Different Effects of FK506, Rapamycin, and Mycophenolate Mofetil on Glucose-Stimulated Insulin Release and Apoptosis in Human Islets

2009 ◽  
Vol 18 (8) ◽  
pp. 833-845 ◽  
Author(s):  
James D. Johnson ◽  
Ziliang Ao ◽  
Peter Ao ◽  
Hong Li ◽  
Long-Jun Dai ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Insulin Release ◽  
Caspase 3 ◽  
Cell Function ◽  
Graft Function ◽  
Human Islets ◽  
Pancreatic Islet Transplantation ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Pancreatic islet transplantation has the potential to be an effective treatment for type 1 diabetes mellitus. While recent improvements have improved 1-year outcomes, follow-up studies show a persistent loss of graft function/survival over 5 years. One possible cause of islet transplant failure is the immunosuppressant regimen required to prevent alloimmune graft rejection. Although there is evidence from separate studies, mostly in rodents and cell lines, that FK506 (tacrolimus), rapamycin (sirolimus), and mycophenolate mofetil (MMF; CellCept) can damage pancreatic β-cells, there have been few side-by-side, multiparameter comparisons of the effects of these drugs on human islets. In the present study, we show that 24-h exposure to FK506 or MMF impairs glucose-stimulated insulin secretion in human islets. FK506 had acute and direct effects on insulin exocytosis, whereas MMF did not. FK506, but not MMF, impaired human islet graft function in diabetic NOD.scid mice. All of the immunosuppressants tested in vitro increased caspase-3 cleavage and caspase-3 activity, whereas MMF induced ER-stress to the greatest degree. Treating human islets with the GLP-1 agonist exenatide ameliorated the immunosuppressant-induced defects in glucose-stimulated insulin release. Together, our results demonstrate that immunosuppressants impair human β-cell function and survival, and that these defects can be circumvented to a certain extent with exenatide treatment.

Glucose Responsiveness of β-Cells Depends on Fatty Acids

2019 ◽  
Vol 128 (10) ◽  
pp. 644-653
Author(s):  
Felicia Gerst ◽  
Christine Singer ◽  
Katja Noack ◽  
Dunia Graf ◽  
Gabriele Kaiser ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Cell Function ◽  
Human Islets ◽  
In Vitro Tests ◽  
High Concentration ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Glucose Responsiveness

AbstractGlucose-stimulated insulin secretion (GSIS) is the gold standard for β-cell function. Both experimental and clinical diabetology, i. e., preceding transplantation of isolated human islets, depend on functional testing. However, multiple factors influence GSIS rendering the comparison of different in vitro tests of glucose responsiveness difficult. This study examined the influence of bovine serum albumin (BSA)-coupled fatty acids on GSIS. Isolated islet preparations of human donors and of 12-months old mice displayed impaired GSIS in the presence of 0.5% FFA-free BSA compared to 0.5% BSA (fraction V, not deprived from fatty acids). In aged INS-1E cells, i. e. at a high passage number, GSIS became highly sensitive to FFA-free BSA. Readdition of 30 µM palmitate or 30 µM oleate to FFA-free BSA did not rescue GSIS, while the addition of 100 µM palmitate and the raise of extracellular Ca2+from 1.3 to 2.6 mM improved glucose responsiveness. A high concentration of palmitate (600 µM), which fully activates FFA1, largely restored insulin secretion. The FFA1-agonist TUG-469 also increased insulin secretion but to a lesser extent than palmitate. Glucose- and TUG-induced Ca2+oscillations were impaired in glucose-unresponsive, i. e., aged INS-1E cells. These results suggest that fatty acid deprivation (FFA-free BSA) impairs GSIS mainly through an effect on Ca2+sensitivity.

scholarly journals In Vitro Studies to Assess the α-Glucosidase Inhibitory Activity and Insulin Secretion Effect of Isorhamnetin 3-O-Glucoside and Quercetin 3-O-Glucoside Isolated from Salicornia herbacea

Processes ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 483
Author(s):  
Dahae Lee ◽  
Jun Yeon Park ◽  
Sanghyun Lee ◽  
Ki Sung Kang
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Ethanolic Extract ◽  
Ethyl Acetate Fraction ◽  
Gradient Elution ◽  
Glucosidase Activity ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Salicornia Herbacea

In this study, we examined the effect of ethanolic extract of Salicornia herbacea (ESH), isorhamnetin 3-O-glucoside (I3G), quercetin 3-O-glucoside (Q3G), quercetin, and isorhamnetin on α-glucosidase activity and glucose-stimulated insulin secretion (GSIS) in insulin-secreting rat insulinoma (INS-1) cells. A portion of the ethyl acetate fraction of ESH was chromatographed on a silica gel by a gradient elution with chloroform and methanol to provide Q3G and I3G. ESH, Q3G, and quercetin inhibited α-glucosidase activity, and quercetin (IC50 value was 29.47 ± 3.36 μM) inhibited the activity more effectively than Q3G. We further demonstrated that ESH, Q3G, quercetin, I3G, and isorhamnetin promote GSIS in INS-1 pancreatic β-cells without inducing cytotoxicity. Among them, I3G was the most effective in enhancing GSIS. I3G enhanced the phosphorylation of total extracellular signal-regulated kinase (ERK), insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1), which are associated with insulin secretion and β-cell function. As components of ESH, Q3G has the potential to regulate blood glucose by inhibiting α-glucosidase activity, and I3G enhances the insulin secretion, but its bioavailability should be considered in determining biological importance.

