Abstract
Diabetes is a metabolic disorder characterized by hyperglycemia. Insulin, which is secreted by pancreatic beta cells, is recognized as the critical regulator of blood glucose, but the molecular machinery responsible for insulin trafficking remains poorly defined. In particular, the roles of cytosolic factors that govern the formation and maturation of insulin granules are unclear. Here we report that PICK1 and ICA69, two cytosolic lipid-binding proteins, formed heteromeric BAR-domain complexes that associated with insulin granules at different stages of their maturation. PICK1-ICA69 heteromeric complexes associated with immature secretory granules near the trans-Golgi network (TGN). A brief treatment of Brefeldin A, which blocks vesicle budding from the Golgi, increased the amount of PICK1 and ICA69 at TGN. On the other hand, mature secretory granules were associated with PICK1 only, not ICA69. PICK1 deficiency in mice caused the complete loss of ICA69 and led to increased food and water intake but lower body weight. Glucose tolerance tests demonstrated that these mutant mice had high blood glucose, a consequence of insufficient insulin. Importantly, while the total insulin level was reduced in PICK1-deficient beta cells, proinsulin was increased. Lastly, ICA69 knockout mice also displayed similar phenotype as the mice deficient in PICK1. Together, our results indicate that PICK1 and ICA69 are key regulators of the formation and maturation of insulin granules.
Highlights
Diabetes affects hundreds of millions of people worldwide and its incidence is increasing due to changing lifestyles and an aging population [1]
Insulin is a key regulator of blood glucose and insufficient insulin leads to diabetes
We show that without PICK1 or ICA69, insulin granules cannot be properly formed and, as a result, proinsulin cannot be effectively processed into mature insulin
Summary
Diabetes affects hundreds of millions of people worldwide and its incidence is increasing due to changing lifestyles and an aging population [1]. In type 1 diabetes, the destruction of insulin-producing beta cells of the pancreas, mainly by autoimmune processes, results in a gross lack of insulin that leads to hyperglycemia. After budding from the TGN, ISGs go through many changes during their conversion to mature secretory granules (MSGs), changes that include the proteolytic cleavage of proinsulin to insulin, the enrichment of secretory contents, and the removal of unwanted contents by further sorting and budding from ISGs. After maturation, a small fraction of MSGs is mobilized and primed on the plasma membrane to become the readily releasable pool that undergoes regulated exocytosis [7]. In addition to releasing mature insulin via MSGs, beta cells release proinsulin from ISGs and the elevated ratio of secreted proinsulin to insulin found in patients with type 2 diabetes indicates that the maturation of insulin granules is impaired in this form of the disease [8]. The molecular machinery responsible for insulin trafficking, such as the sorting, budding, and subsequent refinement of insulin granules, has not been fully elucidated
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