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

Yale University23 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

Conditions

Type1 Diabetes Mellitus Adiposity

Interventions

Euglycemic hyperinsulinemic clamp with tracer enhancementPROCEDURE

To characterize the impact of adiposity on metabolism during puberty, adolescents will undergo the euglycemic hyperinsulinemic clamp study with tracer enhancement.

Euglycemic hyperinsulinemic clamp with tracer enhancementPROCEDURE

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.

Eligibility

Sex: ALLMin age: 12 YearsMax age: 24 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Yale Pediatric Diabetes Research Program

New Haven, Connecticut, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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