Effect of Adiposity on Hepatic and Peripheral Insulin Resistance in Type 1 Diabetes (T1D)

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.

Study Overview

• Status: Terminated
• Conditions: Adiposity; Type1 Diabetes Mellitus
• Intervention / Treatment: Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement; Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Michelle Van Name, MD; Phone Number: 475-774-2386; Email: michelle.vanname@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale Pediatric Diabetes Research Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 24 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• All Participants:

  1. Clinical diagnosis of T1D
  2. HbA1c ≤9%
  3. Diabetes duration of at least 12 months

Adolescents with T1D:

1. Age 12-16 years
2. BMI <75th for lean pediatric subjects, > 85th percentile for overweight/obese pediatric subjects;
3. Tanner stage 2-5
4. Parent able to provide written consent and participant able to provide assent
5. Not meeting MRI safety criteria
6. Claustrophobia that will prevent participation in the MRI

Lean, young adults with T1D:

1. Age 18-24 years
2. BMI 18.5-24.9 kg/m2
3. Able to provide written consent.

Exclusion Criteria:

1. Use of adjunctive diabetes medications
2. Weight loss medications within the past six months
3. Current psychiatric disorders, including eating disorders (DSM-V criteria)
4. Known liver disease other than nonalcoholic hepatic steatosis
5. Females who are pregnant or lactating
6. Anemia or another medical condition that precludes participation in the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Adolescent Overweight; Adolescents with T1D and overweight/obesity	Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement; To characterize the impact of adiposity on metabolism during puberty, adolescents will undergo the euglycemic hyperinsulinemic clamp study with tracer enhancement.; Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement; 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.
Other: Adolescent Typical; Lean adolescents with T1D	Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement; To characterize the impact of adiposity on metabolism during puberty, adolescents will undergo the euglycemic hyperinsulinemic clamp study with tracer enhancement.; Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement; 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.
Other: Young Adult; Young adults with T1D with a euglycemic hyperinsulinemic clamp with tracer enhancement	Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement; To characterize the impact of adiposity on metabolism during puberty, adolescents will undergo the euglycemic hyperinsulinemic clamp study with tracer enhancement.; Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Glucose Metabolism	Insulin function will be measured using a euglycemic hyperinsulinemic clamp procedure. A clamp measures insulin sensitivity. During the low does insulin phase, this reflects hepatic glucose metabolism, which is reported here. A higher glucose infusion rate number indicates more sensitivity to insulin; a lower number means more resistance to insulin.	120 minutes
Rate of Lipid Metabolism	Insulin function will be measured using a euglycemic hyperinsulinemic clamp procedure. A clamp measures insulin sensitivity. During the low dose insulin phase, glycerol turnover (rate of appearance) can reflect adipose specific insulin sensitivity, which is reported here. Insulin should suppress glycerol turnover. A higher number reflects more resistance to insulin; a lower number means more sensitivity to insulin.	120 minutes
Hepatic Sensitivity to Low Dose Insulin	Insulin function will be measured using a euglycemic hyperinsulinemic clamp procedure. A clamp measures insulin sensitivity. Insulin should suppress glucose production. Change of the glucose rate of appearance (which is reported here, and the glucose rate of appearance is measured here utilizing isotopic enrichment) during the low dose insulin phase reflects hepatic sensitivity to insulin. A greater degree of decline reflects more sensitivity to insulin; a smaller number means more resistance to insulin. This is calculated as the low dose insulin phase glucose rate of appearance minus the baseline phase glucose rate of appearance, divided by the basal phase glucose rate of appearance and multiplied x 100.	120 minutes
Peripheral Sensitivity to High Dose Insulin	Insulin function will be measured using a euglycemic hyperinsulinemic clamp procedure. A clamp measures insulin sensitivity. Insulin should suppress glucose production. Change of the glucose rate of appearance (which is reported here, and the glucose rate of appearance is measured here utilizing isotopic enrichment) during the high dose phase reflects peripheral sensitivity to insulin. A greater degree of decline reflects more sensitivity to insulin; a smaller number means more resistance to insulin. This is calculated as the high dose insulin phase glucose rate of appearance minus the baseline phase glucose rate of appearance, divided by the basal phase glucose rate of appearance and multiplied x 100.	240 minutes

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): January 1, 2019
• Primary Completion (Actual): August 12, 2022
• Study Completion (Actual): August 12, 2022

Study Registration Dates

• First Submitted: June 15, 2018
• First Submitted That Met QC Criteria: June 27, 2018
• First Posted (Actual): July 11, 2018

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: March 5, 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; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 1; Obesity; Insulin Resistance
• Other Study ID Numbers: 2000023149; 1K23DK115894-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes