Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells

Abstract

Recent developments indicate that the regeneration of beta cell function and mass in patients with diabetes is possible. A regenerative approach may represent an alternative treatment option relative to current diabetes therapies that fail to provide optimal glycemic control. Here we report that the inactivation of GSK3 by small molecule inhibitors or RNA interference stimulates replication of INS-1E rat insulinoma cells. Specific and potent GSK3 inhibitors also alleviate the toxic effects of high concentrations of glucose and the saturated fatty acid palmitate on INS-1E cells. Furthermore, treatment of isolated rat islets with structurally diverse small molecule GSK3 inhibitors increases the rate beta cell replication by 2-3-fold relative to controls. We propose that GSK3 is a regulator of beta cell replication and survival. Moreover, our results suggest that specific inhibitors of GSK3 may have practical applications in beta cell regenerative therapies.

Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

“…Since the integrity of the insulin signalling cascade in beta cells is responsible for preservation of beta cell mass and for insulin secretion [43], and since JNK inhibition affects IRS-1/AKT in peripheral tissues [13][14][15], we tested the effect of L-JNKI in human islet insulin pathway with our main focus on AKT and its substrates. Among those substrates, GSK-3B and p70S6K participate in the regeneration of beta cell mass via increased mitogenesis [44,45], while PRAS40 is also activated by insulin in peripheral tissues and is implicated in protection of neurons against ischaemic injury [46,47]. We found that JNK inhibition in human islets treated with either L-JNKI or SP600125 specifically stimulated the phosphorylation of AKT and GSK-3B (Fig.…”

Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

“…Concerning that, we have observed a higher Ser phosphorylation of Akt in food-restricted animals and, subsequently, a lower activation of GSK-3a/b during the suckling period. Previous studies have demonstrated that inhibition of GSK-3 protected b-cells from non-esterified fatty acids (NEFA)-or endoplasmic reticulum stress-induced apoptosis (Srinivasan et al 2005, Mussmann et al 2007. Certainly, GSK-3 may not be the only mediator of the partial suppression of b-cell apoptosis observed in undernourished neonates, as other distal signals have also been implicated in b-cell apoptosis.…”

GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

“…31,37 Also, increased proliferation of both primary and transformed rodent b-cells following GSK-3 inactivation by small molecule inhibitors including BIO or 1-AKP have been reported. 39 A study demonstrated increased proliferation of highly differentiated primary rodent cardiomyocytes after BIO-mediated GSK-3 inhibition. 40 GSK-3 is localized in both cytosol and nuclei [26][27][28] and we also have seen nuclear and cytoplasmic localization of GSK-3 in purified single adult human b-cells (Sup .…”