Insulin demand regulates β cell number via the unfolded protein response

A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt?

“…ATF6a may also be important in b-cell compensation, as ATF6a null mice placed on an HFD have exacerbated glucose intolerance due to a reduction in insulin secretion compared with their wild-type HFD-fed controls (31). Moreover, in vitro studies on dispersed mouse or human islets indicate that increased b-cell proliferation in response to an increase in insulin demand is mediated by the activation of ATF6 (32). However, b-cell-specific deletion of ATF6a in mice has no discernible effect on b-cell development or function (33), and human carriers of Atf6a "hypomorphic" mutations have only been characterized to have achromatopsia, a cone photoreceptor defect (34).…”

“…b-cell-specific ablation of PERK in mice results in the development of diabetes (6,35) likely due to a reduction in b-cell proliferation and neonatal b-cell expansion (35), whereas the conditional deletion of PERK in adult mice has been reported to cause increased b-cell death (32). However, PERK's role in b-cell compensation in these transgenic mouse models has not been explored, although mice carrying a nonphosphorylatable mutant of eIF2a (PERK's primary and perhaps only substrate) in b-cells develop glucose intolerance due to b-cell failure likely caused by an inability to mount an effective UPR (25).…”

“…Similarly, mild hyperglycemia imposed on human islets when transplanted into mouse recipients also results in the activation of an adaptive UPR (41). These effects on the UPR are likely due to an increased demand for insulin rather than hyperglycemia per se (32,42). Indeed, a reduction in insulin synthesis has been shown to reduce ER stress in mice (42).…”

4μ8C Inhibits Insulin Secretion Independent of IRE1α RNase Activity

“…4μ8C is a widely-used inhibitor of IRE1α (Cross et al, 2012;Eletto et al, 2016;Harding et al, 2012;Sharma et al, 2015). However, its off-target effects have not been reported.…”

Advances in β cell replacement and regeneration strategies for treating diabetes

“…Glucose and insulin have been identified as inducers of β cell replication (Figure 3). Multiple studies have demonstrated increased proliferation of rodent and human β cells following glucose infusion (97)(98)(99)(100)(101)(102)(103). Glucose metabolism is required for β cell proliferation, as lack of glucokinase, a key enzyme in glycolysis that converts glucose to glucose-6-phosphate, decreases β cell proliferation whereas treatment with a small-molecule glucokinase activator stimulates β cell proliferation (104).…”