin secretion (16,20). Activation amplifying pathway also using signals issued from glucose of PKA or PKC, or of GEF/Epac, augments the efficacy of metabolism. The nature of these signals and their intracel- Ca2ϩ on exocytosis. The biochemical mechanisms of this lular targets are still unclear, but a role of ATP and ADP is type of amplification are, however, distinct from those plausible (11–13). The same dual regulation applies to all implicated in the amplifying pathway of glucose and other nutrients that are actively metabolized and increase the nutrients (5). ATP/ADP ratio in ␤-cells (5). Although no direct evidence Finally, inhibitory hormones and neurotransmitters also is as yet available, both clinical investigation of diabetic act via two pathways. They depress insulin secretion patients and experimental studies of animal models sug- partly by decreasing the triggering signal (via membrane gest that the two pathways, triggering and amplifying, may repolarization) and mainly by reducing the efficacy of Ca2ϩ be impaired in ␤-cells affected by type 2 diabetes (4). on exocytosis (attenuating pathway operating via kinases 2ϩ Importantly, the triggering signal (rise in [Ca ]i) can or small guanosine triphosphate [GTP]-binding proteins) also be produced or augmented by mechanisms that are (21). independent of KATP channels (Fig. 1). Some hormones and neurotransmitters mobilize Ca2ϩ from intracellular stores (14–16). Agents acting on various ionic channels HOW CAN DRUGS FOOL ␤-CELLS TO SECRETE (e.g., inhibitors of voltage-dependent Kϩ channels) can EXCESSIVE AMOUNTS OF INSULIN? augment glucose-induced depolarization, thereby potenti- Hypoglycemia induced by excessive insulin secretion is a 2ϩ ating the [Ca ]i rise (17). Cationic amino acids, like major complication of current pharmacological treatments arginine, are poorly metabolized but depolarize ␤-cells of type 2 diabetes. Under physiological conditions, it is the because of their entry in a positively charged form, thus triggering pathway that determines whether insulin is without direct interaction with an ionic channel (5). secreted. The amplifying pathway serves to optimize the Stimulatory hormones and neurotransmitters, such as secretory response induced by the triggering signal but 2ϩ glucagon-like peptide 1 (GLP-1) and acetylcholine, usually does not induce secretion if [Ca ]i is not increased (5). potentiate insulin secretion by a dual action. They moder- This strict hierarchy between the two pathways can be 2ϩ ately increase the triggering signal (rise in [Ca ]i) through perturbed by pathological defects or by drugs. Theoreti- complex, variable, but largely glucose-dependent mecha- cally, actions on either the triggering or amplifying path- DIABETES, VOL. 53, SUPPLEMENT 3, DECEMBER 2004 S49 PHARMACOLOGICAL INSULIN SECRETAGOGUES TABLE 1 Site 1: Improvement of ␤-cell metabolism. Alterations Potential sites of action of
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