scholarly journals PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2′-O-Me-cAMP-AM in human islets of Langerhans

2010 ◽  
Vol 298 (3) ◽  
pp. E622-E633 ◽  
Author(s):  
Oleg G. Chepurny ◽  
Grant G. Kelley ◽  
Igor Dzhura ◽  
Colin A. Leech ◽  
Michael W. Roe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Islets Of Langerhans ◽  
Human Islets ◽  
Human Islet ◽  
Second Phase ◽  
Acetoxymethyl Ester ◽  
Insulin Secretagogue ◽  
Camp Analog ◽  
Human Islets Of Langerhans ◽  
Glucose Stimulated Insulin Secretion

Potential insulin secretagogue properties of an acetoxymethyl ester of a cAMP analog (8-pCPT-2′- O-Me-cAMP-AM) that activates the guanine nucleotide exchange factors Epac1 and Epac2 were assessed using isolated human islets of Langerhans. RT-QPCR demonstrated that the predominant variant of Epac expressed in human islets was Epac2, although Epac1 was detectable. Under conditions of islet perifusion, 8-pCPT-2′- O-Me-cAMP-AM (10 μM) potentiated first- and second-phase 10 mM glucose-stimulated insulin secretion (GSIS) while failing to influence insulin secretion measured in the presence of 3 mM glucose. The insulin secretagogue action of 8-pCPT-2′- O-Me-cAMP-AM was associated with depolarization and an increase of [Ca2+]i that reflected both Ca2+ influx and intracellular Ca2+ mobilization in islet β-cells. As expected for an Epac-selective cAMP analog, 8-pCPT-2′- O-Me-cAMP-AM (10 μM) failed to stimulate phosphorylation of PKA substrates CREB and Kemptide in human islets. Furthermore, 8-pCPT-2′- O-Me-cAMP-AM (10 μM) had no significant ability to activate AKAR3, a PKA-regulated biosensor expressed in human islet cells by viral transduction. Unexpectedly, treatment of human islets with an inhibitor of PKA activity (H-89) or treatment with a cAMP antagonist that blocks PKA activation (Rp-8-CPT-cAMPS) nearly abolished the action of 8-pCPT-2′- O-Me-cAMP-AM to potentiate GSIS. It is concluded that there exists a permissive role for PKA activity in support of human islet insulin secretion that is both glucose dependent and Epac regulated. This permissive action of PKA may be operative at the insulin secretory granule recruitment, priming, and/or postpriming steps of Ca2+-dependent exocytosis.

scholarly journals Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans

Diabetologia ◽  
2006 ◽  
Vol 49 (2) ◽  
pp. 321-331 ◽  
Author(s):  
R. D. Ramracheya ◽  
D. S. Muller ◽  
Y. Wu ◽  
B. J. Whitehouse ◽  
G. C. Huang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Angiotensin Ii ◽  
Islets Of Langerhans ◽  
Human Islets ◽  
Human Islets Of Langerhans ◽  
Direct Regulation

scholarly journals GPR55-dependent stimulation of insulin secretion from isolated mouse and human islets of Langerhans

2016 ◽  
Vol 18 (12) ◽  
pp. 1263-1273 ◽  
Author(s):  
Bo Liu ◽  
Shuang Song ◽  
Inmaculada Ruz-Maldonado ◽  
Attilio Pingitore ◽  
Guo C. Huang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Islets Of Langerhans ◽  
Human Islets ◽  
Human Islets Of Langerhans ◽  
Stimulation Of

scholarly journals The Effect of Recovery Warm-up Time Following Cold Storage on the Dynamic Glucose-stimulated Insulin Secretion of Isolated Human Islets

2020 ◽  
Vol 29 ◽  
pp. 096368972090827
Author(s):  
Oscar Alcazar ◽  
Alejandro Alvarez ◽  
Camillo Ricordi ◽  
Elina Linetsky ◽  
Peter Buchwald
Keyword(s):  
Insulin Secretion ◽  
Cold Storage ◽  
Islet Cell ◽  
Cell Function ◽  
Human Islets ◽  
Second Phase ◽  
Islet Cell Transplantation ◽  
Warm Up ◽  
Recovery Times ◽  
Glucose Stimulated Insulin Secretion

