A team of researchers from the German Research Centre for Environmental Health has found a new marker regulating the normal subdivision of insulin-producing beta cells in the pancreas.
The study findings, published in the journal Nature, show that the maturation of pancreatic beta cells, which was thought to be an homogeneous process, is highly individualised and governed by the expression of a protein called Flattop.
The research team conducted two analyses into the physiology and specialisation of insulin-producing beta cells which revealed that not all beta cells in the pancreas are identical.
This study shows that the protein supports the growth of mature beta cells that maintained optimal glucose metabolism and insulin production. This discovery could enable scientists to regenerate beta cells in a targeted manner to replace dysfunctional cells in diabetic patients.
The researchers, working in collaboration with scientists of Helmholtz Zentrum München and colleagues from the Technical University of Munich, knew that different subpopulations of beta cells existed, but the underlying molecular mechanisms responsible for their destruction or loss of function had remained elusive until now.
In the current study, the cohort of researchers led by Professor Heiko Lickert searched for specific molecular markers subdividing the respective subgroups of beta cells using a genetic test known as lineage tracing that maps the fate of single beta cells.
The protein Flattop rapidly stood out as an important precursor of mature beta cells. It was present in about 80 per cent of all beta cells and seemed to effectively ensure these cells sampled the glucose concentration of their environment correctly and secreted the corresponding amount of insulin.
Conversely, beta cells in which no Flattop was measurable proliferated up to four times more often than those that had it. It has long been known that a dysregulation of beta cell proliferation can disrupt the body’s ability to ensure proper glucose homeostasis, and as such is a fundamental feature in the pathogenesis of diabetes mellitus.
Until recently, the only hypothesis for a decrease in functional beta cell mass in type 2 diabetes patients was thought to be mediated by the action of Glucagon-like peptide 1 (GLP-1) analogues. But studies on GLP1 were for the most part inconclusive, showing proliferation was neither significant nor consistent.
This study, however, uncovers a new, more reliable, factor modulating the proliferative capacity of human beta cells and possible biomarker for beta cell regenerative therapies.
How does Flattop work?
After further genetic analyses, the scientists discovered that in beta cells without Flattop, only genes responsible for sensing the environment were expressed, while in cells with Flattop, classic healthful metabolic programs took place.
Studies done on mice have shown that a health promotion gene regulating these important metabolic programs encoded a transcription factor in pancreatic beta cells known as FOXA2.
FOXA2 is an essential activator of genes that function in multiple pathways of insulin secretion and has been found to bind the Flattop promoter in pancreatic beta cell islets, indicating that Flattop is a direct target of FOXA2 and expressed in these cells.
Unsurprisingly, the absence of Flattop in the mice’s beta cells led to FOXA2 deficiency, which resulted in excessive insulin release and hyperinsulinemic hypoglycemia.

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