Effect of somatostatin on insulin secretion and cAMP content of isolated pancreatic rat islets

doi:10.1016/0026-0495(78)90060-4

Metabolism

Volume 27, Issue 9, Supplement 1, September 1978, Pages 1291-1294

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Abstract

In a variety of endocrine glands and cells, somatostatin inhibits the release of peptide hormones. The inhibition of insulin and glucagon secretion has been uniformly reported in vivo as well as in vitro by using the perfused pancreas.¹ With the collagenase-isolated islets, however, conflicting data concerning the effect of somatostatin on insulin^2–7 and glucagon release³ have appeared. Therefore, we compared the effect of somatostatin on insulin secretion from islets prepared by microdissection or collagenase digestion in response to various initiators at concentrations that induce a maximal hormone secretion in islets from normal Wistar rats. Furthermore, since it has been suggested that the action of somatostatin on insulin secretion is mediated via cyclic adenosine-3′,5′-monophosphate (cAMP),^2,4.6 the effect of somatostatin on islet cAMP content and the B cell response was investigated in the presence of stimulators of adenylate cyclase and inhibitors of phosphodiesterase.

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Cited by (14)

The somatostatin receptor in human pancreatic β-cells
2014, Vitamins and Hormones
Citation Excerpt :
This suggests that the inhibition of exocytosis under these conditions was independent of cAMP. This is in agreement with a previous study showing inhibition of insulin secretion by SST without lowering of cAMP levels under some experimental conditions in rat islets (Hahn, Gottschling, & Woltanski, 1978). Under voltage-clamp conditions (to prevent SST-evoked changes of the membrane potential), SST moderately reduced Ca2 + entry in isolated human β-cells (by 15%), but restoring Ca2 + influx to control levels by prolonging the stimulation rescued exocytosis only to a small extent (Kailey et al., 2012).
The peptide hormone somatostatin (SST) is produced in the brain, the gut, and in δ-cells in pancreatic islets of Langerhans. SST secretion from δ-cells is stimulated by glucose, amino acids, and glucagon-like peptide-1. Exogenous SST strongly inhibits the secretion of the blood glucose-regulating hormones insulin and glucagon from pancreatic β-cells and α-cells, respectively. Endogenous SST secreted from δ-cells is a paracrine regulator of insulin and glucagon secretion, although the exact physiological significance of this regulation is unclear. Secreted SST binds to specific receptors (SSTRs), which are coupled to G_i/o proteins. In both β- and α-cells, activation of SSTRs suppresses hormone secretion by reducing cAMP levels, inhibiting electrical activity, decreasing Ca^2 + influx through voltage-gated Ca^2 + channels and directly reducing exocytosis in a Ca^2 + and cAMP-independent manner. In rodents, β-cells express predominantly SSTR5, whereas α-cells express SSTR2. In human islets, SSTR2 is the dominant receptor in both β- and α-cells, but other isoforms also contribute to the SST effects. Evidence from rodent models suggests that SST secretion from δ-cells is dysregulated in diabetes mellitus, which may contribute to the metabolic disturbances in this disease. SST analogues are currently used for the treatment of hyperinsulinism and other endocrine disorders, including acromegaly and Cushing's syndrome.
Inhibition by somatostatin of the vasopressin-stimulated adenylate cyclase in a kidney-derived line of cells grown in defined medium
1984, FEBS Letters
LLC-PK_1L cells, a kidney-derived cell line grown in defined medium, possess a vasopressin-sensitive adenylate cyclase. Somatostatin was able to inhibit the vasopressin-induced increase in adenylate cyclase activity, without affecting the basal enzyme activity. This inhibition was competitive. No effect of somatostatin could be detected on [³H]vasopressin binding suggesting an interaction of somatostatin with the vasopressin-sensitive system distal to the hormone—receptor interaction. At variance with N6-L-2-phenylisopropyladenosine (PIA), GTP did not potentiate the inhibition by somatostatin. The inhibition of the vasopressin stimulation by somatostatin and that by PIA were additive. Changing the composition of the cell growth medium increased the number of vasopressin receptors per cell. Cells with a high number of vasopressin receptors were less sensitive to inhibition by somatostatin. Such results suggested that somatostatin and vasopressin receptors and/or the inhibitory (Ni) and stimulatory (Ns) regulatory transducing components are regulated by different mechanisms.
Vanadate and Somatostatin Having Divergent Effects on Pancreatic Islet Na,K-ATPase
1983, Current Topics in Membranes and Transport
