Role of Insulin Action in Psoriasis Pathogenesis

Psoriasis Clinical Trial

Official title:

Role of Insulin Action in Psoriasis Pathogenesis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06242847
• Other study ID #: AAAU4674
• Status: Recruiting
• Start date: February 2, 2024
• Est. completion date: May 2025

Study information

• Verified date: February 2024
• Source: Columbia University
• Contact: Zachary Sone
• Phone: 2123059336
• Email: zds2120[@]cumc.columbia.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: May 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Insulin Resistance
• Overweight
• Overweight and Obesity
• Plaque Psoriasis
• PreDiabetes
• Psoriasis

Intervention

Diagnostic Test:
• Oral glucose tolerance test (OGTT)
Participants ingest 75 g of glucose in 10 fl oz aqueous solution (fruit flavored) after an overnight fast. Blood is drawn at baseline (t = 0 min) and at 120 min after ingestion. This test is non-experimental.

Procedure:
• Skin punch biopsy
Punch biopsies are taken from lesional (psoriatic) and non-lesional skin after an overnight fast and at 120 min after ingestion of glucose during OGTT. This procedure is non-experimental.

Locations

Country	Name	City	State
United States	Columbia University Irving Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Columbia University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Skin insulin sensitivity: ratio of phosphorylated to total AKT in skin biopsies	Investigators will perform Western blots on skin biopsies using antibodies to phosphorylated (T308, S473) and total AKT. The ratio of phosphorylated to total AKT will be determined using densitometry of Western blots and/or by enzyme-linked immunosorbent assays (ELISA), each measured in arbitrary units (AU).	Up to 120 minutes from the start of OGTT
Primary	Fasting plasma glucose level	Plasma glucose (units: mg/dL) after an overnight fast (> 8 hours). A blood test will be done. A healthy (normal) fasting blood glucose level for someone without diabetes is 70 to 99 mg/dL.	Before OGTT (baseline = 0 minutes), During OGTT (up to 120 minutes from start of OGTT)
Primary	Fasting serum insulin level	Serum insulin (units: µIU/mL) after an overnight fast (> 8 hours). A blood test will be done. The normal range of fasting insulin varies somewhat between labs, but around 2 to 20 mIU/mL is considered normal by most.	Before OGTT (baseline = 0 minutes), During OGTT (up to 120 minutes from start of OGTT)
Primary	Fasting serum C-peptide level	Serum C-peptide (units: ng/mL) after an overnight fast (> 8 hours). A blood test will be done. A normal result of a C-peptide test ranges from 0.5 ng/mL to 2.0 ng/mL (or 0.17 to 0.83 nmol/L).	Before OGTT (baseline = 0 minutes), During OGTT (up to 120 minutes from start of OGTT)
Secondary	Serum triglyceride (TG) level during OGTT	Measurement of serum triglyceride level (units: mg/dL) during OGTT. A blood test will be done.	During OGTT (up to 120 minutes from start of OGTT)
Secondary	Serum free fatty acid (FFA) levels during OGTT	Measurement of serum free fatty acid levels (units: mmol/L) during OGTT. A blood test will be done.	During OGTT (up to 120 minutes from start of OGTT)
Secondary	Serum total cholesterol level	Serum total cholesterol (units: mg/dL) after an overnight fast (> 8 hours). A blood test will be done.	Before OGTT (baseline = 0 minutes)
Secondary	Serum high-density lipoprotein (HDL) cholesterol level	Serum high-density lipoprotein cholesterol (units: mg/dL) after an overnight fast (> 8 hours). A blood test will be done.	Before OGTT (baseline = 0 minutes)
Secondary	Serum low-density lipoprotein (LDL) cholesterol level	Serum low-density lipoprotein cholesterol (units: mg/dL) after an overnight fast (> 8 hours). A blood test will be done.	Before OGTT (baseline = 0 minutes)