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 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 Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Yaser Albadr ◽  
Andrew Crowe ◽  
Rima Caccetta
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Teucrium Polium

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed.

scholarly journals Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin

2016 ◽  
Vol 101 (4) ◽  
pp. 1798-1806 ◽  
Author(s):  
Anna Vanderheiden ◽  
Lindsay B. Harrison ◽  
Jeremy T. Warshauer ◽  
Beverley Adams-Huet ◽  
Xilong Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Treatment ◽  
Glycosylated Hemoglobin ◽  
Challenge Test ◽  
Glucagon Secretion ◽  
Mechanisms Of Action ◽  
High Dose ◽  
C Peptide

Abstract Context: The mechanisms of action of incretin mimetics in patients with long-standing type 2 diabetes (T2D) and high insulin requirements have not been studied. Objective: To evaluate changes in β-cell function, glucagon secretion, and fat distribution after addition of liraglutide to high-dose insulin. Design: A single-center, randomized, double-blind, placebo-controlled trial. Setting: University of Texas Southwestern and Parkland Memorial Hospital clinics. Patients: Seventy-one patients with long-standing (median, 17 years) T2D requiring high-dose insulin treatment (>1.5 U/kg/d; average, 2.2 ± 0.9 U/kg/d). Intervention: Patients were randomized to liraglutide 1.8 mg/d or matching placebo for 6 months. Main Outcome Measures: We measured changes in insulin and glucagon secretion using a 4-hour mixed-meal challenge test. Magnetic resonance-based techniques were used to estimate sc and visceral fat in the abdomen and ectopic fat in the liver and pancreas. Results: Glycosylated hemoglobin improved significantly with liraglutide treatment, with an end-of-trial estimated treatment difference between groups of −0.9% (95% confidence interval, −1.5, −0.4%) (P = .002). Insulin secretion improved in the liraglutide group vs placebo, as measured by the area under the curve of C-peptide (P = .002) and the area under the curves ratio of C-peptide to glucose (P = .003). Insulin sensitivity (Matsuda index) and glucagon secretion did not change significantly between groups. Liver fat and sc fat decreased in the liraglutide group vs placebo (P = .0006 and P = .01, respectively), whereas neither visceral nor pancreatic fat changed significantly. Conclusions: Treatment with liraglutide significantly improved insulin secretion, even in patients with long-standing T2D requiring high-dose insulin treatment. Liraglutide also decreased liver and sc fat, but it did not alter glucagon secretion.

scholarly journals Amyloid precursor protein in pancreatic islets

2017 ◽  
Vol 235 (1) ◽  
pp. 49-67 ◽  
Author(s):  
Joshua A Kulas ◽  
Kendra L Puig ◽  
Colin K Combs
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Precursor Protein ◽  
Pancreatic Islets ◽  
Culture Media ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Precursor Protein ◽  
Protein Levels ◽  
Glucose Levels

The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque-forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrate the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by Western blot from C57BL/6 (WT), APP−/− and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.

scholarly journals Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without Type 2 diabetes

2014 ◽  
Vol 306 (4) ◽  
pp. G301-G309 ◽  
Author(s):  
Sara Chowdhury ◽  
Dominic N. Reeds ◽  
Dan L. Crimmins ◽  
Bruce W. Patterson ◽  
Erin Laciny ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Gastric Emptying ◽  
Postprandial Glucose ◽  
Nerve Fibers ◽  
Intense Staining ◽  
Glucose Levels ◽  
Healthy Humans ◽  
Glucagon Like Peptide 1

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10–14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol·kg−1·min−1 was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

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.

scholarly journals Gene Transcription of Receptors for Growth Hormone-Releasing Peptide and Somatostatin in Human Pituitary Adenomas1

