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

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).

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Other: Standard Carb Diet; Other: Low Carb Diet

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: T. Jordan Smith, RN, BSN; Phone Number: 615-936-6324; Email: metabolism@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: T. Jordan Smith, RN, BSN; Phone Number: 615-936-6324; Email: metabolism@vumc.org
      • Principal Investigator: Justin M Gregory, MD, MSCI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Additional exclusion criteria for T1DM subjects

• any diabetes medication except insulin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard Carb Diet then Low Carb Diet	Other: Standard Carb Diet; Approximately 50% of caloric intake will come from carbohydrate consumption.; Other: Low Carb Diet; Approximately 25% of caloric intake will come from carbohydrate consumption.
Experimental: Low Carb Diet then Standard Carb Diet	Other: Standard Carb Diet; Approximately 50% of caloric intake will come from carbohydrate consumption.; Other: Low Carb Diet; Approximately 25% of caloric intake will come from carbohydrate consumption.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin sensitivity - diet 1	Change in insulin sensitivity based on diet	baseline to 1 week
Change in insulin sensitivity - diet 2	Change in insulin sensitivity based on diet	baseline to 1 week
Change in endothelial function - diet 1	will quantify brachial artery, endothelium-dependent flow-mediated vasodilation using high-resolution ultrasound	baseline to 1 week
Change in endothelial function - diet 2	will quantify brachial artery, endothelium-dependent flow-mediated vasodilation using high-resolution ultrasound	baseline to 1 week

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Justin M Gregory, MD, MSCI, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2019
• Primary Completion (Estimated): February 28, 2024
• Study Completion (Estimated): February 28, 2024

Study Registration Dates

• First Submitted: October 2, 2019
• First Submitted That Met QC Criteria: October 4, 2019
• First Posted (Actual): October 8, 2019

Study Record Updates

• Last Update Posted (Actual): August 18, 2023
• Last Update Submitted That Met QC Criteria: August 14, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: endothelial dysfunction; insulin resistance; low carbohydrate diet; vascular health; hyperinsulinemia
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Resistance; Hyperinsulinism
• Other Study ID Numbers: 190630

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The datasets generated during and/or analyzed during the current study can be available from the corresponding author upon reasonable request. Data sets can be made available beginning 3 months and ending 5 years following article publication. No applicable resources have yet been generated or analyzed during the current study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No