Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)
Study Details
Study Description
Brief Summary
The purpose of this study is to determine the key factors influencing insulin sensitivity in type 1 diabetes (T1DM) and maturity onset diabetes of the young, type 2 (MODY2).
Our study tests the hypothesis that decreased insulin sensitivity is primarily driven by chronically elevated insulin levels in the blood rather than chronic elevations in blood sugar.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This research will determine whether insulin resistance (IR) in T1DM is predominantly an effect of chronic hyperglycemia, as is commonly accepted, or a consequence of iatrogenic hyperinsulinemia in the peripheral circulation, as alternatively hypothesized. IR is a consistent but under-recognized finding in T1DM. Despite its independent contribution to micro- and macrovascular disease, its underlying cause has not been established nor have strategies to mitigate it been developed. This research will also characterize IR in maturity onset diabetes of the young, type 2 (MODY2), a population for whom IR has been inadequately studied to date.
Insulin therapy in T1DM attempts to achieve euglycemia but does so in an "unphysiologic" way, by delivering insulin into the subcutaneous tissue as compared to physiologic delivery directly into the hepatic portal circulation. Although life-saving, peripheral insulin delivery in T1DM results in a loss of the normal insulin distribution; the physiologic state maintains insulin at 3-fold higher concentrations in the portal circulation compared with the peripheral circulation. IR in T1DM could therefore occur in response to peripheral hyperinsulinemia, a mechanism that would protect against hypoglycemia and ensure adequate glucose delivery to the central nervous system.
MODY2 is a condition that results a mutation in the gene encoding glucokinase (GCK), which in turn causes a defect in β-cell sensitivity to glucose due to reduced glucose phosphorylation. This effectively raises the "set point" for insulin secretion in response to increased glycemia. Because MODY2 patients retain pancreatic insulin secretion, they usually require no insulin therapy and have a normal insulin distribution between the portal and peripheral circulations.
We therefore hypothesize that IR in T1DM 1) is a homeostatic response to increased peripheral insulin concentrations resulting from peripheral insulin delivery and not significantly attributable to hyperglycemia and 2) results primarily from peripheral tissue IR (especially muscle) and not primarily from hepatic IR. Further, we anticipate that patients with MODY2, a population that has hyperglycemia without hyperinsulinemia, will have insulin sensitivity similar to that of otherwise healthy, nondiabetic individuals.
To test this hypothesis, the hyperinsulinemic, euglycemic clamp will be used to assess IR in a cross-sectional study of 3 groups of subjects:
-
non-diabetic control subjects,
-
patients with well controlled T1DM, and
-
patients with MODY2
Key metabolic differences between these 3 groups will enable us to parse out the relative contributions of peripheral hyperinsulinemia vs. hyperglycemia to IR in T1DM and MODY2. Further, the proposed research will provide information on whether novel therapeutic strategies to restore the normal portal to peripheral insulin distribution can normalize insulin sensitivity (e.g. hepatopreferential insulin analogs, intraperitoneal insulin delivery).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Hyperinsulinemic, euglycemic clamp: T1DM Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. |
Drug: Hyperinsulinemic, euglycemic clamp
Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
Other Names:
Drug: 20% dextrose
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.
|
| Other: Hyperinsulinemic, euglycemic clamp:MODY2 Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. |
Drug: Hyperinsulinemic, euglycemic clamp
Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
Other Names:
Drug: 20% dextrose
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.
|
| Other: Hyperinsulinemic euglycemic clamp:Control Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. |
Drug: Hyperinsulinemic, euglycemic clamp
Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
Other Names:
Drug: 20% dextrose
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.
|
Outcome Measures
Primary Outcome Measures
- Whole-body Glucose Utilization (Rd) [End of clamp study (the study will last 8 hours)]
The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts.
Secondary Outcome Measures
- Hepatic Insulin Sensitivity [4 1/2 hours into clamp study]
Glucose production (Ra) will be determined using stable isotopic tracer techniques. The extent to which Ra is suppressed at the end of 4 1/2 hours (when glucose Ra by liver has been submaximally suppressed) compared to basal (ΔRa) is directly proportional to hepatic insulin sensitivity.
- Adipose Tissue Insulin Sensitivity [4 1/2 hours into clamp study]
Insulin sensitivity at fat is directly proportional to insulin's ability to suppress lipolysis. Thus, we will determine the extent to which submaximal insulin stimulation (4 1/2 hours into the study) suppresses glycerol and non-esterified free fatty acids (NEFAs) compared to baseline. The extent to which these two metabolites are suppressed is directly proportional to insulin sensitivity in adipose tissue. Here the suppression of NEFA is taken as the secondary outcome parameter.
