scholarly journals Pancreatic Islet Composition Affects Hormone Secretion in Isolated Alpha and Beta cells

2020 ◽  
Vol 3 ◽  
Author(s):  
William Phillips ◽  
Marcella Brissova ◽  
Julie Kilburn ◽  
Joyce Niland ◽  
Carmella Evans-Molina
Keyword(s):  
African American ◽  
Stimulation Index ◽  
Hormone Secretion ◽  
Total Content ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Β Cells ◽  
Cell Composition ◽  
Islet Hormone ◽  
Glucose Stimulated Insulin Secretion

Background/Objective:   The Integrated Islet Distribution Program (IIDP) distributes islets from five isolation Centers and serves as the main source of human islets for research in the U.S.  In 2016, the IIDP initiated the Human Islet Phenotyping Program (HIPP), which provides standardized post-shipment assessment of islet hormone secretion and endocrine cell composition for each IIDP-supported islet isolation.  To date, islets from 276 non-diabetic donors have been analyzed.  We hypothesized that analysis of this unique resource will provide novel insights into how demographic and clinical features impact islet health.     Methods:  Relationships between insulin and glucagon secretion assessed by perifusion and islet composition (% of β- and α-cells) were analyzed using SAS Version 9.4.  For each analysis, the isolation center was used as a covariate.      Results:    Of the 276 donors, 60% were male; 59% of donors were Caucasian, 28% were Hispanic, 9% were African-American; 4% were Asian; and 0.36% were American Indian.  The % of β-cells was moderately correlated with insulin responses to 16.7 mM glucose (r=0.2785; p<0.0001) and 20 mM KCL (r=0.3109, p<0.0001).  Similarly, the α-cell% was moderately correlated with total glucagon content (r=0.3362, p<0.0001) and glucagon responses to 1.7 mM glucose + 1mM epinephrine (r=0.2015, p=0.0001). The % of β -cells was negatively correlated with glucagon total content (r=-.243,p=.0001), while the α-cell% was negatively correlated with insulin stimulation index to KCL (r=-0.2573, p<0.0001). Notably, Asian donors exhibited a significantly higher β-cell% compared to other groups (p<0.05).  Consistent with this, glucose-stimulated insulin secretion was higher in Asian donors compared to responses observed in islets from African American donors (p<0.01).    Conclusion:   These data indicate that islet cell composition influences insulin and glucagon secretory responses and suggests that race may impact islet composition and hormone secretion. Continued analysis of the HIPP dataset may aid in our understanding of risk factors for the development islet dysfunction in diabetes.   

scholarly journals Combinatorial transcription factor profiles predict mature and functional human islet α and β cells

2021 ◽  
Author(s):  
Shristi Shrestha ◽  
Diane C. Saunders ◽  
John T. Walker ◽  
Joan Camunas-Soler ◽  
Xiao-Qing Dai ◽  
...  
Keyword(s):  
Islet Cells ◽  
Hormone Secretion ◽  
Developmental State ◽  
Human Islets ◽  
Glucose Sensing ◽  
Pancreatic Tissue ◽  
Β Cells ◽  
Cellular Processes ◽  
Normal Human ◽  
Multiple Donors

ABSTRACTIslet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled >40,000 cells from normal human islets by scRNA-seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells co-expressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-seq, MAFA/MAFB co-expressing β cells showed enhanced electrophysiological activity. Thus, these results indicate combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.

Intra-islet regulation of hormone secretion by glucagon-like peptide-1-(7--36) amide

1995 ◽  
Vol 269 (6) ◽  
pp. G852-G860 ◽  
Author(s):  
R. S. Heller ◽  
G. W. Aponte
Keyword(s):  
Monoclonal Antibodies ◽  
Insulin Secretion ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Posttranslational Processing ◽  
Alpha Cells ◽  
Islet Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Peptide Product

