A role for islet somatostatin in mediating sympathetic regulation of glucagon secretion

Hauge-Evans, Astrid C.; King, Aileen; Fairhall, K. M.; Persaud, Shanta J.; Jones, Peter M.

doi:10.4161/isl.2.6.13858

Cited by 18 publications

(15 citation statements)

References 15 publications

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“…Interestingly, a switch-off signal from zinc atoms, whether bound to insulin or not, also seems to be involved in the initiation of glucagon release from the a-cell, as could be shown in streptozotocin-induced diabetic Wistar rats (Zhou et al 2007). The removal of somatostatinmediated inhibition of glucagon secretion via pancreatic d-cells by sympathetic activation may further contribute to inadequate glucagon secretion (Hauge-Evans et al 2010). As indicated by the present data, the multifactorial regulation of glucagon secretion and its importance with respect to glucose metabolism need to be further elucidated.…”

Section: Discussionmentioning

confidence: 99%

Glucagon secretion after metabolic surgery in diabetic rodents

Eickhoff¹,

Louro²,

Matafome³

et al. 2014

Journal of Endocrinology

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Excessive or inadequate glucagon secretion promoting hepatic gluconeogenesis and glycogenolysis is believed to contribute to hyperglycemia in patients with type 2 diabetes. Currently, metabolic surgery is an accepted treatment for obese patients with type 2 diabetes and has been shown to improve glycemic control in Goto-Kakizaki (GK) rats, a lean animal model for type 2 diabetes. However, the effects of surgery on glucagon secretion are not yet well established. In this study, we randomly assigned forty 12-to 14-week-old GK rats to four groups: control group (GKC), sham surgery (GKSS), sleeve gastrectomy (GKSG), and gastric bypass (GKGB). Ten age-matched Wistar rats served as a non-diabetic control group (WIC). Glycemic control was assessed before and 4 weeks after surgery. Fasting-and mixed-meal-induced plasma levels of insulin and glucagon were measured. Overall glycemic control improved in GKSG and GKGB rats. Fasting insulin levels in WIC rats were similar to those for GKC or GKSS rats. Fasting glucagon levels were highest in GKGB rats. Whereas WIC, GKC, and GKSS rats showed similar glucagon levels, without any significant meal-induced variation, a significant rise occurred in GKSG and GKGB rats, 30 min after a mixed meal, which was maintained at 60 min. Both GKSG and GKGB rats showed an elevated glucagon:insulin ratio at 60 min in comparison with all other groups. Surprisingly, the augmented post-procedural glucagon secretion was accompanied by an improved overall glucose metabolism in GKSG and GKGB rats. Understanding the role of glucagon in the pathophysiology of type 2 diabetes requires further research.

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Section: Discussionmentioning

confidence: 99%

Glucagon secretion after metabolic surgery in diabetic rodents

Eickhoff¹,

Louro²,

Matafome³

et al. 2014

Journal of Endocrinology

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“…Although somatostatin is a potent inhibitor of islet hormone secretion, it is insufficient to suppress glucagon secretion from purified ␣-cells (30, 33). During diabetes, where insulin signaling is mostly dysfunctional, somatostatin is also insufficient to counter the observed chronic hyperglucagonemia, suggesting a role for insulin signaling (8,21,24,37,43).Knockdown of the insulin receptor (IR) in isolated islets leads to changes in glucagon inhibition without any effect on insulin secretion, which points to a role of IR in ␣-cells (11). ␣-Cell-specific IR-knockout mice exhibit hyperglycemia, hyperglucagonemia, and glucose intolerance, although islet glucagon secretion has not been reported (26).…”

