Beta‐cell excitability and excitability‐driven diabetes in adult Zebrafish islets

Abstract

Islet β ‐cell membrane excitability is a well‐established regulator of mammalian insulin secretion, and defects in β ‐cell excitability are linked to multiple forms of diabetes. Evolutionary conservation of islet excitability in lower organisms is largely unexplored. Here we show that adult zebrafish islet calcium levels rise in response to elevated extracellular [glucose], with similar concentration–response relationship to mammalian β ‐cells. However, zebrafish islet calcium transients are nor well coupled, with a shallower glucose‐dependence of cytoplasmic calcium concentration. We have also generated transgenic zebrafish that conditionally express gain‐of‐function mutations in ATP‐sensitive K + channels (K ATP ‐GOF) in β ‐cells. Following induction, these fish become profoundly diabetic, paralleling features of mammalian diabetes resulting from equivalent mutations. K ATP ‐GOF fish become severely hyperglycemic, with slowed growth, and their islets lose glucose‐induced calcium responses. These results indicate that, although lacking tight cell‐cell coupling of intracellular Ca 2+ , adult zebrafish islets recapitulate similar excitability‐driven β ‐cell glucose responsiveness to those in mammals, and exhibit profound susceptibility to diabetes as a result of inexcitability. While illustrating evolutionary conservation of islet excitability in lower vertebrates, these results also provide important validation of zebrafish as a suitable animal model in which to identify modulators of islet excitability and diabetes.

Innervation modulates the functional connectivity between pancreatic endocrine cells

“…In mammals, cx36 encoded gap junctions mediate the majority of the functional coupling between beta cells [29][30][31] . While previous reports have described the lack of beta cell expression of the zebrafish homolog cx35 32 , we found that cx43 is highly expressed in zebrafish beta cells by 100 hpf ( Figure 5A, Figure 5 - Fig. Suppl.…”

“Take Me To Your Leader”: An Electrophysiological Appraisal of the Role of Hub Cells in Pancreatic Islets

“…In more recent work, it was reported that photoablation of leader cells abolishes glucose-induced b-cell [Ca 21 ] i oscillations in zebrafish islets (8). However, in other studies the b-cell glucose-induced [Ca 21 ] i oscillations in zebrafish islets were poorly correlated, and thus islets in this species might lack strong gap-junctional coupling (35). It is therefore of interest that connexin-35b, the zebrafish ortholog of connexin-36, is not detected in zebrafish islets (35).…”

Small subpopulations of β-cells do not drive islet oscillatory [Ca2+] dynamics via gap junction communication

“…Little change in [Ca 2+ ] activity is observed in the model when removing either those cells with earlier Ca 2+ oscillations (S4 Fig) or those cells with elevated metabolic activity that when hyperpolarized silences islet [Ca 2+ ] (Fig 1,2). However, differences do exist between zebrafish islets and mouse islets which our model is based upon and has been validated against, including islet size, gap junction protein isoform and Ca 2+ dynamics [44,45]. Thus, species differences may account for these observations.…”