Effect of Adiposity on Hepatic and Peripheral Insulin Resistance in Type 1 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to assess the effects of adiposity on resistance to insulin's ability to suppress hepatic glucose production and to stimulate peripheral glucose metabolism in adolescents with type 1 diabetes. In addition, this study will also examine the role of fatty liver disease on the insulin resistance of obesity in adolescents with type 1 diabetes.

Detailed Description
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A major focus of this program of research will be directed at advancing the understanding of the metabolic consequences of obesity and puberty in adolescents with T1D. Thus, an innovative aspect of this research is that it will be the first to use these sophisticated metabolic techniques to examine the effects of obesity and hepatic steatosis on insulin sensitivity in pubertal adolescents with T1D; namely, the 2-step hyperinsulinemic euglycemic clamp with tracer enhancement, which will allow for definition of hepatic and peripheral insulin resistance, glycerol turnover, and glucose and fat oxidation. Further, a second novel aspect is that this will be the first study to utilize gold standard MRI methods to quantify and compare intrahepatic fat content in lean and obese adolescents with T1D. This will allow a global and more detailed understanding of the potential alterations of insulin's effects on key insulin sensitive tissues in youth that are impacted by both T1D and obesity. Furthermore, evaluation of biomarkers for insulin resistance and fatty liver disease in this population will be performed for the first time.

Official Title
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Effect of Adiposity on Hepatic and Peripheral Insulin Resistance in Type 1 Diabetes

Conditions
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Type1 Diabetes Mellitus, Adiposity

Intervention / Treatment
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* Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement
* Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Participants: Clinical diagnosis of T1D HbA1c ≤9% Diabetes duration of at least 12 months Adolescents with T1D: Age 12-16 years BMI <75th for lean pediatric subjects, > 85th percentile for overweight/obese pediatric subjects; Tanner stage 2-5 Parent able to provide written consent and participant able to provide assent Not meeting MRI safety criteria Claustrophobia that will prevent participation in the MRI Lean, young adults with T1D: Age 18-24 years BMI 18.5-24.9 kg/m2 Able to provide written consent. Exclusion Criteria: Use of adjunctive diabetes medications Weight loss medications within the past six months Current psychiatric disorders, including eating disorders (DSM-V criteria) Known liver disease other than nonalcoholic hepatic steatosis Females who are pregnant or lactating Anemia or another medical condition that precludes participation in the study

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Adolescent Overweight<br>The study aims to enroll 36 adolescents with T1D and overweight/obesity, 36 lean adolescents with T1D, and 36 young adults with T1D that will receive a euglycemic hyperinsulinemic clamp with tracer enhancement. | Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement<br>* To characterize the impact of adiposity on metabolism during puberty, adolescents will undergo the euglycemic hyperinsulinemic clamp study with tracer enhancement.<br>|
| Other: Adolescent Typical<br>The study aims to enroll 36 adolescents with T1D and overweight/obesity, 36 lean adolescents with T1D, and 36 young adults with T1D a euglycemic hyperinsulinemic clamp with tracer enhancement. | Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement<br>* To characterize the impact of adiposity on metabolism during puberty, adolescents will undergo the euglycemic hyperinsulinemic clamp study with tracer enhancement.<br>|
| Other: Young Adult<br>The study aims to enroll 36 adolescents with T1D and overweight/obesity, 36 lean adolescents with T1D, and 36 young adults with T1D a euglycemic hyperinsulinemic clamp with tracer enhancement | Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement<br>* A comparison control group of 36 lean young adults with T1D will also be enrolled, since they will be unaffected by the adverse metabolic effects of puberty or obesity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Glucose Metabolism | euglycemic hyperinsulinemic clamp | 120 minutes | 
| Rate of Lipid Metabolism | euglycemic hyperinsulinemic clamp | 120 minutes | 
| Hepatic Sensitivity to Low Dose Insulin | euglycemic hyperinsulinemic clamp | 120 minutes | 
| Peripheral Sensitivity to High Dose Insulin | euglycemic hyperinsulinemic clamp | 120 minutes |