A decline in skin quality, its ability to heal, and its normal aging process is often observed in individuals with chronic hyperglycemia.
A team of researchers from Inserm, the University of Bordeaux, and LVMH Research investigated how hyperglycemia alters human dermis, particularly the cells involved in wound healing, called fibroblasts. Their findings, published in
Redox Biology, reveal that excessively high glucose concentrations in the dermis disrupt a finely regulated mechanism of energy production in fibroblasts, affecting their ability to maintain skin integrity.
Human fibroblasts observed under fluorescence microscopy. Mitochondria are marked in red, fibroblast nuclear DNA is marked in blue.
© Nivea Dias Amoedo/Inserm
Glucose is a vital sugar for mammalian cells: it enables the synthesis of essential molecules like DNA and facilitates energy conversion by mitochondria—the body's "powerhouses"—through mitochondrial respiration. Although glucose levels in the dermis (one of the skin's three layers, located between the epidermis—the outer layer—and the hypodermis) mirror those in the blood, glucose metabolism in the skin remains poorly studied.
Within the dermis, fibroblasts play a key role in epidermal regeneration and wound healing by producing collagen and migrating to injury sites. These skin fibroblasts are directly affected by the metabolic stress caused by hyperglycemia [1], a consequence of high-sugar diets.
Hyperglycemia and related metabolic disorders (such as diabetes) are often associated with impaired skin quality and integrity, including slower wound healing and premature aging. Understanding how hyperglycemia impacts skin metabolism and structure could help mitigate these effects.
A research team co-led by Rodrigue Rossignol, Inserm research director and co-head of the Rare Diseases: Genetics and Metabolism lab (Inserm/University of Bordeaux), and Anne-Laure Bulteau at LVMH Research examined how dermal fibroblasts and their mitochondria respond to varying degrees of hyperglycemia: normal, moderate, high, and extreme [2].
The study used four complementary models: cultured fibroblasts
in vitro, a reconstructed dermis (a 3D
in vitro model), reconstructed human skin (combining dermis and epidermis), and skin biopsies from diabetic patients.
The results highlight a highly sensitive and complex system regulating energy metabolism and mitochondrial activity in fibroblasts in response to glucose fluctuations.
The scientists found that increasing hyperglycemia inhibits mitochondrial respiration in the skin. They identified novel molecular mechanisms starting with mitochondrial suppression, leading to their fragmentation, and ultimately their degradation.
"
Blocking mitochondrial respiration produces toxic molecules linked to skin aging," explains Rodrigue Rossignol, "
this is known as oxidative stress."
Among the regulators of mitochondrial activity, the team identified a growth factor called GDF15, whose activity was strongly inhibited even at moderate hyperglycemia and continued to decline with rising glucose levels. This inhibition reduced mitochondrial production in fibroblasts. However, supplementing skin models with GDF15 reversed the metabolic disruptions, even under persistent hyperglycemia.
"
Our findings suggest GDF15 could be central to pharmacological or dermatological strategies aimed at reducing skin damage from metabolic stress in hyperglycemic individuals," says Rodrigue Rossignol. He cautions, however: "
In real-world conditions, chronic hyperglycemia involves inflammatory processes not replicated in our models, which might hinder GDF15's protective effects."
Finally, the team observed that impaired mitochondrial activity in fibroblasts degraded their ability to produce high-quality collagen networks.
"
During skin injury, the collagen network helps fibroblasts migrate to repair damaged areas," Rodrigue Rossignol details. "
Our results show that under hyperglycemia, the weakened network hinders fibroblast movement, making skin reconstruction less efficient."
These findings provide fundamental insights into how hyperglycemia alters skin physiology and mitochondrial function. They offer new perspectives on skin quality deterioration in hyperglycemic individuals and pave the way for innovative strategies targeting mitochondria.
Notes:
[1] According to WHO, normal blood glucose levels range from 700 to 1000 mg per liter of blood (3.9 to 5.6 mmol/L). Between 1200 and 2162 mg/L (6.9 to 12 mmol/L), a person is considered hyperglycemic; 1200 mg/L is moderate hyperglycemia, and 2162 mg/L is severe hyperglycemia.
[2] 25 mmol/L, roughly twice the threshold for severe hyperglycemia.