scholarly journals Selective Somatostatin 5 (SST5) and Somatostatin 2 (SST2) Nonpeptide Agonists Potently Suppress Glucose- and Tolbutamide-Stimulated Dynamic Insulin Secretion From Isolated Human Islets

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A325-A325
Author(s):  
Elizabeth Rico ◽  
Jian Zhao ◽  
Mi Chen ◽  
Ana Karin Kusnetzow ◽  
Yun Fei Zhu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Somatostatin Receptor ◽  
Physiological Role ◽  
Glucagon Secretion ◽  
Receptor Activation ◽  
Human Islets ◽  
Receptor Subtypes ◽  
Congenital Hyperinsulinism ◽  
Somatostatin Receptor Subtypes ◽  
Selective Agonists

Abstract Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in newborns and infants and arises from dysregulated insulin secretion. Rapid recognition and treatment are vital to prevent seizures, permanent developmental delays, coma, or even death. Very few medical options exist to treat congenital HI patients: the KATP channel activator diazoxide, the injectable somatostatin receptor peptide agonists octreotide and lanreotide, or chronic glucose infusions. However, side effects and/or limited efficacy render these therapies inadequate for many patients. Somatostatin is a 14-amino acid peptide hormone with a broad spectrum of biological actions, which are regulated through five somatostatin receptor subtypes (SST1-SST5). Somatostatin’s common physiological role is to down-regulate secretion of other hormones in various tissues. Its role in the maintenance of euglycemia is to regulate insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Somatostatin regulates insulin secretion by decreasing the intracellular levels of cAMP, inhibition of voltage-gated calcium channels (VGCC), activation of the G protein-activated inward rectifier K+ channel (GIRK), and direct inhibition of insulin exocytosis. Several studies have evaluated the effect of somatostatin, somatostatin peptide analogs, and a limited number of nonpeptide somatostatin receptor agonists on insulin secretion in static assays using isolated human islets. However, the lack of highly selective agonists has made the interpretation of the contribution of SST receptor sub-types difficult to discern. Our programs for the treatment of hyperinsulinism, acromegaly, and other indications have led to the development of selective nonpeptide SST2, SST3, SST4, and SST5 agonists, possessing EC50s < 1 nM in cell-based assays of receptor activation and selectivity > 130 times over the other members of the family. The ability of these selective nonpeptide agonists to regulate glucose- and tolbutamide-stimulated dynamic insulin secretion from human islets was evaluated using a perifusion system (Biorep, FL). We found that selective SST2 and SST5 agonists potently suppressed dynamic insulin secretion in contrast to SST3 or SST4 selective agonists. Importantly, SST5 agonists were shown to have a greater effect than selective SST2 agonists or diazoxide, demonstrating their potential utility in human conditions such as congenital HI. In addition, SST5 activation is also known to have a smaller effect on glucagon secretion and is also less prone to agonist-driven desensitization than SST2 activation. Taken together, these studies support our program to identify, characterize, and develop potent, nonpeptide, orally-bioavailable, selective SST5 agonists with appropriate pharmaceutical and safety characteristics for the treatment of congenital HI.

scholarly journals MON-089 Discovery and Identification of Late Stage Selective Nonpeptide Somatostatin Subtype 5 (sst5) Agonists for the Treatment of Hyperinsulinemic Hypoglycemia

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Melissa A Fowler ◽  
Jian Zhao ◽  
Emmanuel Sturchler ◽  
Elizabeth Rico ◽  
Rosalia de Necochea-Campion ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Somatostatin Receptor ◽  
Liver Microsomes ◽  
Glucagon Secretion ◽  
Receptor Activation ◽  
Hyperinsulinemic Hypoglycemia ◽  
Repeat Dose ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
In Vivo Models

