Adiposity, Type1 Diabetes Mellitus
Conditions
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.
Interventions
PROCEDUREEuglycemic 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.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 24 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
One participant enrolled but did not have any baseline or study data obtained due to scheduling conflicts.
Participants by arm
| Arm | Count |
|---|---|
| Adolescent Typical Weight Adolescents with T1D and body mass index \<75% will undergo a euglycemic hyperinsulinemic clamp with tracer enhancement.
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. | 7 |
| Adolescent Overweight/Obese Adolescents with T1D and body mass index ≥85% will undergo a euglycemic hyperinsulinemic clamp with tracer enhancement.
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. | 13 |
| Young Adult Young Adults with T1D and body mass index 18.5 to \<25 kg/m2 will undergo a euglycemic hyperinsulinemic clamp with tracer enhancement. | 2 |
| Total | 22 |
Baseline characteristics
| Characteristic | Adolescent Typical Weight | Adolescent Overweight/Obese | Young Adult | Total |
|---|---|---|---|---|
| Age, Continuous | 14.3 years STANDARD_DEVIATION 1.11 | 14.5 years STANDARD_DEVIATION 1.19 | 20.65 years STANDARD_DEVIATION 2.48 | 15.57 years STANDARD_DEVIATION 2.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 11 Participants | 2 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| percentage of glycated hemoglobin | 7.32 percentage STANDARD_DEVIATION 0.6 | 7.74 percentage STANDARD_DEVIATION 0.41 | 6.35 percentage STANDARD_DEVIATION 0.49 | 7.48 percentage STANDARD_DEVIATION 0.62 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 11 Participants | 2 Participants | 20 Participants |
| Region of Enrollment United States | 7 participants | 13 participants | 2 participants | 22 participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 0 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 7 | 0 / 2 |
| other Total, other adverse events | 0 / 13 | 0 / 7 | 0 / 2 |
| serious Total, serious adverse events | 0 / 13 | 0 / 7 | 0 / 2 |
Outcome results
Primary
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
Population: Only adolescents were analyzed due to the availability of data in the aftermath of the COVID shutdown- data were not collected on the young adult group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adolescent Overweight | Hepatic Sensitivity to Low Dose Insulin | -27.9 percentage of suppression of Ra glucose | Standard Deviation 25.8 |
| Adolescent Typical | Hepatic Sensitivity to Low Dose Insulin | -35.8 percentage of suppression of Ra glucose | Standard Deviation 15.3 |
p-value: 0.466t-test, 2 sided
Primary
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.
Time frame: 240 minutes
Population: Only adolescents were analyzed due to the availability of data in the aftermath of the COVID shutdown- data were not collected on the young adult group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adolescent Overweight | Peripheral Sensitivity to High Dose Insulin | -75.99 percentage of suppression of Ra glucose | Standard Deviation 58.8 |
| Adolescent Typical | Peripheral Sensitivity to High Dose Insulin | -96.48 percentage of suppression of Ra glucose | Standard Deviation 32.5 |
p-value: 0.414t-test, 2 sided
Primary
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
Population: Only adolescents were analyzed due to the availability of data in the aftermath of the COVID shutdown- data were not collected on the young adult group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adolescent Overweight | Rate of Glucose Metabolism | 1.74 mg/kg/min | Standard Deviation 0.77 |
| Adolescent Typical | Rate of Glucose Metabolism | 1.56 mg/kg/min | Standard Deviation 0.41 |
p-value: 0.525t-test, 2 sided
Primary
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
Population: Only adolescents were analyzed due to the availability of data in the aftermath of the COVID shutdown- data were not collected on the young adult group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adolescent Overweight | Rate of Lipid Metabolism | 0.099 mg/kg/min | Standard Deviation 0.077 |
| Adolescent Typical | Rate of Lipid Metabolism | 0.12 mg/kg/min | Standard Deviation 0.099 |
p-value: 0.607t-test, 2 sided