IV. Other islet hormones and paracrine communication

A. Circadian oscillators in the islets

Islet cells are also under the control of circadian oscillators, which act as an anticipatory mechanism of nutrients (presence or absence). The central clock in the suprachiasmatic nucleus synchronizes these peripheral oscillators by a plethora of neural and humoral signals.50 Interestingly, cell-autonomous circadian oscillators, operative in α-cells, have distinct properties from those of β-cells.51,52 As shown in Figure 8, the phase difference between α- and β-cellular clocks may contribute to the phase shift observed between insulin and glucagon secretion profiles measured

in the blood to maintain glucose homeostasis.51 In accordance, mutant mice lacking a functional clock due to the knockout of essential core-clock components, such as CLOCK and BMAL1, have a diabetic phenotype.53 In humans, as explained in Charna Dibner’s lecture, circadian misalignment may lead to the development of metabolic diseases, such as obesity and T2D.54,55

B. Paracrine and juxtacrine signals

Inappropriate glucagon secretion is a major contributor to the etiology of diabetes.56 The detailed mechanisms regulating glucagon exocytosis in α-cells is, however, only partly known. Elevated intracellular Ca2+ is required for α-cell exocytosis, but the total Ca2+ activity is slightly increased with glucose, indicating that Ca2+ is likely to serve a permissive rather than a regulatory role in glucagon secretion (conversely to what happens in β-cells, where Ca2+ is crucial).57 In α-cells, cAMP is a more likely candidate to control glucagon secretion in response to paracrine signals from β-cells and somatostatin secreting δ-cells.58 In addition to these paracrine signals, data from 3D electron microscopy shows that α-cells may also take up insulin granules from adjacent β-cells,

and David Piston et al hypothesized that this “vesicle swapping” may be a form of juxtacrine signaling to maintain multihormonal islet cell phenotypes (along with the well-described de-differentiation and trans-differentiation mechanisms) (Figure 9).59 Along the same line, Franco Folli’s lecture discussed the fact that the physiological interaction of α-, β-, and δ-cells is required for the control of insulin and glucagon secretion and that alterations in these interactions (eg, in case of δ-cell death) lead to T2D.60