Abstract Congenital hyperinsulinism (CHI) results from mutations within the insulin secretion pathway and is characterized by excessive and/or inappropriate insulin secretion by pancreatic islet β-cells. CHI is the most common cause of persistent hypoglycemia in newborns and infants and is estimated to affect 1:2500 to 1:50,000 live births. Prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. If medical control of CHI is unsuccessful, a near-total pancreatectomy may be required, but hypoglycemia often persists. The neuropeptide somatostatin is an important modulator of pancreatic hormonal signaling and activity at different somatostatin receptor (sst) subtypes dictates the suppression of insulin and/or glucagon. The injectable peptide drugs octreotide and lanreotide are potent sst2 agonists used to treat CHI, but in addition to suppressing insulin, the sst2 activity of these peptides may also inhibit glucagon secretion, potentially reducing effectiveness and compromising a key defense against hypoglycemia. Glucagon secretion from α-cells is inhibited through activation of sst2 receptors, while insulin secretion from β-cells is inhibited through activation of sst2 and sst5. We therefore hypothesize that agonists selectively targeting sst5 and lacking sst2 activity will offer an improved efficacy/safety profile for patients with hyperinsulinemic hypoglycemia. Using iterative medicinal chemistry and pharmacology, Crinetics has discovered several classes of highly potent, orally bioavailable, small molecule sst-subtype selective agonists with drug-like pharmaceutical properties. Our discovery efforts aimed at finding a compound to treat CHI have yielded potent and selective nonpeptide sst5 agonists with sub-nanomolar EC50s in cell-based assays of receptor activation. Insulin secretion from isolated human and rat islets was suppressed upon exposure to sst5 agonists. Potent and selective sst5 agonists were then evaluated in a number acute and repeat dose in vivo models (e.g., oGTT, fed/fasted conditions, sulfonylurea-induced hypoglycemia) to assess physiological effects and to gain mechanistic insights. As predicted by the in vitro pharmacology, selective nonpeptide sst5 agonists suppressed insulin secretion and raised blood glucose levels in each model, while having minimal effects on glucagon secretion. Leading sst5 agonists were also evaluated for drug like characteristics, including stability in liver microsomes, lack of inhibition of cytochromes P450 and the hERG ion channel, and were shown to exhibit good exposure upon oral dosing in both rats and dogs. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in genotoxicity, safety pharmacology, and general toxicity studies to determine the molecule most suitable for evaluation in human clinical trials.

scholarly journals Antidiabetic Activity of a Highly Potent and Selective Nonpeptide Somatostatin Receptor Subtype-2 Agonist

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4664-4673 ◽  
Author(s):  
Mathias Z. Strowski ◽  
Doreen E. Cashen ◽  
Elizabeth T. Birzin ◽  
Lihu Yang ◽  
Vandana Singh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Somatostatin Receptor ◽  
Glucagon Secretion ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Glucose Levels ◽  
Somatostatin Receptor Subtypes ◽  
Novel Approach

Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst1–sst5) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst2, whereas B cells express sst5. In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst2-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst2-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst2-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst2 selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst2-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.

scholarly journals N-Type Ca2+-Channels in Murine Pancreatic β-Cells Are Inhibited by an Exclusive Coupling with Somatostatin Receptor Subtype 1

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 741-748 ◽  
Author(s):  
Paul A. Smith
Keyword(s):  
Insulin Secretion ◽  
Somatostatin Receptor ◽  
Inhibitory Effect ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Somatostatin Receptor Subtypes ◽  
Perforated Patch Clamp ◽  
Ca2 Channels

Somatostatin (SRIF) is a well-established inhibitor of insulin secretion, an effect in part mediated by a direct inhibition of voltage-operated Ca2+-channels. However, the identity of the somatostatin receptor subtypes (SSTRs) and voltage-operated Ca2+-channels involved in this process are unknown. Whole-cell perforated patch-clamp methods were applied to the murine pancreatic β-cell line, MIN6, to explore the molecular pharmacology of this problem. SRIF-14 inhibited voltage-gated Ca2+ currents (ICa2+) by 19 ± 3% (n=24) with a pEC50 = 9.05 (95% confidence limits 9–9.1). This action was mimicked solely by 100 nm CH-275, a selective agonist at the somatostatin type 1 receptor (SSTR1), but not by 100 nm BIM-23027, L-362855, or NNC-269100; agonists selective for the other four SSTRs known to exist in MIN6. The inhibition of ICa2+ produced by SRIF and CH-275 was insensitive to pertussis toxin but was reversed by a prepulse to +100 mV. The inhibition of ICa2+ by SRIF-14 was unaffected by 20 μm nifedipine, an inhibitor of L-type Ca2+ channels. Application of the specific N-type Ca2+ channel (Cav2.2) inhibitor ω-conotoxin GV1A at 100 nm mimicked, and as a consequence abolished, the inhibitory effect of SRIF-14 on ICa2+. SRIF selectively inhibits N-type Ca2+-channels in murine pancreatic β-cells via exclusive coupling with SSTR1. These findings help explain how SSTR1 activation can inhibit insulin secretion in pancreatic β-cells and suggest a possible new therapeutic lead for treatment of hyperinsulinemia. In pancreatic β-cells, somatostatin selectively inhibits N-type, but not other, Ca2+-channels via a direct and exclusive coupling with somatostatin receptor subtype 1.

