According to the German Diabetes Health Report 2018, more than 5.7 million people in Germany suffer from type 2 diabetes. The affected individuals react inadequately to the hormone insulin, which leads to elevated blood glucose levels. This in turn can lead to strokes, heart attacks, retinal or kidney damage and nerve/vascular disorders. Since the metabolic disease develops gradually, initial damage has usually already occurred at the time of diagnosis. Beside the classical genetic predisposing genes, a research team has reported ithat epigenetic changes increase the risk of type 2 diabetes. Moreover, people with high blood levels of the binding protein IGFBP2 are less likely to develop this metabolic disorder. The changes in the blood are already detectable a few years prior to the onset of the disease. In addition to insulin, insulin-like growth factor 1 (IGF-1) is also involved in the metabolism of sugar and fat.
The effect of this growth factor is weakened by binding to the IGF-binding protein 2 (IGFBP2). If the liver does not release enough IGFBP2 into the blood, the balance of the glucose and lipid metabolism may be disrupted. The research team led by Schürmann and Professor Matthias Schulze, head of the Department of Molecular Epidemiology at DIfE, investigated how the diminished effect of the IGFBP2 gene could influence the development of type 2 diabetes. Human studies show that people suffering from fatty liver produce and release less IGFBP2. Schürmann’s team observed similar effects in earlier mouse experiments, which showed that IGFBP2 levels were already reduced prior to the liver disease. This is due to the transfer of methyl groups at certain sites of the IGFBP2 DNA sequence (methylation), which inhibited the gene in the liver. These so-called epigenetic changes are caused, among other things, by lifestyle factors.
Such modifications of the DNA in the IGFBP2 gene were also previously detected in blood cells of overweight people with impaired glucose tolerance. The interdisciplinary research team led by Schürmann and Schulze used findings from the clinic and laboratory to evaluate blood samples and data from the EPIC Potsdam Study. Recent analyses by the researchers indicate that inhibition of the IGFBP2 gene promotes type 2 diabetes. This was observbed in 2016 when researchers noted that epigenetic modifications got in the path. Early methylation of Igfbp2 gene promoter in the mouse liver was able to induce a fatty organ later. A prevoius analysis between the mouse the human transcriptome, was also able to reveal an overlapping pattern of gene involvement in diabetes predisposition. Beside IGFBP2, other signaling molecules like Grb10, Cdk2, and transcription factors like Tcf7 and PRC1, were overlapping between human and mouse cells.
In addition, the team of scientists observed that leaner study participants and study participants with lower liver fat levels had higher concentrations of the protective binding protein in the blood. Higher plasma concentrations of IGFBP2 were associated with a lower risk of developing type 2 diabetes in subsequent years. Methylation of single CpG sites located in the intronic region of Igfbp-2 gene in the liver was linked to development of obesity and elevated hepatic fat storage in mice. Similarly, in humans, hepatic hypermethylation in the homologous CpG site was associated with nonalcoholic fatty liver disease (NAFLD). The researchers think that a possible explanation for the relationship between circulating IGFBP-2 and type 2 diabetes risk is an involvement of IGFBP-2 in insulin-regulated pathways; and the association structure in EPIC-Potsdam is consistent with a substantial role of impaired IGFBP-2 signaling in type 2 diabetes incidence.
Professor Annette Schürmann, head of the Department of Experimental Diabetology, commented: “This study is a good example of how translational research works: a clinical finding is taken up, analyzed mechanistically in the laboratory and finally examined in a population-wide study. Our data confirms the hypothesis that the IGF-1 signaling pathway also plays an important role in the development of type 2 diabetes in humans. In the future, our findings may help to identify risk potentials for type 2 diabetes even earlier and help to counteract the disease with more specific prevention acts”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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