The Effects of Glucagon-like Peptide-I (GLP-I) on Hormone Secretion from Isolated Human Pancreatic Islets

Fehmann, Hans-Christoph; Hering, B. J.; Wolf, M.; Brandhorst, Heide; Brandhorst, Daniel; Bretzel, Reinhard G.; Federlin, K.; Göke, Burkhard

doi:10.1097/00006676-199508000-00014

Cited by 61 publications

(45 citation statements)

References 2 publications

(2 reference statements)

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“…are glucagonostatic, in both healthy subjects as well as subjects with T1DM and T2DM (Gutniak et al, 1992). The suppression of glucagon secretion in vivo, therefore, especially in humans where δ cells are present throughout islets, is likely due to increased intra-islet release of somatostatin and/or insulin by GLP-1 (Fehmann et al, 1995). Increased somatostatin secretion in response to GLP-1 has been shown in both perfused rat pancreas (Schmid et al, 1990) and isolated islets (Fehmann et al, 1995).…”

Section: Effects On Glucagon Secretion Are They Direct or Indirect?mentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

577

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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Section: Effects On Glucagon Secretion Are They Direct or Indirect?mentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

577

465

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“…Although GLP-1 augments Ca 2+ -dependent exocytosis in rat pancreatic alpha cells [57], GLP-1 has been shown to inhibit glucagon release from the perfused rat pancreas [58][59][60][61], isolated rat islets in static incubations [62], the perfused canine pancreas [60,63], the perfused porcine pancreas, the perfused porcine nonantral stomach [64] and cultured human islets [65]. The glucagonostatic effect of GLP-1 does not appear to be mediated by a local endocrine effect of insulin, since glucagon release is inhibited even when insulin is unstimulated [61,64].…”

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

confidence: 99%

“…Many studies use a relatively low glucose level (∼3 mmol/l) in the perfusate or culture media, often with arginine or a mixture of amino acids to establish a high baseline secretory rate and thus a broad dynamic range. Under these conditions it has been shown that GLP-1 exerts an inhibitory effect on glucagon release [65,67]. The effect of GLP-1 on alpha cell glucose sensing in vitro has not been assessed.…”

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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“…GLP-1 enhances insulin secretion from isolated islets only when the extracellular glucose is raised to 48 mM. [12][13][14] In addition, studies have suggested that GLP-1 participates in maintaining b-cell glucose (Figure 4a). Since the plasma GLP-1 in normal rats reaches 10 pM after an intraduodenal glucose load, 34 these data suggested that transduced pituitary cells could respond to physiological levels of GLP-1 in vivo.…”

Section: Insulin Secretion By Transduced Pituitary Cellsmentioning

confidence: 99%

“…11 The rise of incretins in the circulation coincides with the postprandial increases in blood glucose, and the insulin-releasing effect of GLP-1 on b cells requires the presence of elevated extracellular glucose. 3,5,[12][13][14] Although GLP-1 signaling interacts with the signaling of glucose metabolism in b cells, the fact that GLP-1 stimulates insulin secretion from b cells in type 2 diabetes suggests that it can also exert its effect independent of the signaling of glucose metabolism. [15][16][17][18] Engineering regulated insulin secretion in both b and non-b cells has mostly focused on recreating the signal transduction pathway of glucose.…”

Section: Introductionmentioning

confidence: 99%

Engineering physiologically regulated insulin secretion in non-β cells by expressing glucagon-like peptide 1 receptor

Nicholson

et al. 2003

Gene Ther

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The Effects of Glucagon-like Peptide-I (GLP-I) on Hormone Secretion from Isolated Human Pancreatic Islets

Cited by 61 publications

References 2 publications

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Mechanisms of action of glucagon-like peptide 1 in the pancreas

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

Engineering physiologically regulated insulin secretion in non-β cells by expressing glucagon-like peptide 1 receptor

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