Similarities in Calcium Oscillations Between Neonatal Mouse Islets and Mature Islets Exposed to Chronic Hyperglycemia

• Published in: Endocrinology (Philadelphia) 2022-07, Vol.163 (7), p.1
• Main Authors: D’Angelo, Cathleen V, West, Hannah L, Whitticar, Nicholas B, Corbin, Kathryn L, Donovan, Lauren M, Stiadle, Benjamin I, Nunemaker, Craig S
• Format: Article
• Language: English
• Subjects: Adenosine; Animals; Animals, Newborn; Beta cells; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium imaging; Calcium ions; Calcium Signaling; Calcium signalling; Channel gating; Dextrose; Diabetes; Diabetes mellitus; Endocrinology; Fluorescence; Glucose; Glucose - metabolism; Glucose - pharmacology; Hyperglycemia; Hyperglycemia - metabolism; Infants (Newborn); Insulin; Insulin - metabolism; Islets of Langerhans - metabolism; Mice; Neonates; Oscillations; Pluripotency; Stem cells; Tolbutamide; Type 2 diabetes
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqac066

Pulsatility is important to islet function. As islets mature into fully developed insulin-secreting micro-organs, their ability to produce oscillatory intracellular calcium ([Ca2+]i) patterns in response to glucose also matures. In this study, we measured [Ca2+]i using fluorescence imaging to characterize oscillations from neonatal mice on postnatal (PN) days 0, 4, and 12 in comparison to adult islets. Under substimulatory (3-mM) glucose levels, [Ca2+]i was low and quiescent for adult islets as expected, as well as for PN day 12 islets. In contrast, one-third of islets on PN day 0 and 4 displayed robust [Ca2+]i oscillations in low glucose. In stimulatory glucose (11 mM) conditions, oscillations were present on all neonatal days but differed from patterns in adults. By PN day 12, [Ca2+]i oscillations were approaching characteristics of fully developed islets. The immature response pattern of neonatal islets was due, at least in part, to differences in adenosine 5′-triphosphate (ATP)-sensitive K+-channel activity estimated by [Ca2+]i responses to KATP channel agents diazoxide and tolbutamide. Neonatal [Ca2+]i patterns were also strikingly similar to patterns observed in mature islets exposed to hyperglycemic conditions (20 mM glucose for 48 hours): elevated [Ca2+]i and oscillations in low glucose along with reduced pulse mass in high glucose. Since a hallmark of diabetic islets is dedifferentiation, we propose that diabetic islets display features of “reverse maturation,” demonstrating similar [Ca2+]i dynamics as neonatal islets. Pulsatility is thus an important emergent feature of neonatal islets. Our findings may provide insight into reversing β-cell dedifferentiation and to producing better functioning β cells from pluripotent stem cells.