Overview

Prospective, monocentric, pathophysiological study, comparing 3 parallel groups: healthy controls; patients with diabetes and without DFU; patients with diabetes and with DFU. To address secondary objectives, samples from a fourth group will be collected.

Eligibility

Inclusion criteria:

Groups 1,2,3,4:

• Informed consent signed
• Affiliated to social security insurance or beneficiary of social security insurance
• Aged of 18 or older

Group 1: healthy volunteers:

-Free from all acute and chronic pathology

Group 2: diabetic patients without DFU:

        -Patients with type 2 diabetes according to the criteria of the American Diabetes
        Association (ADA), without DFU or history of DFU
        Group 3: diabetic patients with DFU or recent history of DFU (occurred within the last two
        years):
        -Patients with type 2 diabetes according to the criteria of the American Diabetes
        Association (ADA) with: One or more active grade 1A, 1C, 2A or 2C (University of Texas
        Classification of Diabetic Foot) foot ulcer of microvascular or mixed etiology; Or a recent
        history (<2 years) of foot ulcer of microvascular or mixed etiology.
        Group 4 (to collect samples of foot skin biopsies to address secondary objectives ):
        -Patients with type 2 diabetes according to the criteria of the American Diabetes
        Association (ADA),with neuropathy and DFU undergoing lower-limb surgery for skin ulcer
        (e.g. toe amputation).
        Exclusion criteria
        Groups 1, 2 and 3:
          -  Unstable diabetes that has resulted in hyperosmolar coma or ketoacidosis, and/or
             documented increase or decrease in HbA1c of more than 2.0% within the previous 3
             months.
          -  Presence of diabetic peripheral neuropathy above the ankle, defined as a scoring >3 of
             at least two of the four stimuli of the Neuropathy Disability Score (i.e. pinprick
             sensation, light touch, vibration, and temperature perception) (37).
          -  Infected wound, treated with antibiotics in the past 15 days.
          -  Critical ischemia of the lower limb, defined as leg pain at rest associated with ankle
             pressure <70 mmHg.
          -  History of hypersensitivity reaction to treprostinil, fluconazole, other azole
             compounds, L-NMMA, ketorolac, meloxicam, or any NSAIDs or acetylsalicylic acid,
             lidocaine (or any local anesthetic with an amide bond), or their excipients
          -  History of asthma, rhinitis, nasal polyps, angioedema, hives rash, or any other
             allergic reaction due to acetylsalicylic acid or any NSAID taking
          -  Pulmonary veno-occlusive disease (PVOD)
          -  Porphyria
          -  Hyperkalemia
          -  Active or uncontrolled cardiovascular disease as follows: Myocardial infarction, or
             angina within the previous 6 months; Severe ischemic heart disease; Arrhythmia
             (uncontrolled, symptomatic, requiring treatment or life-threatening); Congestive heart
             failure, or decompensated heart failure not medically controlled; Stroke or transient
             ischemic attack within the previous 3 months; Uncontrolled hypertension: systolic
             blood pressure (SBP)> 180 mmHg or diastolic blood pressure (DBP)> 105 mmHg (2 abnormal
             readings during visit) Valvular heart disease
          -  Severe liver disease (Child-Pugh C) at the time of enrollment
          -  Renal disease (creatinine >2 mg/dL and/or estimated glomerular filtration rate (GFR)
             <30 mL/min, history of dialysis)
          -  Active peptic ulcer disease, recent gastrointestinal bleeding or perforation, or
             history of peptic ulcer disease or gastrointestinal bleeding or perforation with
             NSAIDs
          -  Intracerebral or gastrointestinal hemorrhage, hemostasis disorder or every clinical
             status that may lead to bleeding
          -  Chronic venous disease defined as stage 4a and 4b of the
             Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification
          -  Cutaneous condition deemed incompatible with skin biopsy and dermal microdialysis by
             the investigator
          -  History of necrotic angiodermatitis
          -  Trauma or any clinical event susceptible to be responsible for hemorrhage within the
             previous 6 months
          -  Concomitant treatment with pentoxifylline, anticoagulants, probenecid, medicinal
             products known to prolong the QT interval or anti-inflammatory or analgesic dose of
             acetylsalicylic acid
          -  If concomitant treatment with NSAIDs, participants have to be stopped 1 week before
             the inclusion
          -  Pregnancy or Lactation
          -  Females with childbearing potential, defined as a premenopausal female capable of
             becoming pregnant, and not using an highly effective form of birth control. Effective
             birth control methods include: oral, implant or patch hormone contraception;
             intrauterine device; abstinence and outercourse; tubal ligation; vasectomy.
        Groups 1,2,3 and 4:
          -  Participant involved in another interventional clinical study
          -  Person deprived of liberty by judicial order
          -  Person under guardianship or curatorship