Glucagon-like peptide (GLP)-1-(7--36) amide, a peptide product of the posttranslational processing of pancreatic and intestinal proglucagon, has been shown to regulate insulin secretion. Monoclonal antibodies to glucagon and GLP-1-(7--36) amide were generated to localize GLP-1-(7--36) amide in the pancreatic islets by immunocytochemistry and radioimmunoassay. GLP-1-(7--36) amide immunoreactivity was found in some, but not all, glucagon-containing alpha-cells. Displaceable receptor binding for GLP-1-(7--36) amide and nonamidated GLP-1-(7--37) on hormone secretion were investigated using isolated pancreatic islet preparations. GLP-1-(7--37) and -(7--36) amide significantly increased insulin and somatostatin release in the concentration range of 0.01-100 nM in 11.0 mM glucose. GLP-1-(7--37) and -(7--36) amide had no effect on glucagon secretion in the presence of 11.0 mM glucose. GLP-1-(7--36) amide was released from isolated islets in response to 2.25, 5.5, and 11.0 mM glucose. These results suggest that pancreatic GLP-1 may be important in the regulation of intra-islet hormone secretion.

scholarly journals Human pseudoislet system enables detection of differences in G-protein-coupled-receptor signaling pathways between α and β cells

2019 ◽  
Author(s):  
John T. Walker ◽  
Rachana Haliyur ◽  
Heather A. Nelson ◽  
Matthew Ishahak ◽  
Gregory Poffenberger ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Signaling Pathways ◽  
G Protein ◽  
Intracellular Signaling ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Integrated Approach ◽  
Designer Drugs ◽  
Β Cells ◽  
G Protein Coupled

SUMMARYG-protein-coupled-receptors (GPCRs) modulate insulin secretion from β cells and glucagon secretion from α cells. Here, we developed an integrated approach to study the function of primary human islet cells using genetically modified pseudoislets that resemble native islets across multiple parameters. We studied the Gi and Gq GPCR pathways by expressing the designer receptors exclusively activated by designer drugs (DREADDs) hM4Di or hM3Dq. Activation of Gi signaling reduced insulin and glucagon secretion, while activation of Gq signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion. Further, we developed a microperifusion system that allowed synchronous acquisition of GCaMP6f biosensor signal and hormone secretory profiles and showed that the dual effects for Gq signaling occur through changes in intracellular Ca2+. By combining pseudoislets with a microfluidic system, we co-registered intracellular signaling dynamics and hormone secretion and demonstrated differences in GPCR signaling pathways between human β and α cells.

Cell type-specific activation of metabolism reveals that β-cell secretion suppresses glucagon release from α-cells in rat pancreatic islets

2006 ◽  
Vol 290 (2) ◽  
pp. E308-E316 ◽  
Author(s):  
Rui Takahashi ◽  
Hisamitsu Ishihara ◽  
Akira Tamura ◽  
Suguru Yamaguchi ◽  
Takahiro Yamada ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Activation ◽  
Tricarboxylic Acid Cycle ◽  
Expression System ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Glucagon Release ◽  
Β Cells ◽  
Β Cell

Abnormal glucagon secretion is often associated with diabetes mellitus. However, the mechanisms by which nutrients modulate glucagon secretion remain poorly understood. Paracrine modulation by β- or δ-cells is among the postulated mechanisms. Herein we present further evidence of the paracrine mechanism. First, to activate cellular metabolism and thus hormone secretion in response to specific secretagogues, we engineered insulinoma INS-1E cells using an adenovirus-mediated expression system. Expression of the Na+-dependent dicarboxylate transporter (NaDC)-1 resulted in 2.5- to 4.6-fold ( P < 0.01) increases in insulin secretion in response to various tricarboxylic acid cycle intermediates. Similarly, expression of glycerol kinase (GlyK) increased insulin secretion 3.8- or 4.2-fold ( P < 0.01) in response to glycerol or dihydroxyacetone, respectively. This cell engineering method was then modified, using the Cre- loxP switching system, to activate β-cells and non-β-cells separately in rat islets. NaDC-1 expression only in non-β-cells, among which α-cells are predominant, caused an increase (by 1.8-fold, P < 0.05) in glucagon secretion in response to malate or succinate. However, the increase in glucagon release was prevented when NaDC-1 was expressed in whole islets, i.e., both β-cells and non-β-cells. Similarly, an increase in glucagon release with glycerol was observed when GlyK was expressed only in non-β-cells but not when it was expressed in whole islets. Furthermore, dicarboxylates suppressed basal glucagon secretion by 30% ( P < 0.05) when NaDC-1 was expressed only in β-cells. These data demonstrate that glucagon secretion from rat α-cells depends on β-cell activation and provide insights into the coordinated mechanisms underlying hormone secretion from pancreatic islets.

