Researchers at the University of Geneva (UNIGE) have highlighted one mechanism: the fact that the liver seems to be able to produce large amounts of glucose independently of any hormonal signals. In patients with excess liver fat, this excess glucose production may lead to type 2 diabetes, regardless of the hormonal circuit. These results, published by the Journal of Biological Chemistry, underscore a reinterpretation of the origins of diabetes in overweight patients.
2. The main hormone that regulates blood sugar
Blood sugar levels are regulated primarily by two antagonistic hormones: insulin, which lowers blood sugar levels, and glucagon, which increases blood sugar levels. The liver plays an important role in regulating blood sugar levels by producing and redistributing glucose under the influence of these two hormones. Overweight people thus face two threats: on the one hand, the risk of developing insulin resistance, a precursor to type 2 diabetes, and, on the other hand, the accumulation of fat in liver cells, a syndrome known as “fatty liver”. This accumulation of lipids indeed induces changes in the morphology and structure of the mitochondria (the energy plants of cells).
3. Mitochondria of liver cells are regulated by proteins
Do these alterations have an effect on mitochondrial function? Is there a link between liver cell mitochondria, obesity and diabetes? To find out, they focused on a protein called OPA1, whose “long” form, in other words the non-protein degradable form, has the function of maintaining mitochondrial structure.
The scientists inactivated OPA1 function in mice to be able to analyze the exact role of the mitochondria. “The livers of mice without long-form OPA1 lost their ability to produce sugar in just a few weeks,” said Lingzi Li, a doctoral student in Prof. Maechler’s lab and first author of the study. “The morphology of mitochondria in liver cells was altered, confirming their importance in glucose metabolism.”
4. The liver is not stimulated to produce glucose
To refine their analysis, Pierre Maechler and colleagues reintroduced a functional OPA1 protein in mice, where it had been previously deleted. “Mitochondria returned to their normal form, but not their activity. In this field, shape did not determine function either! Mitochondria did not look normal, so they might not function properly,” the scientists said.
However, the biggest surprise is yet to come. By looking at controls, healthy mice that had been introduced with OPA1 in its long form, they found that when equipped with these “supermitochondria,” they produced more glucose than necessary, and that their livers produced sugar without any hormonal calls. Thus, this study shatters the long-held view that glucose production by the liver is necessarily dependent on external stimuli.
5. Fatty liver releases glucose to cause diabetes
This is the first time glucose production by the liver has been observed independently of external signals, especially hormones. This finding might explain the development of type 2 diabetes in patients with the “fatty liver” syndrome, in addition to any overt insulin imbalance. To confirm this, the UNIGE researchers are considering changing the shape of the mitochondria in the liver cells of overweight mice to see whether this excess production of glucose triggers abnormally high blood sugar levels that lead to diabetes.
Therefore, for obese type 2 diabetes, improving fatty liver can improve blood sugar.