scholarly journals Selective Regulation of Somatostatin Receptor Subtype Signaling: Evidence for Constitutive Receptor Activation

2007 ◽  
Vol 21 (10) ◽  
pp. 2565-2578 ◽  
Author(s):  
Anat Ben-Shlomo ◽  
Oxana Pichurin ◽  
Nicole J. Barshop ◽  
Kolja A. Wawrowsky ◽  
John Taylor ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Somatostatin Receptor ◽  
Hormone Secretion ◽  
Receptor Activation ◽  
Receptor Subtype ◽  
Pituitary Hormone ◽  
Receptor Subtypes ◽  
Camp Accumulation ◽  
Acth Secretion ◽  
Somatostatin Receptor Subtypes

Abstract Anterior pituitary hormone secretion is under tonic suppression by hypothalamic somatostatin signaling through somatostatin receptor subtypes (SSTs). Because some hormonal axes are known to be abnormally regulated by ligand-independent constitutively active G protein-coupled receptors, we tested pituitary SSTs for selective constitutive signaling. We therefore differentially silenced endogenous SST2, SST3, and SST5 in somatostatin-sensitive ACTH-secreting mouse AtT-20 pituitary corticotroph cells using small inhibitory RNA (siRNA) and analyzed downstream SSTs-regulated pathways. Transfection with siRNA reduced specific receptor subtype mRNA expression up to 82%. Specificity of receptor silencing was validated against negative controls with different gene-selective siRNAs, concordance of mRNA and cAMP changes, reduced potency of receptor-selective agonists, and phenotype rescue by overexpression of the silenced receptor. Mouse SST3 > SST5 > SST2 knockdown increased basal cAMP accumulation (up to 200%) and ACTH secretion (up to 60%). SST2- and SST5-selective agonist potencies were reduced by SST3- and SST5-silencing, respectively. SST5 > SST2 = SST3 silencing also increased basal levels of ERK1/2 phosphorylation. SST3- and SST5-knockdown increased cAMP was only partially blocked by pertussis toxin. The results show that SST2, SST3, and SST5 exhibit constitutive activity in mouse pituitary corticotroph cells, restraining adenylate cyclase and MAPK activation and ACTH secretion. SST3 mainly inhibits cAMP accumulation and ACTH secretion, whereas SST5 predominantly suppresses MAPK pathway activation. Therefore, SST receptor subtypes control pituitary cell function not only through somatostatin binding to variably expressed cell membrane receptor subtypes, but also by differential ligand-independent receptor-selective constitutive action.

Somatostatin receptors

1995 ◽  
Vol 269 (6) ◽  
pp. G813-G820 ◽  
Author(s):  
T. Reisine
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
Receptor Subtypes ◽  
Binding Domains ◽  
Somatostatin Receptor Subtypes ◽  
Selective Agonists ◽  
The Individual ◽  
Subtype Selective ◽  
Biological Actions

Somatostatin induces its biological actions by activating a family of receptor subtypes. The recent cloning of five somatostatin receptor subtypes has led to the development of subtype-selective agonists. These compounds are revealing distinct functions of the individual receptor subtypes. Mutagenesis studies have revealed domains of several of the receptors involved in specific recognition of somatostatin analogues. Molecular modeling of both of these ligand-binding domains and the constrained somatostatin analogues that they interact with may lead to the development of nonpeptide somatostatin drugs that could be useful in the treatment of tumors and various metabolic, gastrointestinal, and central nervous system disorders.

scholarly journals Somatostatin receptor activation is involved in the control of daily torpor in a seasonal mammal

2015 ◽  
Vol 309 (6) ◽  
pp. R668-R674 ◽  
Author(s):  
Frank Scherbarth ◽  
Victoria Diedrich ◽  
Rebecca A. Dumbell ◽  
Herbert A. Schmid ◽  
Stephan Steinlechner ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Receptor Activation ◽  
The Body ◽  
Receptor Subtypes ◽  
Marginal Effect ◽  
Hormonal Changes ◽  
Daily Torpor ◽  
Siberian Hamsters ◽  
Somatostatin Receptor Subtypes

