II. Intracellular regulators: Ca2+ and cAMP

A. Ca2+ is a key intracellular regulator of insulin secretion
In response to high glucose levels, the ATP-sensitive K+ (KATP) channel closes and the plasma membrane depolarizes, leading to sophisticated machinery that drives pulsatile cytosolic Ca2+ changes that will act as an ultimate trigger for insulin exocytosis. Guy Rutter discussed the regional calcium dynamics in β- cells and islets. The use of targeted Ca2+ probes showed that, during each cytosolic Ca2+ pulse, the uptake of Ca2+ by the mitochondria, endoplasmic reticulum (ER), secretory granules, and lysosomes fine tunes cytosolic Ca2+ dynamics and controls organellar function.32 In this regard, the Ca2+ binding protein Sorcin appears to provide a link between ER Ca2+ levels and ER stress, which affects beta cell function and survival.33 The same team also showed that the transcription factor Pax6 is required for Ca2+ dynamics in adult mouse beta cells.34

B. cAMP is essential for the neurohormonal amplification of insulin release and GSIS
Anders Tengholm’s lecture recalls that cAMP is generally considered to be an amplifier of insulin secretion that is triggered by Ca2+ elevation in β-cells. Also named “second messenger,” it is one of the most important cellular signalling molecules and its actions are mediated by protein kinase A and the guanine nucleotide exchange factor Epac.35 cAMP levels are regulated by hormones, neural factors, and nutrients via adenylyl cyclase–catalyzed generation and phosphodiesterase-mediated degradation.36 Any alteration in this cAMP system in β-cells is associated with diabetic features. In other words, genetic variations and metabolic conditions that compromise the cAMP signalling pathway in β-cells contribute to type 2 diabetes.35 Indeed, a deterioration in cAMP signalling leads to a lower stimulation of insulin secretion and then to a loss of β-cell mass in the long term since cAMP also protects beta cells from apoptosis. The cAMP signalling system others different potential targets for the treatment and prevention of type 2 diabetes, such as specific inhibitors of overexpressed Galpha-i-coupled receptors37 or activation of alternative pathways for cAMP generation, such as adenylate cyclase 5.38

C. Insulin secretagogues: integration of different signalling pathways toward better insulin secretion
As presented by Susumu Seino, the different drugs used to stimulate and preserve insulin secretion exert their effects via different mechanisms. Recent advances in β-cell signaling studies provide a better understanding of how insulin secretagogues act and open the way for conceiving treatments with additive or synergistic actions (Figure 5A).39 The combination treatment of a sulfonylurea and glucagon-like peptide-1 (GLP-1) in wild-type mice augments insulin secretion (Figure 5B), whereas this synergistic effect is markedly reduced in Epac2A knockout mice.40 Of note, this integration of different signalling pathways in response to secretagogues also plays a role in alpha cells to stimulate glucagon secretion in response to hypoglycemia.41