δ-Cells: The Neighborhood Watch in the Islet Community

Somatostatin-secreting δ-cells have aroused great attention due to their powerful roles in coordination of islet insulin and glucagon secretion and maintenance of glucose homeostasis. δ-cells exhibit neuron-like morphology with projections which enable pan-islet somatostatin paracrine regulation despite their scarcity in the islets. The expression of a range of hormone and neurotransmitter receptors allows δ-cells to integrate paracrine, endocrine, neural and nutritional inputs, and provide rapid and precise feedback modulations on glucagon and insulin secretion from α- and β-cells, respectively. Interestingly, the paracrine tone of δ-cells can be effectively modified in response to factors released by neighboring cells in this interactive communication, such as insulin, urocortin 3 and γ-aminobutyric acid from β-cells, glucagon, glutamate and glucagon-like peptide-1 from α-cells. In the setting of diabetes, defects in δ-cell function lead to suboptimal insulin and glucagon outputs and lift the glycemic set-point. The interaction of δ-cells and non-δ-cells also becomes defective in diabetes, with reduces paracrine feedback to β-cells to exacerbate hyperglycemia or enhanced inhibition of α-cells, disabling counter-regulation, to cause hypoglycemia. Thus, it is possible to restore/optimize islet function in diabetes targeting somatostatin signaling, which could open novel avenues for the development of effective diabetic treatments.

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Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function

Acta Endocrinologica ◽

10.1530/eje.0.1430717 ◽

2000 ◽

pp. 717-725 ◽

Cited By ~ 96

Author(s):

R Perfetti ◽

P Merkel

Keyword(s):

Beta Cell ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Glucagon Secretion ◽

Insulin Biosynthesis ◽

Gut Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a gut hormone synthesized by post-translational processing in intestinal L-cells, and it is released in response to food ingestion. GLP-1 stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro)-insulin biosynthesis and decreases the rate of gastric emptying and acid secretion. GLP-1 has also been shown to have a pro-satiety effect. In addition, it has been demonstrated that a long-term infusion with GLP-1, or exendin-4, a long-acting analog of human GLP-1, increases beta-cell mass in rats. In conclusion, GLP-1 appears to regulate plasma glucose levels via various and independent mechanisms. GLP-1 is an excellent candidate option for the treatment of patients with type 2 diabetes mellitus.

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miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1

Cells ◽

10.3390/cells9071621 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1621 ◽

Cited By ~ 4

Author(s):

Alessandro Matarese ◽

Jessica Gambardella ◽

Angela Lombardi ◽

Xujun Wang ◽

Gaetano Santulli

Keyword(s):

Insulin Release ◽

Cell Function ◽

Specific Interaction ◽

Β Cells ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion ◽

First Time

Glucagon-like peptide-1 (GLP-1) has been shown to potentiate glucose-stimulated insulin secretion binding GLP-1 receptor on pancreatic β cells. β-arrestin 1 (βARR1) is known to regulate the desensitization of GLP-1 receptor. Mounting evidence indicates that microRNAs (miRNAs, miRs) are fundamental in the regulation of β cell function and insulin release. However, the regulation of GLP-1/βARR1 pathways by miRs has never been explored. Our hypothesis is that specific miRs can modulate the GLP-1/βARR1 axis in β cells. To test this hypothesis, we applied a bioinformatic approach to detect miRs that could target βARR1; we identified hsa-miR-7-5p (miR-7) and we validated the specific interaction of this miR with βARR1. Then, we verified that GLP-1 was indeed able to regulate the transcription of miR-7 and βARR1, and that miR-7 significantly regulated GLP-1-induced insulin release and cyclic AMP (cAMP) production in β cells. Taken together, our findings indicate, for the first time, that miR-7 plays a functional role in the regulation of GLP-1-mediated insulin release by targeting βARR1. These results have a decisive clinical impact given the importance of drugs modulating GLP-1 signaling in the treatment of patients with type 2 diabetes mellitus.

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Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

Nutrition Research Reviews ◽

10.1017/s0954422414000031 ◽

2014 ◽

Vol 27 (1) ◽

pp. 48-62 ◽

Cited By ~ 22

Author(s):

Laura Marroquí ◽

Paloma Alonso-Magdalena ◽

Beatriz Merino ◽

Esther Fuentes ◽

Angel Nadal ◽

...

Keyword(s):

Glucose Homeostasis ◽

Cell Function ◽

Glucagon Secretion ◽

Diabetic Patients ◽

Β Cells ◽

Glucagon Receptor ◽

Nutrient Regulation ◽

New Information ◽

Experimental Approaches ◽

Glucagon And Insulin

Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic α- and β-cells, respectively. While β-cells have been the focus of intense research, less is known about α-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of α-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and α-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in α-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

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The glucagon-like peptide-1 metabolite GLP-1-(9–36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00576.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. E1118-E1123 ◽

Cited By ~ 60

Author(s):

Juris J. Meier ◽

Arnica Gethmann ◽

Michael A. Nauck ◽

Oliver Götze ◽

Frank Schmitz ◽

...