Siberian hamsters ( Phodopus sungorus) show spontaneous daily torpor only after ∼2 mo in winter-like short photoperiods (SP). Although some SP-induced hormonal changes have been demonstrated to be necessary for the occurrence of seasonal torpor, the whole set of preconditions is still unknown. Recent findings provide evidence that the hypothalamic pituitary growth axis is involved in endocrine responses to SP exposure in the photoperiodic hamsters. To examine whether suppression of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) secretion affects the incidence of daily torpor, we used two somatostatin receptor agonists, pasireotide (SOM230) and octreotide, with different affinity profiles for receptor subtypes. Pasireotide strikingly increased the torpor frequency in male hamsters compared with sham-treated controls, and torpor duration was often increased, which in some cases exceeded 12 h. In contrast, administration of octreotide reduced the body weight of SP hamsters but had only a marginal effect on torpor frequency in males and no effect in females. Together with measured concentrations of circulating IGF-1, the present results strongly suggest that reduced activity of the GH/IGF-1 axis is not critical for stimulation of torpor expression but activation of specific somatostatin receptors is critical. This putative role for certain somatostatin receptor subtypes in torpor induction provides a promising new approach to unravel the endocrine mechanisms of torpor regulation.

scholarly journals Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas

2007 ◽  
Vol 156 (suppl_1) ◽  
pp. S45-S51 ◽  
Author(s):  
Joost van der Hoek ◽  
Steven W J Lamberts ◽  
Leo J Hofland
Keyword(s):  
Pituitary Adenomas ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Physiological Role ◽  
Receptor Subtypes ◽  
Clinical Experiences ◽  
Endocrine Diseases ◽  
Somatostatin Receptor Subtypes ◽  
Preclinical And Clinical Studies

The patho-physiological role of somatostatin receptor subtypes (sst) in neuro endocrine diseases has gained enhanced scientific interest in the past few years. The development of novel somatotropin-release inhibiting factor analogs, both sst-specific and universal ligands, seem promising as a tool to further increase fundamental insights in sst function. Eventually, this research should result in novel medical therapeutic opportunities in patients suffering from neuro-endocrine diseases. In the present review, the functional role of sst in all types of pituitary adenomas, based on recent preclinical and clinical studies, is being discussed.

Modulation of expression of somatostatin receptor subtypes in Graves’ ophthalmopathy orbits: relevance to novel analogs

2007 ◽  
Vol 293 (6) ◽  
pp. E1630-E1635 ◽  
Author(s):  
Irina Cozma ◽  
Lei Zhang ◽  
James Uddin ◽  
Carol Lane ◽  
Aled Rees ◽  
...  
Keyword(s):  
Limit Of Detection ◽  
Ex Vivo ◽  
Somatostatin Receptor ◽  
Receptor Activation ◽  
In Vitro Models ◽  
Receptor Subtypes ◽  
Graves Ophthalmopathy ◽  
Somatostatin Receptor Subtypes ◽  
Vitro Model

Apart from evaluating orbital inflammation in Graves’ ophthalmopathy (GO), somatostatin (SST) analogs have been proposed as a therapy, but recent trials were disappointing. We aimed to measure somatostatin receptor (SSTR) expression in orbital tissues ex vivo and determine whether the new broad-affinity analog SOM230 might be of therapeutic use. Orbital adipose/connective tissues from 29 GO patients and 10 normal individuals were analyzed. Transcripts were quantified using SYBR Green and a light cycler. In vitro models were used to investigate whether thyrotropin receptor activation (as occurs via thyroid stimulating antibodies) or adipogenesis affected SSTR expression in primary preadipocytes and to compare the biological activity of octreotide and SOM230 in their modulation. The expression of SSTR1 was significantly higher in GO patients than normal controls ( P = 0.024). Although differences in the expression of SSTR2 were not significant, 39% of GO samples had levels above the 97th percentile of the controls. SSTR3, -4, and -5 were at or below the limit of detection (LOD). The lymphocyte contribution was minimal, since CD3α transcripts were at the LOD. TSH receptor activation did not modulate SSTR expression. An in vitro model of adipogenesis indicated upregulation of SSTR1 and SSTR2 during differentiation. SOM230 produced significantly greater inhibition of orbital preadipocyte proliferation than octreotide. Ex vivo analysis of orbital tissues reveals upregulation of SSTR1 and -2 in a group of GO patients. Adipogenesis, a process occurring in GO orbits, provides one possible explanation for some of the observed increase.

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