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

NCT04362917 | Completed DMC

• 1 other identifier: T1DFam
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Type 1 Diabetes

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Measurement of beta cell function during of Second Phase of the first clamp procedure

  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 Outcomes (3)

• Measurement of the Unmethylated and methylated DNA as this is a marker of beta cell death

  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)

  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

  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.

Study Arms (3)

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

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

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

Interventions

There is no intervention OTHER

There is no intervention

Control; FDR+; FDR-

Eligibility Criteria

• Age: 12 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Comparing a population at risk for T1D to healthy controls.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Indiana University: lead
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (1)

Indiana University

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Emily Sims

  Indiana University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Pediatrics

Study Record Dates

• First Submitted: February 19, 2020
• First Posted: April 27, 2020
• Study Start: November 14, 2017
• Primary Completion: August 27, 2021
• Study Completion: August 27, 2021
• Last Updated: March 16, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)