Intercellular Communication in the Islet of Langerhans in Health and Disease

Abstract

Blood glucose homeostasis requires proper function of pancreatic islets, which secrete insulin, glucagon, and somatostatin from the β-, α-, and δ-cells, respectively. Each islet cell type is equipped with intrinsic mechanisms for glucose sensing and secretory actions, but these intrinsic mechanisms alone cannot explain the observed secretory profiles from intact islets. Regulation of secretion involves interconnected mechanisms among and between islet cell types. Islet cells lose their normal functional signatures and secretory behaviors upon dispersal as compared to intact islets and in vivo. In dispersed islet cells, the glucose response of insulin secretion is attenuated from that seen from whole islets, coordinated oscillations in membrane potential and intracellular Ca²⁺ activity, as well as the two-phase insulin secretion profile, are missing, and glucagon secretion displays higher basal secretion profile and a reverse glucose-dependent response from that of intact islets. These observations highlight the critical roles of intercellular communication within the pancreatic islet, and how these communication pathways are crucial for proper hormonal and nonhormonal secretion and glucose homeostasis. Further, misregulated secretions of islet secretory products that arise from defective intercellular islet communication are implicated in diabetes. Intercellular communication within the islet environment comprises multiple mechanisms, including electrical synapses from gap junctional coupling, paracrine interactions among neighboring cells, and direct cell-to-cell contacts in the form of juxtacrine signaling. In this article, we describe the various mechanisms that contribute to proper islet function for each islet cell type and how intercellular islet communications are coordinated among the same and different islet cell types. © 2021 American Physiological Society. Compr Physiol 11:2191-2225, 2021.

Figure 1:

Comparison of insulin and glucagon secretory responses to glucose in intact islets and isolated cells. Green, red and blue cells represent β-, α- and δ-cells respectively.

Figure 2:

Overview of the intercellular communication pathways within the islet. β-cells and δ-cells sense glucose directly through glucose transporters and are coupled via gap junctions. α-cells undergo a series of paracrine regulation by insulin receptors (IR), 5-HT_1F receptors and SSTR2 which are activated by β- and δ-cell secretory products. α-cells are also regulated by EphA-ephrinA juxtacrine signaling through direct cell-to-cell contacts with β-cells. Secretion of insulin, glucagon and somatostatin by β-, α- and δ-cells, respectively, is coupled to intracellular Ca²⁺, ATP/ADP and cAMP concentrations.

Figure 3:

Image of an intact human islet immunostained with insulin (green), glucagon (red) and somatostatin (yellow) for the identification of β-, α- and δ-cells respectively.

Figure 4:

Formation of functional homotypic Cx36 gap junctions between β-cells and non-functional heterotypic Cx36-Cx46 gap junctions between β- and α-cells.

Figure 5:

Overview of paracrine interactions between islet cells.

Figure 6:

Intracellular and intercellular pathway mechanisms that regulate insulin secretion in the β-cell.

Figure 7:

Dependence of intracellular Ca²⁺ dynamics on gap junction coupling in heterozygous Cx36 knockout Cx36^+/− (~50% gap junction conductance; A and B) and homozygous Cx36 knockout Cx36^−/− (~0% gap junction conductance; C and D) intact mouse islets. A phase map of synchronized (colored cells) and unsynchronized or lack (gray cells) of Ca²⁺ oscillations and representative Ca²⁺ intensity traces in four cells of an islet are shown for each islet type. Gradual loss of synchronicity in intracellular Ca²⁺ oscillations is observed as gap junction conductance is reduced with increasing knockout of Cx36. Figure reproduced with permission from (26).

Figure 8:

Intracellular and intercellular pathway mechanisms that regulate glucagon secretion in the α-cell.

Figure 9:

Intracellular and intercellular pathway mechanisms that regulate somatostatin secretion in the δ-cell.