A Study to Determine Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Type 1 Diabetes

NCT ID: NCT04118374

Last Updated: 2025-10-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-24
• Study Completion Date: 2024-06-21

Brief Summary

The investigators will test the hypothesis that reducing insulin doses using a low carbohydrate diet (LCD) will be associated with with improved insulin sensitivity (Aim 1) and blood vessel health (Aim 2).

Detailed Description

Insulin resistance (IR) is consistently found in patients with type 1 diabetes (T1DM) and pathophysiologically links T1DM with atherosclerotic disease. IR and nascent atherosclerosis, as characterized by endothelial dysfunction, are present early in T1DM. Although atherosclerosis leads to cardiovascular disease (CVD)-the predominant cause of death in T1DM-the early cardiometabolic processes driving atherosclerosis are not currently well-characterized. My overarching hypothesis is that IR and endothelial dysfunction in T1DM are, in part, iatrogenic, occurring as a function of nonphysiologic insulin delivery.

Previous research shows IR in T1DM is closely related to iatrogenic hyperinsulinemia. Iatrogenic hyperinsulinemia in T1DM results from injecting insulin into subcutaneous tissue rather than delivering insulin more physiologically into the hepatic portal vein. Hyperinsulinemia, per se, is closely linked with IR and independently predicts CVD in diabetic and nondiabetic populations. Thus, peripheral insulin delivery brings about unintended adverse cardiometabolic consequences in T1DM. The investigators propose a practical intervention to diminish iatrogenic hyperinsulinemia and thereby mitigate CVD risk. The investigators hypothesize that a reduction in iatrogenic hyperinsulinemia brought about by a low carbohydrate diet (LCD) will independently correlate with improved insulin sensitivity (Aim 1) and endothelial function (Aim 2).

In this pilot study, the investigators will mechanistically dissect the contribution of iatrogenic hyperinsulinemia to IR and endothelial dysfunction in 8 adults with T1DM using a crossover study of LCD vs. standard carbohydrate diet (SCD) to experimentally modify hyperinsulinemia. The investigators will quantify insulin sensitivity using hyperinsulinemic, euglycemic clamps and measure endothelium-dependent flow mediated vasodilation using high-resolution ultrasound.

Conditions

Diabetes Mellitus, Type 1

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard Carb Diet then Low Carb Diet

Group Type: EXPERIMENTAL

Standard Carb Diet

Intervention Type: OTHER

Approximately 50% of caloric intake will come from carbohydrate consumption.

Low Carb Diet

Intervention Type: OTHER

Approximately 25% of caloric intake will come from carbohydrate consumption.

Low Carb Diet then Standard Carb Diet

Group Type: EXPERIMENTAL

Standard Carb Diet

Intervention Type: OTHER

Approximately 50% of caloric intake will come from carbohydrate consumption.

Low Carb Diet

Intervention Type: OTHER

Approximately 25% of caloric intake will come from carbohydrate consumption.

Interventions

Standard Carb Diet

Approximately 50% of caloric intake will come from carbohydrate consumption.

Intervention Type: OTHER

Low Carb Diet

Approximately 25% of caloric intake will come from carbohydrate consumption.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age: 18-60
• HbA1c: 5.6-9.0%
• Insulin delivery: must be on an insulin pump
• Glucose Monitor: must use a continuous glucose monitor (CGM)
• BMI 18-33 kg/m^2
• Body Mass >/= 50 kg ( 110 lbs)

Exclusion Criteria

• severe hypoglycemia : >/= 1 episode in the past 3 months
• diabetes comorbidities (>= 1 trip to emergency department for poor glucose control in the past 6 months,
• New York Heart Association Class II-IV cardiac functional status
• SBP > 140 and DBP > 100 mmHg,
• eGFR by MDRD equation of <60 mL/min/1.73m^2
• AST or ALT > 2.5 times the upper limit of normal
• HCT <35%

medications

• any antioxidant vitamin supplement (<2 weeks before STUDY visit)
• any systemic glucocorticoid
• any antipsychotic
• atenolol, metoprolol, propranolol
• niacin
• any thiazide diuretic
• any OCP with > 35 mcg ethinyl estradiol,
• growth hormone
• any immunosuppressant
• any antihypertensive
• any antihyperlipidemic

other:

• pregnancy
• Tanner stage < 5
• peri or postmenopausal woman
• active smoker
• gluten-free diet requirement

• any diabetes medication except insulin

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Justin Gregory

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Justin M Gregory, MD, MSCI

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

Gregory JM, Smith TJ, Duffus SH, Brooks D, Akbar MN, Huntley MA, Gottlieb JA, LeStourgeon LM, Wilson CS, Beckman JA, Cherrington AD. A one-week reduced-carbohydrate diet to mitigate iatrogenic peripheral hyperinsulinemia does not improve insulin sensitivity or endothelial function in a randomized, crossover trial in patients with type 1 diabetes. Cardiovasc Diabetol. 2025 Mar 5;24(1):107. doi: 10.1186/s12933-025-02658-z.

Reference Type: RESULT

PMID: 40045281 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

190630

Identifier Type: -

Identifier Source: org_study_id