Effects of glucose and d-3-hydroxybutyrate on human pancreatic islet cell function

1985 ◽  
Vol 68 (5) ◽  
pp. 567-572 ◽  
Author(s):  
C. J. Rhodes ◽  
I. L. Campbell ◽  
T. M. Szopa ◽  
T. J. Biden ◽  
P. D. Reynolds ◽  
...  
Keyword(s):  
Insulin Release ◽  
Human Tissue ◽  
Islet Cell ◽  
Cell Function ◽  
Human Islets ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Sigmoidal Curve ◽  
Β Cell Function ◽  
Islet Cell Function

1. β-Cell function in human islets derived from a number of kidney donors was investigated by using various types of islet preparations. 2. With fresh islets, both insulin release and biosynthesis were increased by raising glucose concentrations, although the response was a variable one. 3. In fresh islets, the effects of 5 mmol of glucose/l on release were potentiated by 10 mmol of d-3-hydroxybutyrate/l. 4. Insulin release at 20 mmol of glucose/l was inhibited by adrenaline (0.1 mmol/l), and potentiated by theophylline (10 mmol/l) in the presence of 5 mmol of glucose/l, in islets cultured for 4 days. 5. After culture for 8 days, islets still showed an increase in insulin release and biosynthesis in response to glucose. 6. Pancreas slices derived from fresh human tissue also responded to increasing concentrations of glucose with a sigmoidal curve for insulin release.

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

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1621 ◽  
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.

Can Functionally Mature Islet β-Cells Be Derived from Pluripotent Stem Cells? – A Step Towards Ready-To-Use β-Cells in Type 1 Diabetes

2020 ◽  
Vol 15 ◽  
Author(s):  
Bishnu K Khand ◽  
Ramesh R Bhonde
Keyword(s):  
Stem Cells ◽  
Type 1 Diabetes ◽  
Pluripotent Stem Cells ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

: Pluripotent Stem Cells [PSCs] are emerging as an excellent cellular source for treatment of many degenerative diseases such as diabetes, ischemic heart failure, Alzheimer’s disease. PSC-derived pancreatic islet β-cells appear to be as a promising therapy for type 1 diabetes patients with impaired β-cell function. Several protocols have been developed to derive β-cells from PSCs. However, these protocols produce β-like cells that show low glucose stimulated insulin secretion [GSIS] function and mirror GSIS profile of functionally immature neonatal β-cells. Several studies have documented a positive correlation between the sirtuins [a family of ageing-related proteins] and the GSIS function of adult β-cells. We are of the view that GSIS function of PSC-derived β-like cells could be enhanced by improving the function of sirtuins in them. Studying the sirtuin expression and activation pattern during the β-cell development and inclusion of the sirtuin activator and inhibitor cocktail [specific to a developmental stage] in the present protocols may help us derive functionally mature, ready-to-use β-cells in-vitro making them suitable for transplantation in type 1 diabetes.

scholarly journals Intracrine testosterone activation in human pancreatic β cells stimulates insulin secretion.

2020 ◽  
Author(s):  
Ada Admin ◽  
Weiwei Xu ◽  
Lina Schiffer ◽  
M.M. Fahd Qadir ◽  
Yanqing Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Aromatase Inhibitor ◽  
Cell Function ◽  
Human Islets ◽  
Human Pancreas ◽  
Β Cells ◽  
Male And Female ◽  
Β Cell Function ◽  
17Β Estradiol ◽  
Glucose Stimulated Insulin Secretion

Testosterone (T) affects β cell function in men and women. T is a pro-hormone that undergoes intracrine conversion in target tissues to the potent androgen dihydrotestosterone (DHT) via the enzyme 5α-reductase (5α-R), or to the active estrogen 17β-estradiol (E2) via the aromatase enzyme. Using male and female human pancreas sections, we show that the 5α-R type1 isoform (SRD5A1) and aromatase are expressed in male and female β cells. We show that cultured male and female human islets exposed to T produce DHT and downstream metabolites. In these islets, exposure to the 5α-R inhibitors finasteride and dutasteride inhibited T conversion into DHT. We did not detect T conversion into E2 from female islets. However, we detected T conversion into E2 in islets from one out of four male donors. In this donor, exposure to the aromatase inhibitor anastrozole inhibited E2 production. Notably, in cultured male and female islets, T enhanced glucose-stimulated insulin secretion (GSIS). In these islets, exposure to 5α-R inhibitors or the aromatase inhibitor both inhibited T enhancement of GSIS. In conclusion, male and female human islets convert T into DHT and E2 via the intracrine activities of SRD5A1 and aromatase. This process is necessary for T enhancement of GSIS.<b></b>

scholarly journals Intracrine testosterone activation in human pancreatic β cells stimulates insulin secretion.