Standardized islet characterization assays that can provide results in a timely manner are essential for successful islet cell transplantation. A critical component of islet cell quality is β-cell function, and perifusion-based assessments of dynamic glucose-stimulated insulin secretion (GSIS) are the most informative method to assess this, as they provide the most complex in vitro evaluation of GSIS. However, protocols used vary considerably among centers and investigators as they often use different low- and high-glucose concentrations, exposure-times, flow-rates, oxygen concentrations, islet numbers, analytical methods, measurement units, and instruments, which result in different readouts and make comparisons across platforms difficult. Additionally, the conditions of islet storage and shipment prior to assessment may also affect islet function. Establishing improved standardized protocols for perifusion GSIS assays should be an integral part of the ongoing effort to increase the rigor of human islet studies. Here, we performed detailed evaluation of GSIS of human islets using a fully automated multichannel perifusion instrument following various warm-up recovery times after cold storage that corresponds to current shipping conditions (8°C). We found that recovery times shorter than 18 h (overnight) resulted in impaired insulin secretion. While the effects were relatively moderate on second-phase insulin secretion, first-phase peaks were restored only following 18-h incubation. Hence, the biphasic profile of dynamic GSIS was considerably affected when islets were not allowed to recover for a sufficient time after being maintained in cold. Accordingly, while cold storage might improve islet cell survival during shipment and prolong the length of culture, functional assessments should be performed only after allowing for at least overnight recovery at physiological temperatures.

Commiphora myrrha stimulates insulin secretion from mouse and human islets of Langerhans

2021 ◽  
Vol 264 ◽  
pp. 113075
Author(s):  
Altaf Al-Romaiyan ◽  
Guo-Cai Huang ◽  
Peter Jones ◽  
Shanta Persaud
Keyword(s):  
Insulin Secretion ◽  
Islets Of Langerhans ◽  
Human Islets ◽  
Human Islets Of Langerhans

Effects of the β-carbolines, harmane and pinoline, on insulin secretion from isolated human islets of Langerhans

2003 ◽  
Vol 482 (1-3) ◽  
pp. 189-196 ◽  
Author(s):  
E.Jane Cooper ◽  
Alan L. Hudson ◽  
Christine A. Parker ◽  
Noel G. Morgan
Keyword(s):  
Insulin Secretion ◽  
Islets Of Langerhans ◽  
Human Islets ◽  
Human Islets Of Langerhans

scholarly journals Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans

2002 ◽  
Vol 173 (1) ◽  
pp. 73-80 ◽  
Author(s):  
C Gravena ◽  
PC Mathias ◽  
SJ Ashcroft
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Saturated Fatty Acids ◽  
Human Islets ◽  
Dependent Manner ◽  
Acute Effects ◽  
Rat Islets ◽  
Human Islets Of Langerhans

Fatty acids have both stimulatory and inhibitory effects on insulin secretion. Long-term exposure to fatty acids results in impaired insulin secretion whilst acute exposure has generally been found to enhance insulin release. However, there are conflicting data in the literature as to the relative efficacy of various fatty acids and on the glucose dependency of the stimulatory effect. Moreover, there is little information on the responses of human islets in vitro to fatty acids. We have therefore studied the acute effects of a range of fatty acids on insulin secretion from rat and human islets of Langerhans at different glucose concentrations. Fatty acids (0.5 mM) acutely stimulated insulin release from rat islets of Langerhans in static incubations in a glucose-dependent manner. The greatest effect was seen at high glucose concentration (16.7 mM) and little or no response was elicited at 3.3 or 8.7 mM glucose. Long-chain fatty acids (palmitate and stearate) were more effective than medium-chain (octanoate). Saturated fatty acids (palmitate, stearate) were more effective than unsaturated (palmitoleate, linoleate, elaidate). Stimulation of insulin secretion by fatty acids was also studied in perifused rat islets. No effects were observed at 3.3 mM glucose but fatty acids markedly potentiated the effect of 16.7 mM glucose. The combination of fatty acid plus glucose was less effective when islets had been first challenged with glucose alone. The insulin secretory responses to fatty acids of human islets in static incubations were similar to those of rat islets. In order to examine whether the responses to glucose and to fatty acids could be varied independently we used an animal model in which lactating rats are fed a low-protein diet during early lactation. Islets from rats whose mothers had been malnourished during lactation were still able to respond effectively to fatty acids despite a lowered secretory response to glucose. These data emphasise the complex interrelationships between nutrients in the control of insulin release and support the view that fatty acids play an important role in glucose homeostasis during undernutrition.

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