Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?

Walker, Jonathan N.; Ramracheya, Reshma; Zhang, Quan; Johnson, Paul; Braun, Matthias; Rorsman, Patrik

doi:10.1111/j.1463-1326.2011.01450.x

Cited by 153 publications

(204 citation statements)

References 62 publications

(98 reference statements)

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“…Another study [18] and we, here, have reported GLP-1 values in the picomolar range, suggesting intrinsic islet biological variability and/or differences in experimental conditions. In addition, in our study, glucagon release from isolated islets was similar to that reported by some other authors [36,37], but several fold lower than that observed during perifusion experiments [38]. All this led, in our hands, to a glucagon/GLP-1 molar secretion ratio (basal condition) of approximately 5.7, similar to findings previously reported for αTC1-6 cells [16].…”

Section: Discussionsupporting

confidence: 79%

“…All this led, in our hands, to a glucagon/GLP-1 molar secretion ratio (basal condition) of approximately 5.7, similar to findings previously reported for αTC1-6 cells [16]. In addition, when we measured glucagon and active GLP-1 in islet extracts, the values and proportions were close to those found by others [18,37]. Interestingly, however, the bi-hormone secretion ratio with alpha cell fractions tended to decrease (approximate value of 3), suggesting that primary human alpha cells might rapidly change their phenotype.…”

Section: Discussionsupporting

confidence: 75%

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A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

et al. 2012

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Aims/hypothesis Glucagon-like peptide 1 (GLP-1) is a major incretin, mainly produced by the intestinal L cells, with beneficial actions on pancreatic beta cells. However, while in vivo only very small amounts of GLP-1 reach the pancreas in bioactive form, some observations indicate that GLP-1 may also be produced in the islets. We performed comprehensive morphological, functional and molecular studies to evaluate the presence and various features of a local GLP-1 system in human pancreatic islet cells, including those from type 2 diabetic patients. MethodsThe presence of insulin, glucagon, GLP-1, proconvertase (PC) 1/3 and PC2 was determined in human pancreas by immunohistochemistry with confocal microscopy. Islets were isolated from non-diabetic and type 2 diabetic donors. GLP-1 protein abundance was evaluated by immunoblotting and matrix-assisted laser desorption-ionisation-time of flight (MALDI-TOF) mass spectrometry. Single alpha and beta cell suspensions were obtained by enzymatic dissociation and FACS sorting. Glucagon and GLP-1 release were measured in response to nutrients. Diabetologia (2012) 55:3262-3272 DOI 10.1007/s00125-012-2716 Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2716-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Results Confocal microscopy showed the presence of GLP-1-like and PC1/3 immunoreactivity in subsets of alpha cells, whereas GLP-1 was not observed in beta cells. The presence of GLP-1 in isolated islets was confirmed by immunoblotting, followed by mass spectrometry. Isolated islets and alpha (but not beta) cell fractions released GLP-1, which was regulated by glucose and arginine. PC1/3 (also known as PCSK1) gene expression was shown in alpha cells. GLP-1 release was significantly higher from type 2 diabetic than from nondiabetic isolated islets. Conclusions/interpretation We have shown the presence of a functionally competent GLP-1 system in human pancreatic islets, which resides in alpha cells and might be modulated by type 2 diabetes.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 75%

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

et al. 2012

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“…Although the mechanism through which hyperglucagonemia occurs in diabetes is complex, certain metabolic pathways have been implicated such as the paracrine regulation of glucagon secretion by somatostatin and insulin (16). Indeed, the most widely accepted mechanism is that the inappropriate elevation in glucagon during hyperglycemia is due to the lack of intraislet insulin to restrain the glucose Data are expressed as mean 6 SD or median (25th-75th).…”

Section: Discussionmentioning

confidence: 99%

Glucagon Response to Oral Glucose Challenge in Type 1 Diabetes: Lack of Impact of Euglycemia

et al. 2014

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OBJECTIVEPrevious studies have demonstrated aberrant glucagon physiology in the setting of type 1 diabetes (T1D) but have not addressed the potential impact of ambient glycemia on this glucagon response. Thus, our objective was to evaluate the impact of euglycemia versus hyperglycemia on the glucagon response to an oral glucose challenge in T1D. RESEARCH DESIGN AND METHODSTen adults with T1D (mean age 56.6 6 9.0 years, duration of diabetes 26.4 6 7.5 years, HbA 1c 7.5% 6 0.77, and BMI 24.1 kg/m 2 [22.6-25.4]) underwent 3-h 50-g oral glucose tolerance tests (OGTTs) on two separate days at least 24 h apart in random order under conditions of pretest euglycemia (plasma glucose [PG] between 4 and 6 mmol/L) and hyperglycemia (PG between 9 and 11 mmol/L), respectively. RESULTSGlycemic excursion on the OGTT was similar between the euglycemic and hyperglycemic tests (P = 0.72 for interaction between time postchallenge and glycemic setting). Interestingly, glucagon levels increased in response to the OGTT under both glycemic conditions (P < 0.001) and there were no differences in glucagon response between the euglycemic and hyperglycemic days (P = 0.40 for interaction between time postchallenge and glycemic setting). In addition, the incretin responses to the OGTT (glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon-like peptide-2) were also not different between the euglycemic and hyperglycemic settings. CONCLUSIONSIn patients with T1D, there is a paradoxical increase in glucagon in response to oral glucose that is not reversed when euglycemia is achieved prior to the test. This abnormal glucagon response likely contributes to the postprandial hyperglycemia in T1D irrespective of ambient glycemia.

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“…Previous work has demonstrated that interactions between cells within the islet are essential for ensuring the appropriate pattern of insulin secretion [1][2][3][4][5]; and possible interactions between alpha and beta cells within islets have been well studied [1,[6][7][8][9]. For example, alpha cells express the insulin receptor [7] and a number of studies suggest that beta cells negatively regulate glucagon secretion, although it is uncertain whether the paracrine agent is insulin, zinc co-released with insulin or some other beta cell secretory product [7][8][9][10]. Less attention has been paid to the potential intra-islet roles of delta cell-derived somatostatin, but from studies of somatostatin-deficient mice, we recently identified an important paracrine role in the regulation of islet hormone secretion, where locally released delta cell somatostatin inhibited insulin and glucagon secretion [11].…”

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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Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?

Cited by 153 publications

References 62 publications

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

Glucagon Response to Oral Glucose Challenge in Type 1 Diabetes: Lack of Impact of Euglycemia

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

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