Identification of β Cell Dysfunction in Relatives of Individuals With Type 1 Diabetes Mellitus

Despite the valuable information derived from older studies evaluating type 1 diabetes, the diabetes research community has, in large part, overlooked potential contributions of baseline abnormalities in β cell function to T1D development. Newer studies focusing on higher risk individuals often exclude family members without evidence of positive islet autoantibodies. New technologies to assay alternative biomarkers of β cell stress and death remain incompletely explored in both Ab negative and Ab positive family members of T1D patients. Specifically, modern biomarkers of β cell dysfunction have not been rigorously tested in combination with metabolic testing to fully understand their association with insulin secretion.

The investigator's working hypothesis is that individuals at genetic risk for T1D exhibit baseline β cell dysfunction, even before development of detectable islet autoimmunity (seropositivity for islet Abs).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Other: There is no intervention

• Study Type: Observational
• Enrollment (Actual): 70

Contacts and Locations

• Study Contact: Name: Kelly Clinical Coordinator; Phone Number: 317.274.4135; Email: kmoors@iupui.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Comparing a population at risk for T1D to healthy controls.

Description

Inclusion criteria for each subject group* note age limits different for each group*:

• Nonrelative controls: Male and female adults 18-55 years old with no family history of Type 1 Diabetes, who have tested negative for glutamic acid decarboxylase, microinsulin, islet cell, islet antigen 2, and zinc transporter 8 autoantibodies
• Ab negative FDRs: Male and female adults 18-50 years old with a first degree relative (sibling, child, or parent) with T1D, who have tested negative for the above islet autoantibodies
• Ab + T1D Relatives: Male and females aged 12-50 years old with a first or second degree relative diagnosed with T1D, and testing positive for 1 of the above islet autoantibodies either at the screening visit, or through TrialNet screening obtained within the past 12 months.

Criteria for all subjects:

• BMI≤40 kg/m2 (If FDR is 40 kg/m2, the healthy control BMI can not exceed 45 kg/m2)
• HbA1c< 5.7%
• No medical history of diabetes.

Exclusion criteria for all participants:

• Any type of diabetes or hyperglycemia (HbA1c≥5.7%)
• Chronic illness or use of medications which interfere with glucose or islet hormone metabolism.
• Hemoglobin < 12 g/dL
• Presence of any psychiatric disorder that will affect the ability to participate in the study
• Pregnancy
• Severe milk or soy allergy that would disallow Boost® ingestion for MMTT
• Any condition that, in the judgment of the investigator, will adversely affect adequate participation in, or the safety or technical performance of the protocol.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
FDR-; Adults with a first degree relative with T1D, who have tested negative for islet autoantibodies. There is no intervention. Each group will get a MMTT and a clamp to evaluate beta cell function, identify elevations in circulating biomarkers of β cell stress or death, as well as their associations with measures of β cell function, and compare advantages of hyperglycemic clamps in identifying β cell dysfunction in this setting, relative to the mixed meal tolerance test (MMTT). They will repeat both the MMTT and the clamp once, to assess inter-test variability.	Other: There is no intervention; There is no intervention
FDR+; Adolescents and adults with a first or second degree relative with T1D, who has tested positive for at least one islet autoantibody. There is no intervention. Each group will get a MMTT and a clamp to evaluate beta cell function, identify elevations in circulating biomarkers of β cell stress or death, as well as their associations with measures of β cell function, and compare advantages of hyperglycemic clamps in identifying β cell dysfunction in this setting, relative to the mixed meal tolerance test (MMTT). They will repeat both the MMTT and the clamp once, to assess inter-test variability.	Other: There is no intervention; There is no intervention
Control; Adults with no family history of Type 1 Diabetes, who have tested negative for islet autoantibodies There is no intervention. Each group will get a MMTT and a clamp to evaluate beta cell function, identify elevations in circulating biomarkers of β cell stress or death, as well as their associations with measures of β cell function, and compare advantages of hyperglycemic clamps in identifying β cell dysfunction in this setting, relative to the mixed meal tolerance test (MMTT). They will repeat both the MMTT and the clamp once, to assess inter-test variability.	Other: There is no intervention; There is no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of beta cell function during the first phase of the first clamp procedure	Our primary outcome is to assess if there is a difference in first phase beta call function in those genetically at risk for developing type 1 diabetes (first degree relatives) but who are islet autoantibody negative versus healthy controls with no family history of type 1 diabetes. We will calculate the first phase beta cell function by multiplying the acute c-peptide response to glucose (ACPRg) (nmol/L) by the insulin sensitivity (M/I) (x10-5 mmol/kg/min per pmol/L)	The data for this analysis will come from cross-sectional samples collected through study completion, study completion will be on average 13-16 weeks from visit 1.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of beta cell function during of Second Phase of the first clamp procedure	Our secondary outcome is to assess if there is a difference in second phase beta cell function in those genetically at risk for developing type 1 diabetes (first degree relatives) but who are islet autoantibody negative versus healthy controls with no family history of type 1 diabetes. We will calculate the second phase beta cell function by averaging the C-peptide values collected during the steady state of the clamp (nmol*L) and multiplying by the insulin sensitivity (M/I) (x10-5 mmol/kg/min per pmol/L)	The data for this analysis will come from cross-sectional samples collected through study completion, study completion will be on average 13-16 weeks from visit 1.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of the Unmethylated and methylated DNA as this is a marker of beta cell death	Another prespecified outcome measure is to see if there is a difference in unmethylated/methylated INS DNA (which is a biomarker of beta cell death) in those genetically at risk for developing type 1 diabetes (first degree relatives) but who are islet autoantibody negative versus healthy controls with no family history of type 1 diabetes.	The data for this analysis will come from cross-sectional samples collected through study completion, study completion will be on average 13-16 weeks from visit 1.
Measurement of the Fasting Proinsulin to the C-peptide ratio (PI:C)	Another prespecified outcome measure is to see if there is a difference in the Proinsulin/C-peptide ratio (PI:C) in those genetically at risk for developing type 1 diabetes (first degree relatives) but who are islet autoantibody negative versus healthy controls with no family history of type 1 diabetes.	The data for this analysis will come from cross-sectional samples collected through study completion, study completion will be on average 13-16 weeks from visit 1.
Test-retest variability of the above mentioned variables (first phase, second phase, Unmethylated and methylated DNA, fasting PI:C	We will calculate the test-retest variability of the above mentioned variables (first phase, second phase, unmethylated/methylated DNA, fasting proinsulin/c-peptide), by looking at the between-visit coefficients of variation and intraclass correlations.	The data for this analysis will come from cross-sectional samples collected through study completion, study completion will be on average 13-16 weeks from visit 1.

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: Juvenile Diabetes Research Foundation
• Investigators: Principal Investigator: Emily Sims, Indiana University

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2017
• Primary Completion (Actual): August 27, 2021
• Study Completion (Actual): August 27, 2021

Study Registration Dates

• First Submitted: February 19, 2020
• First Submitted That Met QC Criteria: April 23, 2020
• First Posted (Actual): April 27, 2020

Study Record Updates

• Last Update Posted (Actual): March 16, 2023
• Last Update Submitted That Met QC Criteria: March 15, 2023
• Last Verified: March 1, 2023

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: T1DFam

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