Sulfonylurea-induced inhibition of glucagon secretion from the perfused rat pancreas: evidence for a direct, non-paracrine effect

Östenson, Claes‐Göran; Nylén, A.; Grill, Valdemar; Gutniak, M.; Efendić, Suad

doi:10.1007/bf00870141

Cited by 27 publications

(13 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6). This procedure is known to blunt the endogenous SST response (30). Our findings are consistent with the results of a study using batch-incubated islets isolated from SSTR2-knockout mice, in which the glucagon response to arginine and potassium was enhanced twofold, while insulin release was unchanged (36).…”

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats

2003

View full text Add to dashboard Cite

Exogenously administered somatostatin (SST) inhibits secretion of insulin and glucagon. Furthermore, it is hypothesized that islet SST regulates glucagon secretion by a local action. A number of studies utilizing SST antibodies have been performed to test this hypothesis, and their results have been conflicting. Five subtypes of SST receptor (SSTR1-5) mediate the effect of SST on target cells. In rodents, SST inhibits the release of glucagon, but not that of insulin, via SSTR2. A novel SSTR2-selective antagonist, DC-41-33, was synthesized recently. We have investigated the effects of this antagonist on arginine-stimulated glucagon and insulin release in batch incubations of isolated rat islets, perifused isolated rat islets, and isolated perfused rat pancreas. In batch incubations at 3.3 mmol/l glucose, DC-41-33 increased glucagon release in a dose-dependent manner. At the maximum dose tested (2 mol/l), DC-41-33 enhanced the glucagon response by 4.3-to 5-fold. Similarly, this compound increased arginine-induced glucagon release in perifused islets at 3.3 mmol/l glucose (2.8-fold) and perfused pancreas at 3.3 and 5.5 mmol/l glucose (2.5-and 2.3-fold, respectively). In the two latter experimental systems, DC-41-33 had no significant effect on insulin release. In conclusion, our results strongly support the hypothesis that islet SST inhibits glucagon secretion via a local action. Diabetes 52:1176 -1181, 2003 I t is well established that exogenously administered somatostatin (SST) inhibits the release of insulin (1,2) and glucagon (3,4) from the endocrine pancreas. In addition, it has been hypothesized that SST released from islet D-cells regulates the secretion of insulin and glucagon by a local "paracrine" action (5,6). This hypothesis was supported by experiments demonstrating that immunoneutralization of endogenous SST in batch incubations of isolated pancreatic islets enhances glucagon and insulin secretion (7,8). However, the results of these studies do not necessarily depict physiological events, since released hormones accumulate in the medium and islet interstitium during the 30-to 90-min incubation period, reaching concentrations that most probably exceed those that are physiologically relevant. Additionally, isolated islets retain neither their normal interstitial structure nor their microcirculation. Further support for the involvement of local effects of SST came from an in vivo study in dogs, in which low and medium doses of a nonimmunoreactive SST analog suppressed the release of endogenous SST and markedly enhanced glucagon release, while insulin release was enhanced moderately (9). The possibility remains, however, that this analog had systemic effects that influenced hormone release.For the reasons stated above, studies with isolated perfused pancreas are of special relevance when considering paracrine interactions between islet cells. In the perfused isolated canine pancreas, exogenous SST inhibited arginine-stimulated insulin and glucagon secretion at concentrations as low as 20% of those measure...

show abstract

Section: Discussionsupporting

confidence: 90%

“…To abolish the release of endogenous SST, we perfused pancreata with buffer supplemented with only 20% of the standard calcium content (30). In these experiments, at 3.3 mmol/l glucose, insulin and glucagon each responded to arginine in a biphasic manner, while DC-41-33 did not significantly affect these hormonal responses (Fig.…”

Section: Resultsmentioning

confidence: 99%

Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats

2003

View full text Add to dashboard Cite

show abstract

“…These effects will change depending on the extracellular glucose concentrations that necessarily influence K ATP channel activity (MacDonald et al 2007). This biphasic behaviour may explain the disparity of effects found for sulphonylureas (Loubatieres et al 1974, Ostenson et al 1986). In humans, sulphonylureas are associated to a glucagon secretion decrease in healthy and type 2 diabetic subjects (Landstedt-Hallin et al 1999), while they stimulate glucagon levels in type 1 diabetic patients (Bohannon et al 1982).…”

Section: Modulation Of Glucagon Secretionmentioning

confidence: 99%

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Quesada¹,

Tudurí²,

Ripoll³

et al. 2008

Journal of Endocrinology

337

330

View full text Add to dashboard Cite

The secretion of glucagon by pancreatic a-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of a-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on a-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to a-cell function are also discussed in this review. A better understanding of the a-cell physiology is necessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.

show abstract

“…We used 5.6 mm basal glucose concentration for the pre-conditioning of the pancreas because it is close to the fasting plasma glucose level, and because a low glucose concentration is known to stimulate glucagon and somatostatin release. Several previous reports on hormone release by sulphonylureas in perfused rat pancreas have been published (Gotfredsen, 1976;Grodsky et al, 1977;Efendic et al, 1979;Ostenson et al, 1986). Efendic and coworkers described the effect of glibenclamide on insulin release in detail in the presence of various glucose concentrations using perfused rat pancreas (Efendic et al, 1979).…”

Section: Discussionmentioning

confidence: 98%

Effect of a non‐sulphonylurea hypoglycaemic agent, KAD‐1229 on hormone secretion in the isolated perfused pancreas of the rat

Kinukawa

Ohnota

Ajisawa

1996

British J Pharmacology

View full text Add to dashboard Cite

We examined the cooperative effect of a newly synthesized oral hypoglycaemic agent, KAD‐1229 with glucose on insulin, glucagon and somatostatin secretion in the isolated perfused pancreas of the rat. KAD‐1229 stimulated concentration‐dependently the first phase of insulin secretion without the second phase in the presence of 2.8 mM glucose, while it stimulated both the first and the second phase of insulin release in the presence of 5.6 mM glucose. It was confirmed that the first phase of insulin release is depolarization‐induced release with no other additional signal transduction. KAD‐1229 also enhanced insulin release evoked by 16.7 mM glucose, a concentration known to inhibit the ATP‐sensitive K+ current completely. A low concentration (2.8 mM) of glucose stimulated somatostatin release transiently, while a higher concentration (16.7 mM) of glucose exerted a sustained stimulation. KAD‐1229 stimulated somatostatin secretion in a concentration‐dependent manner irrespective of glucose concentrations. When glucagon release was stimulated with 2.8 mM glucose, KAD‐1229 inhibited this hypoglycaemia‐induced glucagon secretion. When pancreata from rats pretreated with streptozotocin (STZ) 60 mg kg−1 were perfused, the basal secretion of glucagon was markedly elevated, and the glucagon response to the low glucose was abolished. Further, the insulin and somatostatin responses to KAD‐1229 were largely attenuated. KAD‐1229 showed transient enhancement followed by inhibition of the glucagon release from the STZ‐pretreated rat pancreas. We conclude that KAD‐1229 stimulates insulin and somatostatin release, while it inhibits glucagon release following transient stimulation.

show abstract

Sulfonylurea-induced inhibition of glucagon secretion from the perfused rat pancreas: evidence for a direct, non-paracrine effect

Cited by 27 publications

References 31 publications

Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats

Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Effect of a non‐sulphonylurea hypoglycaemic agent, KAD‐1229 on hormone secretion in the isolated perfused pancreas of the rat

Contact Info

Product

Resources

About