New insights into the role of connexins in pancreatic islet function and diabetes

Abstract

Multi-cellular systems require complex signaling mechanisms for proper tissue function, to mediate signaling between cells in close proximity and at distances. This holds true for the islets of Langerhans, which are multicellular micro-organs located in the pancreas responsible for glycemic control, through secretion of insulin and other hormones. Coupling of electrical and metabolic signaling between islet β-cells is required for proper insulin secretion and effective glycemic control. β-cell specific coupling is established through gap junctions composed of connexin36, which results in coordinated insulin release across the islet. Islet connexins have been implicated in both Type-1 and Type-2 diabetes; however a clear link remains to be determined. The goal of this review is to discuss recent discoveries regarding the role of connexins in regulating insulin secretion, the regulation of connexins within the islet, and recent studies which support a role for connexins in diabetes. Further studies which investigate the regulation of connexins in the islet and their role in diabetes may lead to novel diabetes therapies which regulate islet function and β-cell survival through modulation of gap junction coupling.

Keywords: Connexin36; Diabetes; Gap junction coupling; Insulin secretion; Pancreatic islet.

Figure 1

Role of Cx36 in regulating electrical activity and insulin secretion under high glucose conditions. (A) Under high glucose, gap junctions synchronize membrane depolarization (V_m), [Ca²⁺]_i, and insulin secretion, by promoting a depolarizing current (I_Ca), including diffusion of Ca²⁺. (B) Coordinated [Ca²⁺]_i oscillations in cells of a wild-type islet with normal gap junction coupling (Cx36^+/+, upper panel) generating overall pulsatile [Ca²⁺]_i across the islet. In cells of an islet lacking gap junction coupling (Cx36^-/-, lower panel) there is a lack of any synchronization between heterogeneous and irregular [Ca²⁺]_i oscillations, leading to a lack of overall pulsatile [Ca²⁺]_i across the islet. Data in B reproduced from [22].

Figure 2

Role of Cx36 in regulating electrical activity and insulin secretion under low glucose conditions. (A) Gap junctions mediate a suppression of electrically active cells with reduced K_ATP activity through a hyperpolarizing current (I_K), and thus suppress [Ca²⁺]_i and insulin secretion. (B) Fraction of cells exhibiting dynamic changes in [Ca²⁺]_i as a function of glucose concentration in wild-type islets with normal gap junction coupling (Cx36^+/+) and islets lacking gap junction coupling (Cx36^-/-), showing a right-shift and sharpening of the dose-response in the presence of Cx36. (C) [Ca²⁺]_i in cells of an islet at 5mM glucose showing largely silent behavior in wild-type islets with normal gap junction coupling (Cx36^+/+, upper panel), but significant presence of spontaneous [Ca²⁺]_i elevations in cells of an islet lacking gap junction coupling (Cx36^-/-, lower panel). Data in B,C reproduced from [51].

Figure 3

Potential mechanisms of regulation for Cx36 gap junctions in the islet. 1. Regulation of gene expression; 2. Regulation through Phosphorylation; 3. Regulation through connexon trafficking; 4. Environmental Factors; and 5. Pharmacological Regulators. Mechanisms of regulation which have been verified for Cx36 in the islet or in MIN6 cells are indicated in italics. Each regulator or potential regulator of Cx36 has an arrow indicating if the mechanism of action acts to increase or decrease Cx36 function.