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confidence: 99%

Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP

Elliott

Ustione

Piston

2015

American Journal of Physiology-Endocrinology and Metabolism

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Elliott AD, Ustione A, Piston DW. Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic ␣-cell by lowering cAMP. Am J Physiol Endocrinol Metab 308: E130 -E143, 2015. First published November 18, 2014 doi:10.1152/ajpendo.00344.2014.-The dysregulation of glucose-inhibited glucagon secretion from the pancreatic islet ␣-cell is a critical component of diabetes pathology and metabolic disease. We show a previously uncharacterized [Ca 2ϩ ]i-independent mechanism of glucagon suppression in human and murine pancreatic islets whereby cAMP and PKA signaling are decreased. This decrease is driven by the combination of somatostatin, which inhibits adenylyl cyclase production of cAMP via the G␣ i subunit of the SSTR2, and insulin, which acts via its receptor to activate phosphodiesterase 3B and degrade cytosolic cAMP. Our data indicate that both somatostatin and insulin signaling are required to suppress cAMP/PKA and glucagon secretion from both human and murine ␣-cells, and the combination of these two signaling mechanisms is sufficient to reduce glucagon secretion from isolated ␣-cells as well as islets. Thus, we conclude that somatostatin and insulin together are critical paracrine mediators of glucoseinhibited glucagon secretion and function by lowering cAMP/PKA signaling with increasing glucose. cyclic AMP; glucagon; pancreatic islets; insulin; somatostatin GLUCAGON PLAYS A CRITICAL ROLE in blood glucose homeostasis, and its secretion from pancreatic islet ␣-cells is inhibited with rising glucose. During diabetes, persistent glucagon secretion from ␣-cells leads to hyperglucagonemia, which overproduces glucose, exacerbating hyperglycemia. This makes the ␣-cell an important target for therapeutic intervention, but relatively little is known about how glucagon secretion is regulated under normal physiological conditions (18). There are many hypotheses about how glucagon is suppressed by glucose, including paracrine regulation by islet factors (28) and changes in ion channel activity (44), but they commonly depend on a decrease in intracellular Ca 2ϩ . However, published data show that glucagon inhibition is independent of intracellular Ca 2ϩ activity, and no hypothesis explains the loss of suppression from purified ␣-cells (30,31,38). Progress toward understanding ␣-cell regulation and function has been hampered by a lack of approaches to measure ␣-cell properties without first separating them from the rest of the islet, which we know critically changes their function.Multiple G protein-coupled somatostatin receptors (SSTRs) have been identified in islets. SSTR2 is the most abundantly expressed and functionally dominant isoform in both human and murine ␣-cells (12, 24). Upon SSTR2 activation by somatostatin, the G␣ i subunit inhibits adenylyl cyclase to reduce cAMP. Isolated islets from SSTR2 knockout mice show a twofold increase in glucagon secretion, suggesting a role for somatostatin in glucose-inhibited glucagon secretion (37). In contrast, global somatostatin deletion does not ...

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“…L-Arg also rapidly stimulates the release of glucagon and SST (13,14). In the current report, we show that the insulin response to L-Arg is dramatically altered in SST-KO.…”

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confidence: 47%

mentioning

confidence: 97%

“…In addition to the stimulatory actions of L-Arg on GH release, L-Arg has also been shown to directly stimulate insulin release from pancreatic ␤-cells. However, in this context, L-Arg also increases SST release from pancreatic ␦-cells, which in turn is thought to suppress the rise in insulin (11)(12)(13)(14)(15).In order to confirm the role of endogenous SST in regulating the stimulatory actions of L-Arg on GH and insulin release in vivo, the current study examined the acute effects of L-Arg on circulating GH and insulin levels in male and female SST-knockout (SST-KO) mice and their wildtype (WT) littermate controls. …”

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confidence: 98%

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Endogenous Somatostatin Is Critical in Regulating the Acute Effects of l-Arginine on Growth Hormone and Insulin Release in Mice

et al. 2013

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l-arginine (l-Arg) rapidly stimulates GH and insulin release in vivo. It has been hypothesized that l-Arg stimulates GH release by lowering hypothalamic somatostatin (SST) tone. l-Arg may also act directly at the pituitary to stimulate GH release. Moreover, l-Arg has a direct stimulatory effect on β-cells, which is thought to be blunted by the release of SST from pancreatic δ-cells. To confirm the role of endogenous SST on l-Arg-induced GH and insulin release, wild-type (WT) and SST-knockout (SST-KO) mice were injected with l-Arg (ip; 0.8 g/kg), and pre-/post-injection GH, insulin, and glucose levels were measured. In WT mice, l-Arg evoked a 6-fold increase in circulating GH. However, there was only a modest increase in GH levels in WT pituitary cell cultures treated with l-Arg. In contrast, l-Arg failed to increase GH in SST-KO beyond their already elevated levels. These results further support the hypothesis that the primary mechanism by which l-Arg acutely increases GH in vivo is by lowering hypothalamic SST input to the pituitary and not via direct pituitary effects. Additionally, l-Arg induced a clear first-phase insulin secretion in WT mice, but not in SST-KO. However, SST-KO, but not WT mice, displayed a robust and sustained second-phase insulin release. These results further support a role for endogenous SST in regulating l-Arg-mediated insulin release.

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A role for islet somatostatin in mediating sympathetic regulation of glucagon secretion

Cited by 18 publications

References 15 publications

Glucagon secretion after metabolic surgery in diabetic rodents

Glucagon secretion after metabolic surgery in diabetic rodents

Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP

Endogenous Somatostatin Is Critical in Regulating the Acute Effects of l-Arginine on Growth Hormone and Insulin Release in Mice

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