Amelioration of Diabetes in a Murine Model upon Transplantation of Pancreatic β-Cells with Optogenetic Control of Cyclic Adenosine Monophosphate

2019 ◽  
Vol 8 (10) ◽  
pp. 2248-2255
Author(s):  
Fan Zhang ◽  
Emmanuel S. Tzanakakis
2019 ◽  
Vol 24 (10) ◽  
pp. 1272-1277 ◽  
Author(s):  
Armin Mooranian ◽  
Nassim Zamani ◽  
Giuseppe Luna ◽  
Hesham Al-Sallami ◽  
Momir Mikov ◽  
...  

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Brian Tenner ◽  
Michael Getz ◽  
Brian Ross ◽  
Donya Ohadi ◽  
Christopher H Bohrer ◽  
...  

Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In β cells, Ca2+, cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback. Here, we describe a mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca2+. We show that in mouse MIN6 β cells, nanodomain clustering of Ca2+-sensitive adenylyl cyclases (ACs) drives oscillations of local cAMP levels to be precisely in-phase with Ca2+ oscillations, whereas Ca2+-sensitive phosphodiesterases maintain out-of-phase oscillations outside of the nanodomain. Disruption of this precise phase relationship perturbs Ca2+ oscillations, suggesting the relative phase within an oscillatory circuit can encode specific functional information. This work unveils a novel mechanism of cAMP compartmentation utilized for localized tuning of an oscillatory circuit and has broad implications for the spatiotemporal regulation of signaling networks.


1977 ◽  
Vol 86 (2) ◽  
pp. 344-354 ◽  
Author(s):  
Eva Gagerman ◽  
Bo Hellman

ABSTRACT The sensitivity of the radioimmunoassay for cGMP was considerably increased by previous 2′-O-succinylation of the nucleotide. The basal content of cGMP in β-cell-rich pancreatic islets isolated from ob/ob-mice was similar to that of cAMP, i. e. about 3 μmoles per kg dry weight. Extracellular Ca2+ was a prerequisite for maintaining this amount of cGMP. The islet cGMP differed from cAMP in being only slightly enhanced or not affected at all when the islets were exposed to high concentrations of glucose, the sulphydryl reagents chloromercuribenzene-p-sulphonic acid and iodoacetamide, or the potent phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine. The data obtained suggest that the turnover rate for cGMP is much slower than that for cAMP in the pancreatic β-cells. The interrelationships between the two cyclic nucleotides do not seem to fit into a simple pattern of antagonism.


Gene Therapy ◽  
2015 ◽  
Vol 22 (7) ◽  
pp. 553-559 ◽  
Author(s):  
T Kushibiki ◽  
S Okawa ◽  
T Hirasawa ◽  
M Ishihara

1971 ◽  
Vol 51 (2) ◽  
pp. 323-332 ◽  
Author(s):  
R. D. G. MILNER ◽  
A. J. BARSON ◽  
M. A. ASHWORTH

SUMMARY Pieces of human foetal pancreas were incubated under control conditions and in media containing different stimuli of insulin release. Insulin secretion was stimulated from the pancreases of foetuses (83–625 g body weight) which were of 16–24 weeks gestational age. Potassium (60 mmol/l), barium (2·54 mmol/l) and ouabain (10−5 mol/l) were effective stimuli in all experiments. Glucagon (5 μg/ml), theophylline (1 mmol/l) and dibutyryl 3′,5′-cyclic adenosine monophosphate (1 mmol/l) stimulated insulin secretion in media containing 0, 0·6 or 3·0 mg glucose/ml. Theophylline and dibutyryl 3′,5′-cyclic adenosine monophosphate were effective in all experients and glucagon stimulated insulin release in four out of six experiments. At all ages studied, histological examination of the pancreas after each experiment revealed islets of Langerhans containing β cells. In most cases the islets were of the mantle type but occasionally bipolar islets were seen. Cellular normality, as judged by light microscopy, was preserved after periods of incubation for up to 5½ h. Glycogen was demonstrable in the pancreatic acinar tissue but not in the islets. The results of these experiments indicate that, between the 16th and 24th week of foetal life, the human β cell is capable of releasing insulin in vitro when stimulated appropriately.


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