Slow and steady is the key to β‐cell replication

Abstract

The β-cells of the pancreas are responsible for insulin production and their destruction results in type I diabetes. β-cell maintenance, growth and regenerative repair is thought to occur predominately, if not exclusively, through the replication of existing β-cells, not via an adult stem cell. It was recently found that all β-cells contribute equally to islet growth and maintenance. The fact that all β-cells replicate homogeneously makes it possible to set up straightforward screens for factors that increase β-cell replication either In vitro or in vivo. It is possible that a circulating factor may be capable of increasing β-cell replication or that intrinsic cell cycle regulators may affect β-cell growth. An improved understanding of the in vivo maintenance and growth of β-cells will facilitate efforts to expand β-cells In vitro and may lead to new treatments for diabetes.

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

“…To measure individual band intensity, background was subtracted for each protein band followed by normalization against the control protein (tubulin). (E) a-e, isolated adult human islets from four independent batches (two [HI-1 and HI-2] from low BMI [26][27] and two [HI-3 and HI-4] from high BMI [40][41][42][43][44][45][46][47][48][49][50] cadaveric donors) with high purity (80-90% for low BMI islets) and low purity (35-40% for high BMI islets) were cultured and equal amounts (50 μg) of human islet lysates or INS-1 CE were fractionated in SDS-PAGE and the transferred peptides were incubated with specific primary antibodies as shown. *p < 0.05; NS, not significant.…”

“…27 Furthermore, GSK-3 inhibitors, due to their proliferation-promoting abilities, may be suitable in combination with immunosuppressive agents for treatment of T1DM patients because studies suggest that in most cases, even those with long-standing T1DM, some b-cells persist and are continually destroyed and also because of enhanced b-cell formation in T1DM. 1,3,45 …”

MicroRNAs contribute to compensatory β cell expansion during pregnancy and obesity

“…These cells, located within the islets of Langerhans, display a slow turnover rate (3,4). Conditions such as pregnancy and obesity are associated with a diminished sensitivity of insulin target tissues and a consequent rise in the insulin demand that is compensated for by an increase in the number and secretory activity of β cells (2,(5)(6)(7).…”

Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

“…These pathways include protein kinase A pathways, mitogen-activated protein kinase (MAPK) pathways, janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, phosphatidyl inositol-3 (PI3) kinase/protein kinase B (AKT) pathways and insulin-receptor-substrate pathways [36]. These signalling cascades lead to G 1 /S transition, mainly by stimulating the activity of the cyclin-dependent-kinase 4-cyclin D complex [8,[37][38][39]. The EGFR has been shown to activate the RAS-and SHC-activated MAPK pathway and the PI3 kinase-activated AKT pathway [40].…”