After eating a bar of chocolate, you might down a glass of water to neutralize the sweet taste. Similarly, when blood glucose concentration runs high, an organ called the pancreas releases a hormone called insulin to bring the sugar levels back to normal.
For diabetic patients, however, insulin function is impaired. In maturity onset diabetes of the young 3 (MODY3), a form of diabetes that typically manifests before the age of 25, pancreatic beta cells fail to secrete enough insulin to lower blood sugar levels.
These dysfunctional beta cells are traced to mutations in the HNF1A gene, but determining how insulin secretion defects arise in human cells had left scientists stumped. Now, researchers led by Adrian Teo, a Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB), have modeled the effects of HNF1A mutations using human induced pluripotent stem cells (hiPSCs) from MODY3 patients.
The H126D mutation in the gene HNF1A decreases the expression of the GLUT2 gene and protein, reducing glucose uptake and ATP production as well as lowering insulin secretion.
© A*STAR Research
Since stem cells can become any of the body’s specialized cells, the team first triggered their differentiation into pancreatic beta cells. This approach overcame the limitations of rodent models, where heterozygous MODY3 mutations do not lead to any insulin secretion problems in mice, noted Teo.
“Rodent models may not be able to fully recapitulate MODY3 diabetes. Furthermore, rodent and human pancreas differ in terms of gene expression and morphology,” he added. To mimic the genetic profile of MODY3 patients, using hiPSCs was the closest way to simulate the changes that occur in mutant beta cells.
Alongside a host of genes involved in pancreatic development, the results revealed a reduced expression of the GLUT2 gene, which codes for a protein that shuttles glucose molecules into beta cells. According to Teo, this was striking because other transporters—GLUT1 and GLUT3—are more abundant than GLUT2, yet were not affected by the mutation.
“The lower expression of GLUT2 has historically made the role of GLUT2 seem relatively insignificant as compared to the other two glucose transporters. However, our findings have highlighted the importance of GLUT2 in human beta cells,” he explained.
While only GLUT2 was reduced among the three transporters, the effects were drastic, as the researchers observed glucose uptake to drop by half. Without the influx of glucose molecules, the mutant pancreatic beta cells are no longer alerted to the elevated blood sugar levels. Moreover, they end up producing less ATP, the body’s main energy molecule, hindering the release of insulin in MODY3 patients.
Given these results, the team is now looking into solutions for increasing glucose uptake in mutant beta cells, as well as investigating how these genetic changes may be involved in other types of diabetes. “Treatment methods that better facilitate glucose entry into the beta cells could help restore insulin secretion function in MODY3 patients,” Teo said.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and the Bioinformatics Institute (BII).
