Interrelationship among insulin, glucagon and somatostatin secretory responses to exendin-4 in the perfused rat pancreas

Silvestre, Ramona A.; Rodriguez-Gallardo, J.; Egido, Eva M.; Marco, José

doi:10.1016/s0014-2999(03)01692-3

Cited by 29 publications

(14 citation statements)

References 23 publications

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“…These results are consistent with previous data on perfused rat pancreata (41,42) and renal subcapsular grafts (37), and may be explained by that glucagon release following switching to low glucose is delayed for at least 10 min in several settings, including pancreas perfusions in rat (9,43,44).…”

Section: Discussionsupporting

confidence: 92%

Islets Transplanted Intraportally into the Liver are Stimulated to Insulin and Glucagon Release Exclusively through the Hepatic Artery

Lau¹,

Jansson²,

Carlsson

2006

American Journal of Transplantation

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Not much is known about the physiology of intraportally transplanted islets. One reason for this is that it is difficult to study such islets, since they are scattered throughout the liver. We employed a perfusion technique to characterize the functional properties of syngeneic intrahepatic 1-month-old islet grafts, and compared them to islets transplanted beneath the kidney capsule, as well as native islets. The cellular composition of the islet grafts was also examined. Glucose and arginine administered through the hepatic artery, but not through the portal vein, induced insulin release from the intraportally implanted islets. Moreover, arginine, only when administered through the hepatic artery, induced glucagon release from the same islets. The first phase of glucose-stimulated insulin release from both islets transplanted to the liver and kidney was delayed, and less prominent when compared to the pancreas. Intraportally transplanted islets contained fewer glucagon-positive cells than islets transplanted to the kidney and native islets. Our findings demonstrate that intraportally transplanted islets respond with insulin and glucagon to secretagogues, but only when stimulated through the hepatic artery. Whether intrahepatic islets may sense other substances than glucose or arginine occurring in high concentrations in the portal vein following intestinal uptake remains to be studied.

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Section: Discussionsupporting

confidence: 92%

Islets Transplanted Intraportally into the Liver are Stimulated to Insulin and Glucagon Release Exclusively through the Hepatic Artery

Lau¹,

Jansson²,

Carlsson

2006

American Journal of Transplantation

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“…However, despite initial reports that GLP-1 receptor (GLP-1R) was produced in the majority of beta, alpha and delta cells [20,50], the same group was later unable to detect the receptor in alpha or delta cells using a range of different, highly sensitive immunohistochemical techniques [51], observations that supported earlier negative studies [52]. The absence of GLP-1R production by delta cells is at odds with the numerous reports that exendin-4 or GLP-1 exerted stimulatory effects on somatostatin release [15][16][17][18][19][20] and may suggest that GLP-1 modifies somatostatin secretion via an indirect mechanism [51]. In the present study, we were unable to detect GLP-1R in TGP52 cells.…”

Section: Discussionmentioning

confidence: 94%

“…Current knowledge of the regulation of somatostatin secretion is limited, but the available evidence suggests that delta cells respond similarly to beta cells. Accordingly, some studies have demonstrated that glucose stimulates both insulin and somatostatin release [11,12], as do membrane-depolarising agents such as arginine and sulfonylureas [11,[13][14][15][16], as well as the incretin, glucagon-like peptide 1 (GLP-1) [15][16][17][18][19][20]. These observations may reflect similar stimulus-response coupling mechanisms in beta and delta cells, but they could also suggest that delta cell secretory responses are indirectly regulated in a paracrine manner by insulin released from beta cells.…”

Section: Introductionmentioning

confidence: 99%

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

et al. 2012

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Aims/hypothesis Somatostatin from islet delta cells inhibits insulin and glucagon secretion, but knowledge of the regulation of pancreatic somatostatin release is limited. Some insulin secretagogues stimulate somatostatin secretion, and here we investigated whether delta cell secretory responses are indirectly regulated in a paracrine manner by insulin released from beta cells. Methods Hormone release from static incubations of primary mouse islets or somatostatin-secreting TGP52 cells was measured by RIA. mRNA expression was assessed by RT-PCR. Results Glucose and a range of other physiological and pharmacological agents stimulated insulin and somatostatin release, and insulin receptor mRNA was expressed in islets, MIN6 beta cells and TGP52 cells. However, exogenous insulin did not modulate basal or glucose-induced somatostatin secretion from islets, nor did pre-incubation with an antibody against the insulin receptor or with the insulin receptor tyrosine kinase inhibitor, HNMPA(AM) 3 . Glucose and tolbutamide stimulated somatostatin release from TGP52 cells, whereas a range of receptor-operating agents had no effect, the latter being consistent with a lack of corresponding receptor mRNA expression in these cells. Parasympathetic activation stimulated insulin, but inhibited somatostatin release from mouse islets in accordance with differences in muscarinic receptor mRNA expression in islets, MIN6 and TGP52 cells. The inhibitory effect on somatostatin secretion was reversed by pertussis toxin or the muscarinic receptor 2 antagonist, methoctramine. Conclusions/interpretations A number of insulin secretagogues have analogous effects on insulin and somatostatin release, but this similarity of response is not mediated by an indirect, paracrine action of insulin on delta cells.

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“…The effect of GLP-1 on alpha cell glucose sensing in vitro has not been assessed. One study with the GLP-1 agonist exenatide (previously known as exendin-4; a naturally occurring peptide isolated from salivary secretions of Heloderma suspectum) did examine glucagon release from the perfused rat pancreas in response to a square wave decrease in glucose level from 11 to 3.2 mmol/l, with or without GLP-1 infusion, and found a small suppressive effect of GLP-1 [68]. However, the alpha cell response to the glucose decrement alone was very modest.…”

Section: Effects Of Glp-1 On Alpha Cells In Vitromentioning

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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Interrelationship among insulin, glucagon and somatostatin secretory responses to exendin-4 in the perfused rat pancreas

Cited by 29 publications

References 23 publications

Islets Transplanted Intraportally into the Liver are Stimulated to Insulin and Glucagon Release Exclusively through the Hepatic Artery

Islets Transplanted Intraportally into the Liver are Stimulated to Insulin and Glucagon Release Exclusively through the Hepatic Artery

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

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

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