Physiologic Markers of Cardiometabolic Risk in People With Type 1 Diabetes

More than 40% of young adults with type 1 diabetes (T1D) also have overweight or obesity. Each of these diagnoses increase the risk of adverse cardiovascular events. Investigators aim to obtain reference data for individuals with T1D who do not have overweight obesity, to understand how close GLP-1 analogue obesity treatment in those with overweight/obesity brings physiologic markers of cardiometabolic risk to those with BMI in the normal range. Specifically, investigators will describe how drivers of gluconeogenesis and lipemia (specifically measured as visceral fat ratio, insulin resistance, and postprandial lipemia,) that contribute to cardiometabolic risk in T1D change over time.

Study Overview

• Status: Recruiting
• Conditions: Obesity; type1diabetes
• Intervention / Treatment: Biological: Hyperinsulinemic-euglycemic clamp; Other: High Fat Mixed Meal Tolerance Test

Detailed Description

Primary Objective

The primary objectives of this physiologic study are to:

1. examine how visceral adipose tissue (VAT), measured as VAT/Subcutaneous Adipose Tissue + VAT changes over 1 year in young adults with T1D and body mass index <25kg/m2.
2. determine how hepatic insulin resistance changes over 1 year in young adults with T1D and body mass index <25kg/m2.
3. determine how the area under the curve of triglycerides after a high fat mixed meal tolerance test changes over 1 year in young adults with T1D and body mass index <25kg/m2.

Secondary Objective

The secondary objective[s] of this study are to determine change in:

Aim 1: Weight and % body fat from baseline to 1 year. Aim 2: Suppression of endogenous glucose production (a measure of insulin resistance), expressed as the change in endogenous glucose rate of appearance (mg/kg/min) at baseline and during the low dose (hepatic) phase, and relationship to VAT/(VAT+SAT) from baseline to 1 year. Glucose rate of appearance, glycerol rate of appearance, glucose oxidation, and fat oxidation will be assessed in all clamp phases baseline to 1 year.

Aim 3: Postprandial rise in other atherogenic lipoproteins baseline to 1 year. The data obtained from this protocol will serve as reference data for a randomized clinical trial of GLP-1 analogue obesity in young adults with T1D and overweight/obesity.

The focus of this registration is the primary objective.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rehema Mtawali; Phone Number: (475) 414-4035; Email: rehema.mtawali@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale Pediatric Diabetes Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female, aged 18 to ≤30 years
• Diagnosed T1D for at least 12 months and with BMI <25 kg/m2.
• HbA1c ≤10%
• Clinical use of continuous glucose monitoring (CGM)

• Any known laboratory safety parameter consistently outside the below extended laboratory ranges in the past year:

  1. Baseline creatinine >1.0mg
  2. Hypertriglyceridemia (>400 mg/dl)
  3. ALT ≥3.5 times the upper normal limit (UNL)

Exclusion Criteria:

• Current use of adjunctive diabetes medication or anti-obesity medication
• Insulin dose <0.5 units/kg/day
• Use of lipid lowering prescription medication other than statins or omega-3 products
• Doesn't meet MRI safety criteria or having claustrophobia
• Known liver disease other than non-alcoholic steatosis or non-alcoholic fatty liver disease
• Known renal impairment
• Pregnancy or lactation, or planning to become pregnant during the study period.
• Anemia or known hematologic condition impacting HbA1c reading, or another medical condition that precludes participation.
• Treatment with another investigational drug within the past 1 month
• Past medical history of or self-reported corn allergy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Young adults with T1D who have a body mass index <25 kg/m2; Young adults with T1D who have a body mass index <25 kg/m2 will have: abdominal MRI, hyperinsulinemic-euglycemic clamp wtih stable isotope tracer, DEXA scan and a High Fat Mixed Meal Tolerance Test.

Biological: Hyperinsulinemic-euglycemic clamp; Hyperinsulinemic-euglycemic clamp will be used to assess insulin resistance. After IVs are placed, participants will be transitioned to intravenous insulin administration for the baseline portion of the study. Stable Isotope Tracer Infusions will assess rates of glucose, lipid metabolism, and beta-hydroxybutyrate turnover during the last 30 minutes of the baseline equilibration period and again during the last 30 minutes of the stepped IV insulin infusion periods.; Other: High Fat Mixed Meal Tolerance Test; After a 12 hour overnight fast, baseline levels of the lipoproteins will be drawn. The YCCI Bionutrition Service kitchen will prepare the standardized high-fat meal. Participants will administer their bolus insulin per their home regimen for the carbohydrates in the high-fat meal, and then they will consume the meal within a 15-minute timeframe.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in VAT/(VAT+SAT) from baseline to 1 year	Measured as VAT/Subcutaneous Adipose Tissue + VAT changes over 1 year in young adults with T1D and body mass index <25kg/m2.	baseline and 1 year
Change in hepatic insulin resistance from baseline to 1 year	Hepatic insulin resistance, measured by beta-hydroxybutyrate (surrogate marker of acetyl-CoA, which regulates gluconeogenesis), changes over 1 year in young adults with T1D and body mass index <25kg/m2.	baseline and 1 year
Change in triglycerides from baseline to 1 year	Change in triglycerides after a high-fat mixed meal tolerance test, expressed as the total Area Under the Curve (AUCTG) over 6 hours from baseline to 1 year.	baseline and 1 year

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Michelle Van Name, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2023
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: October 23, 2023
• First Submitted That Met QC Criteria: October 23, 2023
• First Posted (Actual): October 30, 2023

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: 2000036125; 1R01DK134398-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: No