scholarly journals Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion

2013 ◽  
Vol 2 (2) ◽  
pp. 69-78 ◽  
Author(s):  
L Ahlkvist ◽  
K Brown ◽  
B Ahrén
Keyword(s):  
Cell Function ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Islet Hormone ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Insulin Responses

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

scholarly journals SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells

2012 ◽  
Vol 303 (9) ◽  
pp. E1107-E1116 ◽  
Author(s):  
Balrik Kailey ◽  
Martijn van de Bunt ◽  
Stephen Cheley ◽  
Paul R. Johnson ◽  
Patrick E. MacDonald ◽  
...  
Keyword(s):  
G Protein ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Glucagon Secretion ◽  
Cell Types ◽  
Human Islets ◽  
Β Cells ◽  
Action Potential Firing ◽  
Membrane Hyperpolarization ◽  
Potential Firing

Somatostatin-14 (SST) inhibits insulin and glucagon secretion by activating G protein-coupled somatostatin receptors (SSTRs), of which five isoforms exist (SSTR1–5). In mice, the effects on pancreatic β-cells are mediated by SSTR5, whereas α-cells express SSTR2. In both cell types, SSTR activation results in membrane hyperpolarization and suppression of exocytosis. Here, we examined the mechanisms by which SST inhibits secretion from human β- and α-cells and the SSTR isoforms mediating these effects. Quantitative PCR revealed high expression of SSTR2, with lower levels of SSTR1, SSTR3, and SSTR5, in human islets. Immunohistochemistry showed expression of SSTR2 in both β- and α-cells. SST application hyperpolarized human β-cells and inhibited action potential firing. The membrane hyperpolarization was unaffected by tolbutamide but antagonized by tertiapin-Q, a blocker of G protein-gated inwardly rectifying K+ channels (GIRK). The effect of SST was mimicked by an SSTR2-selective agonist, whereas a SSTR5 agonist was marginally effective. SST strongly (>70%) reduced depolarization-evoked exocytosis in both β- and α-cells. A slightly weaker inhibition was observed in both cell types after SSTR2 activation. SSTR3- and SSTR1-selective agonists moderately reduced the exocytotic responses in β- and α-cells, respectively, whereas SSTR4- and SSTR5-specific agonists were ineffective. SST also reduced voltage-gated P/Q-type Ca2+ currents in β-cells, but normalization of Ca2+ influx to control levels by prolonged depolarizations only partially restored exocytosis. We conclude that SST inhibits secretion from both human β- and α-cells by activating GIRK and suppressing electrical activity, reducing P/Q-type Ca2+ currents, and directly inhibiting exocytosis. These effects are mediated predominantly by SSTR2 in both cell types.

scholarly journals Resveratrol Potentiates Glucose-stimulated Insulin Secretion in INS-1E β-Cells and Human Islets through a SIRT1-dependent Mechanism

2010 ◽  
Vol 286 (8) ◽  
pp. 6049-6060 ◽  
Author(s):  
Laurène Vetterli ◽  
Thierry Brun ◽  
Laurianne Giovannoni ◽  
Domenico Bosco ◽  
Pierre Maechler
Keyword(s):  
Insulin Secretion ◽  
Human Islets ◽  
Β Cells ◽  
Glucose Stimulated Insulin Secretion ◽  
Dependent Mechanism

scholarly journals Perilipin Is Present in Islets of Langerhans and Protects against Lipotoxicity When Overexpressed in the β-Cell Line INS-1

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3049-3057 ◽  
Author(s):  
Jörgen Borg ◽  
Cecilia Klint ◽  
Nils Wierup ◽  
Kristoffer Ström ◽  
Sara Larsson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Line ◽  
Islets Of Langerhans ◽  
Prolonged Exposure ◽  
Human Islets ◽  
Lipid Storage ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
In Cells

Lipids have been shown to play a dual role in pancreatic β-cells: a lipid-derived signal appears to be necessary for glucose-stimulated insulin secretion, whereas lipid accumulation causes impaired insulin secretion and apoptosis. The ability of the protein perilipin to regulate lipolysis prompted an investigation of the presence of perilipin in the islets of Langerhans. In this study evidence is presented for perilipin expression in rat, mouse, and human islets of Langerhans as well as the rat clonal β-cell line INS-1. In rat and mouse islets, perilipin was verified to be present in β-cells. To examine whether the development of lipotoxicity could be prevented by manipulating the conditions for lipid storage in the β-cell, INS-1 cells with adenoviral-mediated overexpression of perilipin were exposed to lipotoxic conditions for 72 h. In cells exposed to palmitate, perilipin overexpression caused increased accumulation of triacylglycerols and decreased lipolysis compared with control cells. Whereas glucose-stimulated insulin secretion was retained after palmitate exposure in cells overexpressing perilipin, it was completely abolished in control β-cells. Thus, overexpression of perilipin appears to confer protection against the development of β-cell dysfunction after prolonged exposure to palmitate by promoting lipid storage and limiting lipolysis.

scholarly journals Dopamine-Mediated Autocrine Inhibitory Circuit Regulating Human Insulin Secretion in Vitro

2012 ◽  
Vol 26 (10) ◽  
pp. 1757-1772 ◽  
Author(s):  
Norman Simpson ◽  
Antonella Maffei ◽  
Matthew Freeby ◽  
Steven Burroughs ◽  
Zachary Freyberg ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Secretory Granules ◽  
Human Islets ◽  
Negative Regulator ◽  
Β Cells ◽  
Regulatory Circuit ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Secretion In Vitro

Abstract We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity.

Effects of galanin on the release of insulin, glucagon and somatostatin from the isolated, perfused dog pancreas

1988 ◽  
Vol 119 (1) ◽  
pp. 91-98 ◽  
Author(s):  
K. Hermansen
Keyword(s):  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Hormonal Control ◽  
Amino Acid Peptide ◽  
Glucose Levels ◽  
Somatostatin Secretion ◽  
Normal Glucose ◽  
Islet Hormone ◽  
Low Glucose ◽  
Dog Pancreas

Abstract. Galanin is a 29 amino acid peptide which has been found in intrapancreatic nerves. The effects of galanin, adrenergic and cholinergic blockade as well as somatostatin on the hormone release from the isolated perfused dog pancreas were studied. It was found that galanin dose-dependently inhibited insulin (P < 0.001) and somatostatin (P < 0.001) but not glucagon secretion at normal glucose levels. The lowest galanin concentration that caused a significant suppression of insulin and somatostatin secretion was 10−11and 10−10 mol/l, respectively. Similar effects were evident during stimulation with 2.5 mmol/l arginine. Galanin (10−9 mol/l) caused a more pronounced inhibition of insulin and somatostatin secretion at high (10 mmol/l) and normal (5 mmol/l) than at low glucose (1.3 mmol/l). In contrast, suppression of the glucagon secretion was only seen at low glucose (1.3 mmol/l). Perfusion of 10−6 mol/l of atropine, phentolamine and propranolol had no effect on the galanin-mediated (10−10 mol/l) inhibition of insulin and somatostatin secretion. Galanin (10−12–10−10 mol/l) and somatostatin (10−12 – 10−10 mol/l) were equipotent in inhibiting insulin secretion whereas only somatostatin exerted a suppression of the glucagon secretion at normal glucose. Thus, galanin exerts a differential effect on islet hormone secretion and may participate in the hormonal control of insulin, glucagon and somatostatin secretion.

Sign in / Sign up

Export Citation Format

Share Document