Impaired glyoxalase activity is associated with reduced expression of neurotrophic factors and pro-inflammatory processes in diabetic skin cells.
Patients suffering from type II diabetes develop several skin manifestations including cutaneous infections, diabetic dermopathy, diabetic bullae and acanthosis nigricans. Diabetic micro- and macroangiopathy as well as diabetic neuropathy are believed to play a crucial role in the development of diabetic skin disorders. A reduced cutaneous nerve fibre density was reported in diabetic subjects, which subsequently leads to impaired sensory nerve functions. Using an innervated skin model, we investigated the impact of human diabetic dermal fibroblasts and keratinocytes on porcine sensory neurons. Diabetic skin cells showed a reduced capacity to induce neurite outgrowth due to a decreased support with neurotrophic factors, such as NGF. Furthermore, diabetic keratinocytes displayed insulin resistance and increased expression of pro-inflammatory cytokines demonstrating the persistent effect of diabetes mellitus on human skin cells. Dysregulations were related to a significantly reduced glyoxalase enzyme activity in diabetic keratinocytes as experimentally reduced glyoxalase activity mimicked the increase in pro-inflammatory cytokine expression and reduction in NGF. Our results demonstrate an impaired crosstalk of diabetic skin cells and sensory neurons favouring hypo-innervation. We suggest that reduced methylglyoxal detoxification contributes to an impaired neurocutaneous interaction in diabetic skin.
Research and Development, Beiersdorf AG, Hamburg, Germany.
Olga
O
Reichert
Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany.
Thomas
T
Fleming
Research and Development, Beiersdorf AG, Hamburg, Germany.
Gitta
G
Neufang
Department of Anesthesiology Mannheim, Heidelberg University, Mannheim, Germany.
Martin
M
Schmelz
Institute of Toxicology, Hannover Medical School, Hannover, Germany.
Harald
H
Genth
Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
Volkhard
V
Kaever
Research and Development, Beiersdorf AG, Hamburg, Germany.
Horst
H
Wenck
Research and Development, Beiersdorf AG, Hamburg, Germany.
Franz
F
Stäb
Research and Development, Beiersdorf AG, Hamburg, Germany.
Lara
L
Terstegen
Research and Development, Beiersdorf AG, Hamburg, Germany.
Ludger
L
Kolbe
Research and Development, Beiersdorf AG, Hamburg, Germany.
Dennis
D
Roggenkamp
D000328:Adult; D000368:Aged; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000473:pathology* / Q000502:physiology; D012867:Skin / Q000294:innervation* / Q000378:metabolism; D013552:Swine; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099301:Hydroxyacylglutathione Hydrolase
D005947:Glucose; D053583:Interleukin-1beta; D015850:Interleukin-6; D007791:Lactoylglutathione Lyase; D020932:Nerve Growth Factor; D011765:Pyruvaldehyde; D012333:RNA, Messenger; D013869:Thiolester Hydrolases; D014409:Tumor Necrosis Factor-alpha; D000099301:Hydroxyacylglutathione Hydrolase; C000597196:GLO1 protein, human
cutaneous innervation; diabetes mellitus; glyoxalase; methylglyoxal; skin models