This chapter presents two main methodologies to study the effects of vanadate and somatostatin on pancreatic islet Na, K–ATPase. First, islets using the method of Lacy and co-workers were perfused after isolating them with collagenase according to the method of Lacy and Kostianovsky. The second technique used was the measurement of Na, K–ATPase activity in a 35,000 g pellet from islet homogenates. Stimuli of insulin secretion, such as glucose, arginine, and ouabain, suppress rat pancreatic islet Na, K–ATPase activity. In contrast, certain insulin secretory inhibitors such as phenytoin, NH₄Cl, or diazoxide enhance the activity of this islet enzyme system. In secretory experiments using vanadate, somatostatin-like immunoreactivity (SLI) as well as immunoreactive insulin (IRI) secretion from the islets was measured.
Evidence that somatostatin inhibits proinsulin synthesis and insulin release by isolated pancreatic islets of the rat
1980, Metabolism
Conflicting reports on the direction and magnitude of the effect of somatostatin on (pro)insulin synthesis prompted our investigation. Two assays for proinsulin synthesis were designed in which [4,5-³H]-L-leucine incorporation into proinsulin was normalized on the basis of postincubation insulin levels rather than on the number of islets incubated. Somatostatin at a concentration of 10 μg/ml inhibited 300 mg/dl glucose-stimulated proinsulin synthesis by 25% from 448 ± 25 dpm/μU insulin to 336 ± 25 dpm/μU insulin (disintegrations per minute in the proinsulin peak per microunit extractable insulin) (p < 0.05). Glucagon (10 μg/ml) reversed the inhibitory effect of somatostatin on proinsulin synthesis from 336 ± 25 dpm/μU insulin to 480 ± 44 dpm/μU insulin (p < 0.02). Somatostatin (10 μg/ml) had no significant effect on proinsulin synthesis in the presence of 70 mg/dl or 150 mg/dl glucose. Insulin release in 300 mg/dl glucose was inhibited 38% by 10 μg/ml somatostatin from 3.05 ± 0.40 mU medium/mU tissue to 1.90 ± 0.10 mU medium/mU tissue (p < 0.01) over a 45-minute incubation period. These data suggest that somatostatin may act on glucose signal transduction on a level at which both insulin synthesis and secretion are affected. Further, the results are consistent with the hypothesis that cyclic AMP participates in mediating somatostatin effects on B-cell metabolism.
Characterization of the inhibitory effect of somatostatin upon insulin and glucagon release in the isolated perfused canine pancreas: Evidence for interaction with calcium
1980, Metabolism
Somatostatin is a potent inhibitor of insulin and glucagon release from the isolated perfused canine pancreas. The present investigation was undertaken to characterize the pancreatic effects of somatostatin by studying its ability to influence insulin and glucagon release from the same perfusion preparation in response to various well-known stimuli and modulators. Somatostatin inhibited insulin and glucagon release in all test situations chosen but one. Thus, somatostatin inhibits pancreatic hormone secretion irrespective of whether it is modulated by (1) a primary initiator of insulin release-glucose (1.3 or 8.3 mM), leucine (4.1 mM), tolbutamide (2.6 mM); (2) a potentiator of insulin release, i.e., a substance that requires the presence of glucose-arginine (1 mM); (3) substances known to increase the level of cyclic AMP (cAMP) in the islets-glucagon (2 ng/ml), cAMP (1 mM), theophylline (1 mM); (4) an autonomic agnet-epinephrine (2 ng/ml), acetylcholine (10 μM); or (5) alpha and beta adrenergic antagonists-phentolamine (1 μM), propranolol (1 μM). In contrast, high Ca⁺⁺ concentrations (4.8 and 8.2 mM) abolished the inhibitory action of somatostatin on both insulin and glucagon release. These findings lend support to the hypothesis that somatostatin acts at a stage of secretory processes, possibly related to Ca⁺⁺ inactivation, late in the chain of events leading to hormone release.
Somatostatin and Insultin secretion in man. I. The effect of phentolamine
1980, Pharmacological Research Communications
To determine whether somatostatin inhibits insulin secretion in humans by interacting with alpha-adrenergic pathways, we studied the effect of phentolamine, a selective alpha-adrenergic blocking agent, upon the insulin response to glucose with or without a concurrent infusion of somatostatin. Acute Insulin Response (AIR, mean change 3′–10′) to glucose (20 g iv) was almost completely blunted by somatostatin (500 μg/h). Similarly, glucose disappearance rate was significantly reduced. These somatostatin-induced decreases failed to be eliminated by a 0.5 mg/min infusion of phentolamine. Infusion of phentolamine alone augmented both AIR and glucose tolerance. These results confirm somatostatin as a potent diabetogenic hormone in healthy humans and also indicate that alpha-adrenergic receptor mechanism does not play a major role in the inhibition of insulin secretion by somatostatin.

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^☆: Supported by the Research Project, “Diabetes mellitus und Fettstoffwechselstorungen.”

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Effect of somatostatin on insulin secretion and cAMP content of isolated pancreatic rat islets☆

Abstract

Biochem Biophys Res Commun

Biochim Biophys Acta

Gen Comp Endocrinol

Biochim Biophys Acta

J Biol Chem

Somatostatin

Rec Prog Horm Res

Somatostatin induced inhibition of insulin secretion from isolated islets of rat pancreas in presence of glucagon

Horm Metab Res