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

Not Applicable

Terminated

• Conditions: Adiposity; Type1 Diabetes Mellitus
• Interventions: Procedure: Euglycemic hyperinsulinemic clamp with tracer enhancement

• Registration Number: NCT03582956
• Lead Sponsor: Yale University

Brief Summary

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

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 Timeline

• Study First Submitted: 2018-06-15
• Study First Submitted QC: 2018-06-27
• Study First Posted: 2018-07-11
• Study Start: 2019-01-01
• Primary Completion: 2022-08-12
• Study Completion: 2022-08-12
• Disposition First Submitted: 2023-04-06
• Disposition First Posted: 2023-04-27
• Results First Submitted: 2023-08-14
• Status Verified: 2024-03
• Results First Submitted QC: 2024-03-05
• Last Update Submitted: 2024-03-05
• Results First Posted: 2024-04-03
• Last Update Posted: 2024-04-03

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 23

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Adolescent Typical	Euglycemic hyperinsulinemic clamp with tracer enhancement	Lean adolescents with T1D
Adolescent Overweight	Euglycemic hyperinsulinemic clamp with tracer enhancement	Adolescents with T1D and overweight/obesity
Young Adult	Euglycemic hyperinsulinemic clamp with tracer enhancement	Young adults with T1D with a euglycemic hyperinsulinemic clamp with tracer enhancement

Primary Outcome Measures

Name	Time	Method
Rate of Glucose Metabolism	120 minutes	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.
Rate of Lipid Metabolism	120 minutes	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.
Hepatic Sensitivity to Low Dose Insulin	120 minutes	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.
Peripheral Sensitivity to High Dose Insulin	240 minutes	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.

Trial Locations

Locations (1)

Yale Pediatric Diabetes Research Program; 🇺🇸 New Haven, Connecticut, United States