A deterioration in skin quality, its ability to heal, and its normal aging, is often observed in people with chronic hyperglycemia. A team of researchers from Inserm, the University of Bordeaux and LVMH Recherche has investigated how hyperglycemia alters the human dermis, and in particular the cells involved in its healing, the fibroblasts. Her work, published in Redox Biology , shows that too high a concentration of glucose in the dermis disrupts the complex, finely-regulated mechanics of energy production by fibroblasts, impacting on their ability to maintain skin integrity.
Glucose is a vital sugar for mammalian cells: in particular, it enables the synthesis of numerous molecules essential to the organism, such as DNA, as well as the transformation of energy by mitochondria, the body’s "energy power plants", via the mechanism known as "mitochondrial respiration". Although glucose concentrations in the dermis (one of the three layers making up the skin, located between the epidermis - the outer layer - and the hypodermis) mirror those found in the blood, glucose metabolism in the skin remains little studied and poorly understood.
Within the dermis are fibroblasts, cells involved in epidermal regeneration and skin healing, thanks to their ability to produce collagen and move to the site of injury. These cutaneous fibroblasts are directly affected by the metabolic stress caused by hyperglycemia [1] , a consequence of high-sugar diets.
Hyperglycemia and related metabolic diseases (such as diabetes) are frequently associated with a deterioration in the quality and integrity of the skin, with in particular poorer healing and premature skin ageing. A better understanding of how hyperglycemia impacts skin metabolism and structure could be one of the keys to limiting these alterations.
A project team co-led by Rodrigue Rossignol, Inserm research director and co-director of the Rare Diseases: Genetics and Metabolism laboratory (Inserm/University of Bordeaux) and Anne-Laure Bulteau at LVMH Recherche, has been investigating how human dermal fibroblasts and the mitochondria they contain behave when exposed to several degrees of hyperglycemia: normal, moderate, high and extreme [2] .
These studies were carried out in 4 complementary models: on fibroblasts cultured in vitro, in reconstituted dermis (an in vitro model reproducing the three-dimensional structure of the dermis), in reconstituted human skin (similar to reconstituted dermis but combining dermis and epidermis) and finally in a skin biopsy taken from a diabetic patient.
The results reveal a highly sensitive and complex system for regulating energy metabolism and mitochondrial activity within human fibroblasts, in response to variations in glucose levels in the dermis.
In particular, the scientists found that increasing hyperglycemia inhibits cutaneous respiration by mitochondria. They identified novel molecular mechanisms starting with the repression of mitochondrial activity, then leading to their fragmentation, until the activation of their degradation.
the blockage of the mitochondrial respiratory chain produces molecules that are toxic to the skin and implicated in its ageing process," explains Rodrigue Rossignol, " this is known as oxidative stress
Among the players involved in regulating mitochondrial activity, the scientists identified a growth factor, called GDF15, whose activity was strongly inhibited as soon as moderate hyperglycemia appeared, and tended to continue decreasing as the surrounding glucose level increased. This inhibition then led to a reduction in the production of new mitochondria in fibroblasts. In contrast, supplementation of the skin models with GDF15 reversed the observed alterations in energy metabolism, even though hyperglycemia persisted.
our results suggest that GDF15 could be at the heart of a potential pharmacological or dermatological strategy aimed at limiting the skin damage caused by metabolic stress in hyperglycemic individuals," says Rodrigue Rossignol. The researcher cautions, however, that in real-life conditions, chronic hyperglycemia involves inflammatory phenomena. These, which are not reproduced in our models, could hinder the protective action of GDF15 supplementation
Finally, the team observed that impaired mitochondrial activity in fibroblasts degraded their ability to produce a qualitative skin collagen network.
in the event of skin damage, the collagen network is used by fibroblasts to move through the dermis to repair damaged areas," explains Rodrigue Rossignol. " Our results show that, under the effect of hyperglycemia, the network was impaired, making it more difficult for fibroblasts to move through it, and skin reconstruction was therefore less effective
These data provide fundamental new insights into how hyperglycemia alters skin and mitochondrial physiology. They offer new insights into the causes of skin quality deterioration in people with hyperglycemia, and pave the way for potential innovative strategies specifically targeting mitochondria
This work is co-financed by Inserm, the University of Bordeaux, LVMH Recherche, the Foundation for Medical Research (FRM) and the Nouvelle-Aquitaine region.
Seyta Ley Ngardigal, the first author of this study and a doctoral student at the University of Bordeaux, has been awarded a doctoral scholarship funded by LVMH Recherche. This work is part of a CIFRE thesis directed by Rodrigue Rossignol and Anne-Laure Bulteau, within the Rare Diseases: Genetics and Metabolism unit (Inserm/University of Bordeaux) and LVMH Recherche (Orléans).
CIFREs, or Conventions Industrielles de Formation par la Recherche, are schemes financed by the French Ministry of Higher Education and Research, with the aim of strengthening exchanges between public research laboratories and the socio-economic world, encouraging the employment of PhDs in companies and contributing to the innovation process of companies established in France
[1] According to the WHO, a normal blood glucose concentration level is 700 to 1000 mg of glucose per liter of blood (3.9 to 5.6 mmol/L). Between 1200 and 2162mg/L (6.9 to 12 mmol/L), the person is considered hyperglycemic; 1200mg/L is considered moderate hyperglycemia and 2162 mg/L high hyperglycemia.
[2] 25mmol/L, i.e. about twice the value of high hyperglycemia.
