Insulin-Glucose-Glucagon Network: Defining a Type 1 Diabetes Progression Index

The type 1 Diabetes (T1D) TrialNet Pathway To Prevention (PTP) Study assesses and recruits at-risk subjects into clinical trials aimed at preventing the development of full blown T1D. Thousands of first and second degree relatives of persons with T1D are screened for autoimmune abnormalities and positive subjects are followed with metabolic and autoantibody tests. The investigators' ancillary study us designed to test whether characterization of the insulin- glucose-glucagon (IGG) interactions in participants in the PTP study can provide new information about the early stages of the disease. When completed, this study will improve the understanding of the pathogenesis of the early stages of T1D and provide new quantitative tools for prediction and evaluation of insulin-glucagon-glucose interactions relevant to individuals at risk for developing T1D, thereby enabling future preventive intervention trials.

The goal of the proposed ancillary studies is to establish whether characterization of the insulin-glucagon-glucose (IGG) interactions in first and second degree relatives of patients with type 1 diabetes (T1D) can provide new information about the pathogenesis, prediction, and progression of the early stages of the disease. The project will enroll individuals from the "Living Biobank" of the TrialNet Pathway to Prevention (PTP) study who are phenotyped with respect to a variety of risk factors, including immunological abnormalities. To the best of available knowledge, the IGG relationships in general and the glucagon phenotype in particular have not been studied in this population. It is known, however, that in T1D the release of glucagon is altered, which is manifested by abnormal postprandial suppression and defective response to hypoglycemia. Several reports indicate that glucagon becomes dysregulated prior to the development of T1D, but comprehensive studies aiming to understand in detail the insulin-glucagon co-dynamics in people at risk for T1D have never been performed. Thus, the goal now is to expand the investigators' existing methodology and transfer expertise in clinical testing and analysis of the IGG system to characterize the IGG interactions in individuals at risk for developing T1D.

Diabetes Mellitus, Type 1 (T1DM), TrialNet, Pathway to Prevention (PTP), First and second degree relatives of persons with T1DM, Insulin-glucagon-glucose (IGG), Immunological risk to develop T1DM

Subjects who are relatives of persons with T1DM and have tested negative for autoantibodies will have a Metabolic Challenge Admission followed by a CGM home test.

Subjects who are relatives of persons with T1DM and have tested positive for one autoantibody will have a Metabolic Challenge Admission followed by a CGM home test..

Subjects who are relatives of persons with T1DM and have tested positive for two or more autoantibodies will have a Metabolic Challenge Admission followed by a CGM home test..

A ten hour clinical test involving drinking a liquid mixed meal followed four hours later by the induction of hypoglycemia with intravenous insulin administration.

A home study starting immediately after the clinical test during which participants will wear a continuous glucose monitor (CGM) for one week.

Test the hypothesis that immunological abnormalities are associated with abnormally high glucagon responses to a meal and reduced glucagon responses to insulin induced hypoglycemia.

To address this aim, subjects in all three groups which are at different level of immunological risk to develop T1D will undergo a single 10-hour clinical test consisting of a mixed meal drink followed by insulin-induced hypoglycemia (Metabolic Challenge) to estimate their postprandial and counterregulatory glucagon responses.

Correlate metrics derived from a minimally-invasive Continuous Glucose Monitor (CGM) home test with glucagon responses to a meal and hypoglycemia measured in the hospital.

Subjects will undergo a CGM home test. They will wear a CGM for a week at home, keep a meal diary, and ingest a mixed meal of known amount with a subsequent collection of urine sample. A novel mathematical methodology will be used to extract from the field data estimates of the glucagon responses to a meal and to a decline in blood glucose levels. It will be then tested whether this estimates correlate to the glucagon responses measured in the hospital.

Inclusion Criteria: Individuals 12 to 45 years old which have a brother, sister, child, or parent with type 1 diabetes, or Individuals 12-20 years old who have have a cousin, aunt, uncle, niece, nephew, half-brother, half-sister, or grandparent with type 1 diabetes. Exclusion Criteria: Have diabetes already (type 1 or type 2) Have a medical condition or being been treated with medications that might interfere with the study