IV. The final step: insulin exocytosis

A. Insulin granules
Michele Solimena showed that the age of the insulin secretory granules has a great impact on their behavior inside the beta cell and the likelihood of their secretion. Technical advances in live-cell imaging, automated image analysis, and correlative light and electron microscopy have improved our knowledge concerning the connection between the age of the insulin secretory granule, the secretory granule dynamics, the intracellular location, and the interactions with other proteins.50,51 Young secretory granules are highly dynamic and preferentially released, whereas old secretory granules are nearly immobile and likely to undergo intracellular degradation within multigranular bodies/lysosomes through autophagy.52 Interestingly, insulin secretory granules differ in their luminal pH; young secretory granules have a low pH around 5.5, while old secretory granules could reach a pH around 6.3.53 Michele Solimena also showed that GLP-1, which acts as an allosteric modulator, can decrease the pH of old secretory granules and activate a rescue pathway by “rejuvenating” the secretory granules.

B. SNARE-regulated exocytosis
The exocytosis underlying secretion is essential for biological processes. It relies on two protein families: Sec1p/Munc18 proteins and soluble N-ethylmaleimide-sensitive attachment protein receptor (SNARE) proteins.54 Herbert Gaisano showed that granule exocytosis involves the specific binding of vesicle (v)-SNARE–associated membrane protein with the target membrane (t)-SNARE complex, composed of the SNAP25/23 and syntaxin (Syn) proteins. In particular, Xie et al showed that, in human pancreatic β-cells, Syn-4 mediates, redundantly with Syn-1A and Syn-3, and promotes the exocytosis of predocked and newcomer secretory granules, which underlies the biphasic GSIS process.5

These new insights into β-cell exocytosis could lead to the development of novel SNARE replacement strategies that can restore the deficient insulin secretion in type 2 diabetic islets, although this approach is challenging both technically and conceptually. It has been shown that a slight excess in the SNARE protein Syn-1A56 (genetically overexpressed in mice) resulted in a paradoxical reduction in GSIS, perhaps as the result of the formation of nonfusion-competent SNARE complexes.57 In addition, some SNAREs could act in an inhibitory manner on insulin granule exocytosis, as it has been demonstrated for Syn-2.58