Regulation of proinsulin conversion
PC2 and PC1/3 are Ca2+-dependent enzyme tasks along with an acidic pH 5 – 5.5 max [91]. Fortunately, the β granule contains an intraorganellar environment of 1 – 10 mM free Ca2+ and acidic pH 5.5, which ideally matches the requirements for excellent PC2, PC1/3 and CP-H tasks within this organelle. This additionally ensures that insulin is developed mainly in the intracellular β-granule compartment in which it is stored [91]. To render PC2 and PC1/3 fully energetic for proinsulin processing in a newly formed β granule, it follows that activation of the proton-pumping ATPase and Ca2+-translocation proteins [91] are essential regulatory events to regulate proinsulin conversion.
Both PC2 and PC1/3 are initially synthesized as preproprotein precursor molecules themselves, along with the “pre” signal peptide region enabling translocation in to the RER lumen throughout translation as along with the signal peptide region of proinsulin (see earlier). ProPC2 and proPC1/3 are transported to β granules along along with their proinsulin substrate in the β cell’s secretory pathway and undergo maturation start in the TGN [91]. However, unlike proinsulin, proPC2 and proPC1/3 are believed to be accompanied by specific chaperon molecules, 7B2 and proSAAS, respectively, that specifically inhibit these endopeptidases’ activity [91]. Proteolytic cleavage of 7B2 by PC2 in the TGN/immature β-granule compartment alleviates the inhibition on proPC2 promoting its maturation and activation to mature PC2. Indeed, 7B2 has actually an vital role in controlling PC2 activity in vivo. The 7B2 knockout mouse has actually multiple neuroendocrine disorders, similar yet a lot more serious compared to the PC2 null mouse [91]. In contrast, the role of proSAAS in regulating proinsulin processing is doubtful, due to the fact that proSAAS null mice have actually typical insulin production and proSAAS is not highly expressed in β cells [96,97].
As previously indicated, the biosynthesis of proPC2 and proPC1/3 is stimulated predominately at a translational degree coordinately along with that of proinsulin [88,91,92]. In the long-term (>12h), glucose additionally regulates PC2 and PC1/3 gene transcription in parallel along with the preproinsulin gene [91]. Thus, it appears that proinsulin conversion is adaptable to adjustments in glucose by coordinate regulation of the endopeptidases that catalyze processing [91,92].
The mature β-granule storage pool
A mature β granule is retained from anywhere between a couple of hours to several days, awaiting transport to the β cell’s plasma membrane and exocytosis under stimulatory conditions, characteristic of a regulated secretory pathway [88,92] (Figure 6.4). It ought to be noted that under typical conditions, the storage compartment of insulin in mature β granules far exceeds the compartment undergoing transport/exocytosis, so that throughout a 1-h stimulation by glucose just ∼1 – 2% of the insulin content of a primary islet β cell is secreted [92]. The insulin content of a β cell is kept at a relatively constant degree under typical physiologic conditions where secreted insulin is promptly replaced at the biosynthetic level. However, in the long-term there is additionally yet another regulatory component that maintains insulin stores at excellent levels, via insulin degradation [92]. The half-life of a β granule is several days, yet if it is not used for exocytosis it is eventually degraded by fusion along with lysosomal compartments by autophagy (additionally known previously as crinophagy) [92].
Dysfunctional proinsulin processing in diabetes
In type 2 diabetes where there is hyperinsulinemia to compensate for peripheral insulin resistance, an increased proportion of the secreted insulin is actually proinsulin or split proinsulin conversion intermediates (mostly des 31,32 proinsulin) so that it is additionally a hyperproinsulinemic state [91]. It is feasible that genetic defects in the proinsulin conversion enzyme genes or the insulin gene itself hamper proinsulin conversion, resulting in an increased proportion of proinsulin secreted. However, such genetic mutations are fairly rare, yet hyperproinsulinemia is a common trait of type 2 diabetes [91]. As such, an increased proportion of secreted proinsulin most likely occurs as a consequence of β-cell secretory dysfunction in type 2 diabetes [91].
In common obesity-linked type 2 diabetes there is chronic hyperglycemia and dyslipidemia [88,91,92]. As a consequence, the β cell is functioning fairly hard, along with The two proinsulin synthesis and insulin secretion are upregulated in an attempt to compensate for peripheral insulin resistance. Normally in β cells there is preferential exocytosis of newly formed β granules, yet under such chronic stimulation from hyperglycemia/ hyperlipidemia newly synthesized proinsulin is not retained long enough to be fully converted to insulin and C-peptide, and as a consequence a better proportion of proinsulin (also as des 31,32 proinsulin) is secreted [88,91]. It ought to additionally be noted that chronic dyslipidemia adversely affects secretory capacity of β cells. Raised fatty acid levels improve the quantity of insulin secreted from the β cell, yet in contrast, fatty acids modestly inhibit glucose-induced proinsulin biosynthesis, which in turn markedly decreases insulin content of islet β cells in vivo [92]. A similar situation could additionally be envisaged along with the prolonged usage of sulfonylureas, which though potent inducers of insulin secretion, do not stimulate proinsulin synthesis and minimize insulin content [92], thus additionally lowering the insulin secretory capacity of the β cell. In general, the chronic hyperglycemia and dyslipidemia in obesity-linked type 2 diabetes are continuously making the β cell job harder to make sufficient insulin to compensate for increased metabolic load and peripheral insulin resistance [91,92]. yet in the future this eventually leads to β-cell dysfunction of which the hyperproinsulinemia is symptomatic. Interestingly, if the β cell in type 2 diabetes patients is allowed to rest, the β-cell secretory dysfunction in vivo is reduced. This emphasizes the importance of protecting β-cell mass and function in the treatment of obesity-linked type 2 diabetes [88,91,92].
Acknowledgments
Work from our laboratories cited in this chapter was supported by the adhering to grants: R01 DK-050610, R01 DK-055267, and the JDRF and Brehm Coalition (C.J. Rhodes); R01 DK-058096 and the Canada Research Chair in Diabetes and Pancreatic Beta-cell Function (V. Poitout), R01 DK 50203, R01 DK-055091 and R01 DK-042502 (R. Stein).
