Cardiometabolic Benefit of Reducing Iatrogenic Hyperinsulinemia Using Insulin Adjunctive Therapy in Type 1 Diabetes (ACT T1D)

This study aims to understand the heart and blood sugar health benefits of using an adjunctive therapy to lower high insulin levels in people with type 1 diabetes. The investigators will also look at people with a specific type of diabetes called Glucokinase-Maturity Onset Diabetes of the Young (GCK-MODY) and those without diabetes to help interpret the results. The investigators will use a medication that helps the body get rid of sugar, called and SGLT2 inhibitor, with the goal to reduce the body's insulin requirements. The investigators believe this could lead to better heart and blood sugar health, including a better response to insulin and more available nitric oxide, a gas that helps blood vessels function well. The investigators will compare heart and blood sugar health risk factors in participants with type 1 diabetes, participants with Glucokinase-Maturity Onset Diabetes of the Young (GCK-MODY), and non-diabetic healthy volunteers under two conditions: high insulin levels typical of type 1 diabetes and normal insulin levels typical of the other two groups.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes Mellitus; Healthy Volunteer; MODY2 Diabetes; Glucokinase-Maturity Onset Diabetes of the Young (GCK-MODY)
• Intervention / Treatment: Procedure: Study Visit 1; Drug: Placebo; Procedure: Study Visit 2; Drug: Sodium Glucose Co-transporter 2 (SGLT2) Inhibitor

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Daniel J Moore, MD, PhD; Phone Number: 615-322-7427; Email: metabolism@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Wendi Welch, CCRP; Email: wendi.m.welch@vumc.org
      • Contact: Daniel J Moore, MD, PhD; Phone Number: (615) 322- 7427; Email: metabolism@vumc.org
      • Principal Investigator: Danield J Moore, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Age: 18-60 years BMI: 18-28 kg/m² Weight: ≥ 50 kg

T1DM Participants:

Duration of T1DM: 1-30 years HbA1c: 5.7-7.5% Insulin Therapy: Using automated insulin delivery

GCK-MODY Participants:

HbA1c: 5.7-7.5% Genetic Confirmation: Positive GCK sequencing

Control Participants:

HbA1c: less than 5.5%

** Exclusion Criteria: Severe Hypoglycemia: ≥1 episode in the past 3 months

Comorbidities:

• Any hospital admissions for diabetic ketoacidosis in the past 6 months
• SBP greater than 140 mmHg and DBP greater than 100 mmHg
• eGFR by MDRD equation of less than 60 mL/min/1.73 m²
• AST or ALT greater than 2.5 times ULN
• Hct less than 35%

Medications:

• Any antioxidant vitamin supplement within 2 weeks before the study
• Any systemic glucocorticoid
• Antipsychotics
• Atenolol, Metoprolol, Propranolol
• Niacin
• Any thiazide diuretic
• Any oral contraceptive pill with greater than 35 mcg ethinyl estradiol
• Growth hormone
• Any immunosuppressant
• Antihypertensive
• Any antihyperlipidemic

Other:

• Pregnancy
• Tanner stage less than 5
• Peri- or post-menopausal women
• Active smoker

T1DM Participants:

Medications: Any diabetes medication except insulin C-peptide: greater than 0.7 ng/mL (fasting)

GCK-MODY Participants:

None specific

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High insulin; Participants will receive a "high insulin infusion" (Hi-Ins) prior to quantifying insulin resistance and endothelial function. This infusion will result in participants having insulin levels similar to patients with type 1 diabetes for five hours.	Procedure: Study Visit 1; Hyperinsulinemic, euglycemic clamp and flow-mediated dilation (FMD) study. The study will randomize participants to first receive a five-hour intravenous insulin infusion to achieve normal plasma insulin concentrations (Eu-Ins) or higher plasma insulin concentrations (Hi-Ins); Drug: Placebo; T1DM participants in the Hi-Ins study will receive an oral placebo. During the Eu-Ins study they will receive an SGLT2i.; CGK-MODY participants and healthy volunteers will receive placebo in both studies.; Procedure: Study Visit 2; Hyperinsulinemic, euglycemic clamp and flow-mediated dilation (FMD) study. Insulin levels infused during the five-hour insulin infusion will be opposite of the first visit.
Active Comparator: Normal insulin; Participants will receive a "normal insulin infusion" (Eu-Ins) prior to quantifying insulin resistance and endothelial function. This infusion will result in participants having insulin levels similar to people without diabetes and people with GCK-MODY for five hours.	Procedure: Study Visit 1; Hyperinsulinemic, euglycemic clamp and flow-mediated dilation (FMD) study. The study will randomize participants to first receive a five-hour intravenous insulin infusion to achieve normal plasma insulin concentrations (Eu-Ins) or higher plasma insulin concentrations (Hi-Ins); Drug: Placebo; T1DM participants in the Hi-Ins study will receive an oral placebo. During the Eu-Ins study they will receive an SGLT2i.; CGK-MODY participants and healthy volunteers will receive placebo in both studies.; Procedure: Study Visit 2; Hyperinsulinemic, euglycemic clamp and flow-mediated dilation (FMD) study. Insulin levels infused during the five-hour insulin infusion will be opposite of the first visit.; Drug: Sodium Glucose Co-transporter 2 (SGLT2) Inhibitor; Concurrent with starting the five-hour infusion, T1DM participants in the Eu-Ins study will receive an SGLT2i dose (empagliflozin 25 mg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aim 1: Tissue glucose disposal (TGD)	The primary outcome will be the difference in tissue glucose disposal (TGD) during a hyperinsulinemic, euglycemic clamp between Eu-Ins and Hi-Ins studies.	8 hours
Aim 2: Nitric Oxide (NO) bioavailability	This study aims to determine the difference in hyperinsulinemia-mediated suppression of nitric oxide (NO) bioavailability between Eu-Ins and Hi-Ins studies, as measured by flow mediated dilation (FMD) of the brachial artery.	8 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary outcome for Aim 1: Differences in endogenous glucose production	This study aims to determine the difference in endogenous glucose production at the end of euinsulinemic vs. hyperinsulinemic infusions	8 hours
Secondary outcome for Aim 2: Nitroglycerin mediated vasodilation of the brachial artery	Through the use of flow mediated dilation (FMD), the study aims to determine nitroglycerin mediated vasodilation of the brachial artery.	8 hours

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Daniel J Moore, MD, PhD, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2025
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: September 20, 2024
• First Submitted That Met QC Criteria: September 20, 2024
• First Posted (Actual): September 24, 2024

Study Record Updates

• Last Update Posted (Actual): December 23, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: insulin sensitivity; healthy volunteer; type 1 diabetes mellitus; nitric oxide; with Glucokinase-Maturity Onset Diabetes of the Young (GCK-MODY); sodium-glucose cotransporter-2 inhibitors (SGLT2i); flow-mediated vasodilation (FMD)
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Hyperinsulinism; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 1; Insulin Resistance
• Other Study ID Numbers: 240996; 1R01DK137997 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in a published article after deidentification (text, tables, figures, and appendices).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes