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

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ClinicalTrials.gov Identifier: NCT04118374
Recruitment Status : Suspended (research-related activities have been impacted by the COVID-19 outbreak (participant recruitment/enrollment/on-site subject visits))
First Posted : October 8, 2019
Last Update Posted : September 30, 2020
Sponsor:
Information provided by (Responsible Party):
Justin Gregory, Vanderbilt University Medical Center

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).

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Other: Standard Carb Diet Other: Low Carb Diet Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study to Determine Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Type 1 Diabetes
Actual Study Start Date : February 14, 2020
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : February 28, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

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.




Primary Outcome Measures :
  1. Change in insulin sensitivity - diet 1 [ Time Frame: baseline to 1 week ]
    Change in insulin sensitivity based on diet

  2. Change in insulin sensitivity - diet 2 [ Time Frame: baseline to 1 week ]
    Change in insulin sensitivity based on diet

  3. Change in endothelial function - diet 1 [ Time Frame: baseline to 1 week ]
    will quantify brachial artery, endothelium-dependent flow-mediated vasodilation using high-resolution ultrasound

  4. Change in endothelial function - diet 2 [ Time Frame: baseline to 1 week ]
    will quantify brachial artery, endothelium-dependent flow-mediated vasodilation using high-resolution ultrasound



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age: 18-60
  • HbA1c: 5.9-9.0%
  • Insulin delivery: must be on an insulin pump
  • Glucose Monitor: must use a continuous glucose monitor (CGM)
  • BMI 18-28 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04118374


Locations
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United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center
Investigators
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Principal Investigator: Justin M Gregory, MD, MSCI Vanderbilt University Medical Center
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Responsible Party: Justin Gregory, Assistant Professor, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT04118374    
Other Study ID Numbers: 190630
First Posted: October 8, 2019    Key Record Dates
Last Update Posted: September 30, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Justin Gregory, Vanderbilt University Medical Center:
low carbohydrate diet
hyperinsulinemia
insulin resistance
endothelial dysfunction
vascular health
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases