The vascular order of islet cellular perfusion in the human pancreas

Stagner, J. I.; Samols, E.

doi:10.2337/diabetes.41.1.93

Cited by 36 publications

(30 citation statements)

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“…The study thus argued against a local regulatory role for SST in the islet (11). This conclusion is supported by a series of immunoneutralization studies in isolated perfused pancreata of rat, dog, and humans, in which anterograde perfusion with polyclonal SST antibodies did not significantly affect either insulin or glucagon secretion (12)(13)(14)(15)(16). In contrast, Brunicardi and colleagues (17,18) reported that neutralization of intraislet SST with monoclonal antibodies enhances both glucagon and insulin secretion from isolated perfused human pancreas.…”

mentioning

confidence: 55%

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

2003

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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...

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confidence: 55%

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

2003

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“…Somatostatin is a potent suppressor of insulin and glucagon release [15,16] and has been suggested to act as an intra-islet regulator of glucagon secretion in rats [9]. This concept, however, has been strongly argued against by Samols and Stagner, who, based on immunoneutralisation studies in the isolated perfused pancreas of dogs, rats and humans, postulated that the order of microvascular cellular perfusion in pancreatic islets is from beta to alpha to delta cells, ruling out a substantial regulatory role for somatostatin [17][18][19].…”

Section: Introductionmentioning

confidence: 94%

Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

et al. 2008

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Aims/hypothesis The glucose-lowering effect of glucagonlike peptide-1 (GLP-1) is based not only upon its potent insulinotropic actions but also on its ability to restrain glucagon secretion. Surprisingly, the closely related glucose-dependent insulinotropic peptide (GIP) stimulates glucagon release. We examined whether the islet hormone somatostatin, which strongly inhibits glucagon secretion, is involved in this divergent behaviour. Methods At 1.5 mmol/l glucose and therefore minimal insulin secretion, the glucagon, insulin and somatostatin responses to 20 mmol/l glucose, GLP-1, GIP and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas. Results In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion significantly to 59.0±6.3% (p<0.004; n=5; SSTR2 series; each vs pre-infusion level) and to 48.0±2.6% (p<0.001; n=6; somatostatin antibody series) respectively. During somatostatin antibody administration, GLP-1 still inhibited glucagon secretion significantly, but the effect was less pronounced than in control experiments (p<0.018). Co-infusion of the SSTR2 antagonist completely abolished the GLP-1-induced suppression of glucagon secretion. In contrast, neither the GIP-induced stimulation of glucagon release nor its inhibition by 20 mmol/l glucose was altered by somatostatin antibody or SSTR2 antagonist administration. Conclusions/interpretationWe conclude that GLP-1 is capable of inhibiting glucagon secretion even in the absence of secretory products from the beta cell. It is highly likely that this is mediated via somatostatin interacting with SSTR2 on rat alpha cells. In contrast, GIP and glucose seem to influence the alpha cell independently of somatostatin secretion.

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“…As detailed in Table 1, numerous hormones (many of which are also neurotransmitters) also affect glucagon release. Insulin suppresses glucagon secretion via a local endocrine effect [11]; somatostatin, by a paracrine effect [12]. Thus, alpha cells are exposed to very high concentrations of insulin and somatostatin, and there is some evidence to suggest that insulin mediates glucose inhibition of glucagon secretion [13] and that withdrawal of this local insulin 'tone' mediates the effect of hypoglycaemia on glucagon release [14].…”

Section: Normal Alpha Cell Functionmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

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The vascular order of islet cellular perfusion in the human pancreas

Cited by 36 publications

References 0 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

Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

Alpha cell function in health and disease: influence of glucagon-like peptide-1

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