Role of Insulin Action in Psoriasis Pathogenesis

The goal of this study is to collect more information from people with plaque psoriasis and to determine if insulin plays a role in the pathogenesis of psoriasis. The main question it aims to answer is if insulin action is preserved or even enhanced in psoriatic lesions despite insulin resistance elsewhere. Participants with plaque psoriasis will have punch biopsies taken of lesional and non-lesional skin after an overnight fast and then during an oral glucose tolerance test. Biopsy specimens will then be assessed for markers of insulin action.

Psoriasis exhibits a clear and robust epidemiologic association with type 2 diabetes mellitus (T2DM). Although T2DM may exacerbate psoriasis and/or complicate its treatment, we do not understand the mechanisms connecting them. As a starting point, psoriasis appears to worsen the insulin resistance (IR) that underlies T2DM. The study investigators hypothesize that the hyperinsulinemia that attempts to compensate for IR retains the ability to drive proliferation of psoriatic lesions. This would set up a vicious cycle in which psoriasis worsens IR, which in turn stimulates insulin hypersecretion that further intensifies psoriasis. In order to test this hypothesis, the investigators must first determine if insulin signaling in psoriatic lesions is actually hyperactive. The investigators therefore propose in this pilot study to elucidate the nature of insulin signaling in psoriasis by measuring phosphorylation of AKT, insulin's key intracellular signaling mediator, in skin biopsies. We will perform shave punch biopsies of lesional and non-lesional skin in overnight-fasted patients with psoriasis who are overweight or obese and therefore at risk of IR. Another set of biopsies will be taken during an oral glucose tolerance test that stimulates endogenous insulin secretion. The investigators expect that AKT phosphorylation will be attenuated in non-lesional skin of patients determined to have IR compared to those who are Insulin Sensitive (IS) or Insulin Intermediate (II), but that AKT phosphorylation will be preserved or even enhanced in lesional skin despite IR. Determining that insulin action is excessive in psoriatic lesions would suggest reducing insulin levels as a novel psoriasis treatment strategy that would also help to spare patients from difficult immunomodulatory treatments.

Eligibility Criteria:
Inclusion Criteria:

1. Body mass index of 25.0-40.0 kg/m2
2. Able to understand written and spoken English and/or Spanish
3. Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
4. Diagnosed with plaque psoriasis, documented using Psoriasis Area and Severity Index (PASI)
5. Glucose metabolism status as follows (determined only retrospectively based on data collected during the study):

   * For Insulin Sensitive (IS) group:

     * Hemoglobin A1c \< 5.7%, and
     * Fasting plasma glucose \< 95 mg/dL, and
     * Fasting plasma insulin \< 10 μIU/mL
   * For Insulin Intermediate (II) group:

     * Hemoglobin A1c \< 6.5%, and
     * Fasting plasma glucose 80-125 mg/dL, and
     * Fasting plasma insulin 10-14 μIU/mL
   * For Insulin Resistant (IR) group:

     * Hemoglobin A1c \< 6.5%, and
     * Fasting plasma glucose 80-125 mg/dL, and
     * Fasting plasma insulin ≥ 15 μIU/mL

Exclusion Criteria:

1. Inability to provide informed consent in English or Spanish
2. Concerns arising at screening visit (any of the following):
3. Laboratory evidence of diabetes mellitus, either determined during the study or based on previous documentation:

   * Hemoglobin A1c ≥ 6.5%, and/or
   * Fasting plasma glucose ≥ 126 mg/dL
   * Plasma glucose ≥ 200 mg/dL at 2 hours after ingestion of a 75-g oral glucose load
   * Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state
4. History of gestational diabetes mellitus
5. Use of antidiabetic medications within the 90 days prior to screening, including those prescribed for other indications (e.g., weight control, restoration of ovulation in of polycystic ovarian syndrome), including:

   • Metformin, thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium/glucose cotransporter 2 (SGLT2) inhibitors, amylin mimetics, acarbose, insulin
6. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)
7. Reproductive concerns

   i. Women of childbearing potential not using highly effective contraception, defined as:
   * Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy)
   * Combined oral contraceptive pills taken daily, including during the study
   * Intrauterine device (levonorgestrel-eluting or copper) active at the time of the study
   * Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of the study
   * Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study
   * Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study

   ii. Women currently pregnant

   iii. Women currently breastfeeding
8. Known, documented history, at the time of screening, of any of the following medical conditions:

   i. Bleeding disorders, including due to anticoagulation or use of P2Y12 inhibitors ii. Anemia requiring treatment iii. Glucose-6-phosphate dehydrogenase (G6PD) deficiency
9. Use of medications associated methemoglobinemia within 48 hours of shave biopsy procedures:

   i. Nitrates/nitrites: nitric oxide, nitroglycerin, nitroprusside, nitrous oxide ii. Antineoplastics: cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase iii. Antibiotics: dapsone, nitrofurantoin, paraaminosalicylic acid, sulfonamides iv. Antimalarials: chloroquine, primaquine v. Anticonvulsants: phenobarbital, phenytoin, valproic acid vi. Others: acetaminophen, metoclopramide, quinine, sulfasalazine
10. History of severe infection or ongoing febrile illness within 30 days of screening
11. Any other disease, condition, or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data.
12. Known allergy/hypersensitivity to any component of the medicinal product formulations (including amide anesthetics), IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
13. Concurrent enrollment in another clinical study of any investigational drug therapy within 6 months prior to screening or within 5 half-lives of an investigational agent, whichever is longer.