Keyword(s):

Gastric Emptying ◽

Plasma Concentrations ◽

Glucagon Secretion ◽

Postprandial Glucose ◽

Glucose Disposal ◽

C Peptide ◽

Postprandial Glycemia ◽

Insulin And Glucagon Secretion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP-1-(7–36) amide is degraded to the metabolite GLP-1-(9–36) amide. The effects of GLP-1-(9–36) amide in humans are less well characterized. Fourteen healthy volunteers were studied with intravenous infusion of GLP-1-(7–36) amide, GLP-1-(9–36) amide, or placebo over 390 min. After 30 min, a solid test meal was served, and gastric emptying was assessed. Blood was drawn for GLP-1 (total and intact), glucose, insulin, C-peptide, and glucagon measurements. Administration of GLP-1-(7–36) amide and GLP-1-(9–36) amide significantly raised total GLP-1 plasma levels. Plasma concentrations of intact GLP-1 increased to 21 ± 5 pmol/l during the infusion of GLP-1-(7–36) amide but remained unchanged during GLP-1-(9–36) amide infusion [5 ± 3 pmol/l; P < 0.001 vs. GLP-1-(7–36) amide administration]. GLP-1-(7–36) amide reduced fasting and postprandial glucose concentrations ( P < 0.001) and delayed gastric emptying ( P < 0.001). The GLP-1 metabolite had no influence on insulin or C-peptide concentrations. Glucagon levels were lowered by GLP-1-(7–36) amide but not by GLP-1-(9–36) amide. However, the postprandial rise in glycemia was reduced significantly (by ∼6 mg/dl) by GLP-1-(9–36) amide ( P < 0.05). In contrast, gastric emptying was completely unaffected by the GLP-1 metabolite. The GLP-1 metabolite lowers postprandial glycemia independently of changes in insulin and glucagon secretion or in the rate of gastric emptying. Most likely, this is because of direct effects on glucose disposal. However, the glucose-lowering potential of GLP-1-(9–36) amide appears to be small compared with that of intact GLP-1-(7–36) amide.

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An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes

Mediators of Inflammation ◽

10.1155/2013/591056 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Alessandra Puddu ◽

François Mach ◽

Alessio Nencioni ◽

Giorgio Luciano Viviani ◽

Fabrizio Montecucco

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Glucagon Secretion ◽

Advanced Glycation ◽

Chronic Hyperglycemia ◽

Gut Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreaticβ-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.

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GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells

The Journal of Cell Biology ◽

10.1083/jcb.201805049 ◽

2019 ◽

Vol 218 (3) ◽

pp. 855-870 ◽

Cited By ~ 1

Author(s):

Bowen Xing ◽

Jian Ma ◽

Zongzhe Jiang ◽

Zijie Feng ◽

Sunbin Ling ◽

...

Keyword(s):

Cell Proliferation ◽

Gene Transcription ◽

Histone Deacetylases ◽

Cell Function ◽

Β Cells ◽

Β Cell ◽

Histone Modifiers ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating β cell function, with menin suppressing, and GLP-1 promoting, β cell function. However, little is known as to whether or how GLP-1 pathway represses menin function. Here, we show that GLP-1 signaling–activated protein kinase A (PKA) directly phosphorylates menin at the serine 487 residue, relieving menin-mediated suppression of insulin expression and cell proliferation. Mechanistically, Ser487-phosphorylated menin gains increased binding affinity to nuclear actin/myosin IIa proteins and gets sequestrated from the Ins1 promoter. This event leads to reduced binding of repressive epigenetic histone modifiers suppressor variegation 3–9 homologue protein 1 (SUV39H1) and histone deacetylases 1 (HDAC1) at the locus and subsequently increased Ins1 gene transcription. Ser487 phosphorylation of menin also increases expression of proproliferative cyclin D2 and β cell proliferation. Our results have uncovered a previously unappreciated physiological link in which GLP-1 signaling suppresses menin function through phosphorylation-triggered and actin/myosin cytoskeletal protein–mediated derepression of gene transcription.

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Interaction of glucagon-like peptide-1(7-36) amide and gastric inhibitory polypeptide or cholecystokinin on insulin and glucagon secretion from the isolated perfused rat pancreas

Metabolism ◽

10.1016/0026-0495(92)90068-l ◽

1992 ◽

Vol 41 (4) ◽

pp. 359-363 ◽

Cited By ~ 10

Author(s):

Seiji Suzuki ◽

Koichi Kawai ◽

Shinichi Ohashi ◽

Yasuko Watanabe ◽

Kamejiro Yamashita

Keyword(s):

Glucagon Secretion ◽

Gastric Inhibitory Polypeptide ◽

Perfused Rat Pancreas ◽

Rat Pancreas ◽

Isolated Perfused Rat Pancreas ◽

Insulin And Glucagon Secretion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Novel Approaches to the Treatment of Type 2 Diabetes

Journal of Pharmacy Practice ◽

10.1177/0897190008326578 ◽

2009 ◽

Vol 22 (3) ◽

pp. 320-332 ◽

Cited By ~ 3

Author(s):

Erin L. St. Onge ◽

Shannon A. Miller ◽

James R. Taylor

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Glucagon Secretion ◽

Current Evidence ◽

Β Cell Function ◽

Dipeptidyl Peptidase Iv Inhibitors ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Third Line

The emergence of the glucoregulatory hormone, glucagon-like peptide-1, has expanded our understanding of glucose homeostasis. The glucoregulatory actions of glucagon-like peptide-1 include enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to potentiate the effects of glucagon-like peptide-1 in those with type 2 diabetes. The glucagon-like peptide-1 analogs, such as exenatide, and dipeptidyl peptidase-IV inhibitors, such as sitagliptin, are currently available whereas others are in the final stages of development. These agents effectively reduce hemoglobin A1c while providing the other benefits associated with increased glucagon-like peptide-1. They also offer the potential to preserve the β-cell function. The effects on cardiovascular disease, if any, are unknown. Based on the current evidence, these agents represent viable second-and third-line options in the management of type 2 diabetes.

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