1998 ◽  
Vol 83 (8) ◽  
pp. 2997-3000
Author(s):  
Steen Nielsen ◽  
Søren Mellemkjær ◽  
Lars M. Rasmussen ◽  
Thomas Ledet ◽  
Jens Astrup ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Messenger Rna ◽  
Somatostatin Receptor ◽  
Pituitary Tumors ◽  
Distinct Pattern ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Human Pituitary ◽  
Somatostatin Receptor Subtypes ◽  
Almost All

abstract Growth hormone (GH)-releasing peptides (GHRP) or secretagogs (GHS) constitute a family of synthetic compounds with potent and specific GH releasing activity. The receptor (GHS-R) has recently been cloned even though the endogenous ligand remains to be identified. GHRPs act both at the hypothalamic and the pituitary level through mechanisms involving amplification of GH-releasing hormone activity and functional somatostatin antagonism. In the present study we examined the co-expression of messenger RNA (mRNA) for GHS-R and all 5 somatostatin receptor subtypes (sstr 1–5) in 28 human pituitary tumors by RT-PCR. GHS-R transcription was detected in 11 out of 12 somatotroph adenomas and in 2 out of 2 prolactinomas, whereas GHS-R expression was detected in only 2 out of 14 clinically nonfunctioning adenomas (NFPA), and no expression was seen in the only ACTH secreting adenoma. Almost all tumors expressed sstr 2 mRNA (n = 24), whereas only 1 tumor expressed sstr 4 mRNA. The expression of sstr 3 mRNA was inversely associated with GHS-R expression (P < 0.001), which could be attributed to a high prevalence of sstr 3 expression in NFPA. This study suggests that GHS-R expression is predominantly observed in somatotroph adenomas and much less so in NFPA. Moreover, the presence of a distinct pattern of somatostatin receptor subtype co-expression is suggested, which may provide a molecular basis for the complex interaction between GHRPs and somatostatin.

scholarly journals Somatostatin Inhibits Insulin and Glucagon Secretion via Two Receptor Subtypes: An in Vitro Study of Pancreatic Islets from Somatostatin Receptor 2 Knockout Mice*

Endocrinology ◽  
2000 ◽  
Vol 141 (1) ◽  
pp. 111-117 ◽  
Author(s):  
M. Z. Strowski ◽  
R. M. Parmar ◽  
A. D. Blake ◽  
J. M. Schaeffer
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Somatostatin Receptor ◽  
Glucagon Secretion ◽  
Endocrine Function ◽  
Receptor Subtype ◽  
Glucagon Release ◽  
Glucagon And Insulin

Abstract Somatostatin (SST) potently inhibits insulin and glucagon release from pancreatic islets. Five distinct membrane receptors (SSTR1–5) for SST are known, and at least two (SSTR2 and SSTR5) have been proposed to regulate pancreatic endocrine function. Our current understanding of SST physiology is limited by the receptor subtype selectivity of peptidyl SST analogs, making it difficult to assign a physiological function to an identified SST receptor subtype. To better understand the physiology of SSTRs we studied the in vitro effects of potent subtype-selective nonpeptidyl SST analogs on the regulation of pancreatic glucagon and insulin secretion in wild-type (WT) and in somatostatin receptor 2 knockout (SSTR2KO) mice. There was no difference in basal glucagon and insulin secretion between islets isolated from SSTR2KO and WT mice; however, potassium/arginine-stimulated glucagon secretion was approximately 2-fold higher in islets isolated from SSTR2KO mice. Neither SST nor any SSTR-selective agonist inhibited basal glucagon or insulin release. SST-14 potently inhibited stimulated glucagon secretion in islets from WT mice and much less effectively in islets from SSTR2KO mice. The SSTR2 selective analog L-779,976 inhibited glucagon secretion in islets from WT, but was inactive in islets from SSTR2KO mice. L-817,818, an SSTR5 selective analog, slightly reduced glucagon release in both animal groups, whereas SSTR1, -3, and -4 selective analogs were inactive. SST and L-817,818 inhibited glucose stimulated insulin release in islets from WT and SSTR2KO mice. L-779,976 much less potently reduced insulin secretion from WT islets. In conclusion, our data demonstrate that SST inhibition of glucagon release in mouse islets is primarily mediated via SSTR2, whereas insulin secretion is regulated primarily via SSTR5.

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