Submission Date: May 28, 2014

Summary: Aims/hypothesis Pancreatic beta cells maintain glucose

homeostasis and beta cell dysfunction is a major risk factor

in developing diabetes. Therefore, understanding the developmental

regulatory networks that define a fully functional beta

cell is important for elucidating the genetic origins of the disease.

Aldehyde dehydrogenase activity has been associated

with stem/progenitor cells and we have previously shown that

Aldh1b1 is specifically expressed in pancreas progenitor

pools. Here we address the hypothesis that Aldh1b1 may regulate

the timing of the appearance and eventual functionality

of beta cells.

Methods We generated an Aldh1b1-knockout mouse line

(Aldh1b1tm1lacZ) and used this to study pancreatic development,

beta cell functionality and glucose homeostasis in the

absence of Aldh1b1 function.

Results Differentiation in the developing pancreas of

Aldh1b1tm1lacZ null mice was accelerated. Transcriptome

analyses of newborn and adult islets showed misregulation of

key beta cell transcription factors and genes crucial for beta cell

function. Functional analyses showed that glucose-stimulated

insulin secretion was severely compromised in islets isolated

from null mice. Several key features of beta cell functionality

were affected, including control of oxidative stress, glucose

sensing, stimulus-coupling secretion and secretory granule

biogenesis. As a result of beta cell dysfunction, homozygous

mice developed glucose intolerance and age-dependent

hyperglycaemia.

Conclusions/interpretation These findings show that

Aldh1b1 influences the timing of the transition from the pancreas

endocrine progenitor to the committed beta cell and

demonstrate that changes in the timing of this transition lead

to beta cell dysfunction and thus constitute a diabetes risk

factor later in life.

GEO Accession ID: GSE58025

PMID: 26518685