2020 ◽  
Author(s):  
Ada Admin ◽  
Weiwei Xu ◽  
Lina Schiffer ◽  
M.M. Fahd Qadir ◽  
Yanqing Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Aromatase Inhibitor ◽  
Cell Function ◽  
Human Islets ◽  
Human Pancreas ◽  
Β Cells ◽  
Male And Female ◽  
Β Cell Function ◽  
17Β Estradiol ◽  
Glucose Stimulated Insulin Secretion

Testosterone (T) affects β cell function in men and women. T is a pro-hormone that undergoes intracrine conversion in target tissues to the potent androgen dihydrotestosterone (DHT) via the enzyme 5α-reductase (5α-R), or to the active estrogen 17β-estradiol (E2) via the aromatase enzyme. Using male and female human pancreas sections, we show that the 5α-R type1 isoform (SRD5A1) and aromatase are expressed in male and female β cells. We show that cultured male and female human islets exposed to T produce DHT and downstream metabolites. In these islets, exposure to the 5α-R inhibitors finasteride and dutasteride inhibited T conversion into DHT. We did not detect T conversion into E2 from female islets. However, we detected T conversion into E2 in islets from one out of four male donors. In this donor, exposure to the aromatase inhibitor anastrozole inhibited E2 production. Notably, in cultured male and female islets, T enhanced glucose-stimulated insulin secretion (GSIS). In these islets, exposure to 5α-R inhibitors or the aromatase inhibitor both inhibited T enhancement of GSIS. In conclusion, male and female human islets convert T into DHT and E2 via the intracrine activities of SRD5A1 and aromatase. This process is necessary for T enhancement of GSIS.<b></b>

ADRENOCORTICOTROPHIN AND THE DEVELOPMENT OF INSULIN SECRETION IN THE RABBIT FOETUS

1975 ◽  
Vol 64 (1) ◽  
pp. 67-75 ◽  
Author(s):  
P. M. B. JACK ◽  
R. D. G. MILNER
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Plasma Insulin ◽  
Cell Function ◽  
Pancreatic Tissue ◽  
High Rate ◽  
Insulin Concentration ◽  
Plasma Insulin Concentration ◽  
Β Cell Function

SUMMARY Foetal rabbits were injected with adrenocorticotrophin (ACTH), decapitated, or decapitated and injected simultaneously with ACTH or cortisol in utero on day 24 of gestation. The foetuses were killed after Caesarian section on day 29, and blood was collected for measurement of plasma insulin concentration and pancreatic tissue was obtained for incubation in physiological buffer. Insulin release from the pancreatic tissue of decapitated foetuses was significantly greater than that from the pancreas of control litter-mates when incubated in media containing 3·3 mm-glucose, 16·5 mm-glucose or 16·5 mm-glucose plus 5 μg glucagon/ml, but was similar when the incubation medium contained 3·3 or 16·5 mm-glucose plus 1 mm-theophylline or 3·3 mm-glucose plus 60 mm-potassium. The pancreata of decapitated or intact foetuses injected with ACTH did not differ significantly from control foetuses in terms of insulin release in response to glucose in vitro. The plasma insulin concentration of decapitated foetuses and decapitated foetuses injected with ACTH was raised, whereas that of intact foetuses injected with ACTH was similar to that of the control foetuses. Cortisol injection at the time of decapitation resulted in a high rate of foetal mortality. The results indicate that foetal ACTH or foetal adrenocortical secretion influences the normal development of glucose-mediated insulin secretion in the rabbit and that exogenous ACTH corrects the effect of decapitation on β cell function in vitro but not on plasma insulin concentration.

scholarly journals In vivo imaging of β-cell function reveals glucose-mediated heterogeneity of β-cell functional development

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jia Zhao ◽  
Weijian Zong ◽  
Yiwen Zhao ◽  
Dongzhou Gou ◽  
Shenghui Liang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
In Vivo Imaging ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Functional Development ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

How pancreatic β-cells acquire function in vivo is a long-standing mystery due to the lack of technology to visualize β-cell function in living animals. Here, we applied a high-resolution two-photon light-sheet microscope for the first in vivo imaging of Ca2+activity of every β-cell in Tg (ins:Rcamp1.07) zebrafish. We reveal that the heterogeneity of β-cell functional development in vivo occurred as two waves propagating from the islet mantle to the core, coordinated by islet vascularization. Increasing amounts of glucose induced functional acquisition and enhancement of β-cells via activating calcineurin/nuclear factor of activated T-cells (NFAT) signaling. Conserved in mammalians, calcineurin/NFAT prompted high-glucose-stimulated insulin secretion of neonatal mouse islets cultured in vitro. However, the reduction in low-glucose-stimulated insulin secretion was dependent on optimal glucose but independent of calcineurin/NFAT. Thus, combination of optimal glucose and calcineurin activation represents a previously unexplored strategy for promoting functional maturation of stem cell-derived β-like cells in vitro.

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