Eligibility Criteria
Criteria
Inclusion Criteria:
Inclusion criteria for all subjects:
- BMI 19-28 kg/m^2
Additional inclusion criteria for T1DM subjects:
-
Age 13-51
-
T1DM duration 1-20 years
-
HbA1c 5.9-8.0%
Additional inclusion criteria for MODY2 subjects:
-
age 13-51
-
positive GCK genetic sequencing
-
HbA1c 5.9-8.0%
Additional inclusion criteria for control subjects:
-
age 18-5.1
-
HbA1c < 5.5%
Exclusion Criteria:
Exclusion criteria for all subjects:
-
severe hypoglycemia (>= 1 episode in the past 3 months or diagnosis of hypoglycemia unawareness)
-
diabetes comorbidities (>= 1 trip to emergency department for poor glucose control in the past 6 months, New York Heart Association Class II-IV cardiac functional status, systolic blood pressure > 140 and diastolic blood pressure > 100 mmHg, fasting triglycerides > 400 mg/dL, liver transaminases > 2 times the upper limit of normal, renal transplantation or serum creatinine > 1.5 mg/dL)
-
confounding medications (any systemic glucocorticoid, any antipsychotic, atenolol, metoprolol, propranolol, niacin, any thiazide diuretic, any oral contraceptive pill with > 35 mcg ethinyl estradiol, growth hormone, any immunosuppressant, any anti-hypertensive, any-antilipidemic)
-
pregnancy
-
Tanner stage < 5
Additional exclusion criteria for T1DM subjects
-
any diabetes medication except insulin
-
fasting c-peptide > 0.7 ng/mL
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Vanderbilt University Medical Center | Nashville | Tennessee | United States | 37232 |
Sponsors and Collaborators
- Vanderbilt University
Investigators
- Principal Investigator: Justin M Gregory, MD, Vanderbilt University School of Medicine
Study Documents (Full-Text)
More Information
Publications
None provided.- 161504
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control |
|---|---|---|---|
| Arm/Group Description | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. |
| Period Title: Overall Study | |||
| STARTED | 12 | 10 | 11 |
| Started Study | 11 | 10 | 10 |
| COMPLETED | 10 | 10 | 10 |
| NOT COMPLETED | 2 | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control | Total |
|---|---|---|---|---|
| Arm/Group Description | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Total of all reporting groups |
| Overall Participants | 12 | 10 | 11 | 33 |
| Age (Count of Participants) | ||||
| <=18 years |
1
8.3%
|
4
40%
|
0
0%
|
5
15.2%
|
| Between 18 and 65 years |
11
91.7%
|
6
60%
|
11
100%
|
28
84.8%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
7
58.3%
|
9
90%
|
8
72.7%
|
24
72.7%
|
| Male |
5
41.7%
|
1
10%
|
3
27.3%
|
9
27.3%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
12
100%
|
10
100%
|
11
100%
|
33
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
1
9.1%
|
1
3%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| More than one race |
0
0%
|
0
0%
|
1
9.1%
|
1
3%
|
| Unknown or Not Reported |
12
100%
|
10
100%
|
9
81.8%
|
31
93.9%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
12
100%
|
10
100%
|
11
100%
|
33
100%
|
Outcome Measures
| Title | Whole-body Glucose Utilization (Rd) |
|---|---|
| Description | The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts. |
| Time Frame | End of clamp study (the study will last 8 hours) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control |
|---|---|---|---|
| Arm/Group Description | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. |
| Measure Participants | 10 | 10 | 10 |
| Mean (95% Confidence Interval) [mg/kg FFM/min] |
8.5
|
11.0
|
12.1
|
| Title | Hepatic Insulin Sensitivity |
|---|---|
| Description | Glucose production (Ra) will be determined using stable isotopic tracer techniques. The extent to which Ra is suppressed at the end of 4 1/2 hours (when glucose Ra by liver has been submaximally suppressed) compared to basal (ΔRa) is directly proportional to hepatic insulin sensitivity. |
| Time Frame | 4 1/2 hours into clamp study |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control |
|---|---|---|---|
| Arm/Group Description | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. |
| Measure Participants | 10 | 10 | 10 |
| Mean (95% Confidence Interval) [mg/kg FFM/min] |
1.9
|
2.1
|
1.7
|
| Title | Adipose Tissue Insulin Sensitivity |
|---|---|
| Description | Insulin sensitivity at fat is directly proportional to insulin's ability to suppress lipolysis. Thus, we will determine the extent to which submaximal insulin stimulation (4 1/2 hours into the study) suppresses glycerol and non-esterified free fatty acids (NEFAs) compared to baseline. The extent to which these two metabolites are suppressed is directly proportional to insulin sensitivity in adipose tissue. Here the suppression of NEFA is taken as the secondary outcome parameter. |
| Time Frame | 4 1/2 hours into clamp study |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control |
|---|---|---|---|
| Arm/Group Description | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. |
| Measure Participants | 10 | 10 | 10 |
| Mean (95% Confidence Interval) [μmol/L] |
122.4
|
382.3
|
392.7
|
Adverse Events
| Time Frame | 1 week | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | per protocol, hyperglycemia and hypoglycemia are not considered adverse events unless serious | |||||
| Arm/Group Title | Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control | |||
| Arm/Group Description | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes) glucagon (0.65 ng/kg/min [1x basal] for 330 minutes) somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts. A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study. | |||
All Cause Mortality |
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| Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/10 (0%) | 0/11 (0%) | |||
Serious Adverse Events |
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| Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/10 (0%) | 0/11 (0%) | |||
Other (Not Including Serious) Adverse Events |
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| Hyperinsulinemic, Euglycemic Clamp: T1DM | Hyperinsulinemic, Euglycemic Clamp:MODY2 | Hyperinsulinemic Euglycemic Clamp:Control | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/12 (33.3%) | 3/10 (30%) | 3/11 (27.3%) | |||
| Cardiac disorders | ||||||
| hypotension | 2/12 (16.7%) | 2 | 0/10 (0%) | 0 | 0/11 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| nausea and vomiting | 1/12 (8.3%) | 1 | 1/10 (10%) | 1 | 1/11 (9.1%) | 1 |
| General disorders | ||||||
| IV site pain | 0/12 (0%) | 0 | 1/10 (10%) | 1 | 2/11 (18.2%) | 2 |
| Nervous system disorders | ||||||
| Vasovagal Response | 1/12 (8.3%) | 1 | 0/10 (0%) | 0 | 0/11 (0%) | 0 |
| headache | 2/12 (16.7%) | 2 | 2/10 (20%) | 2 | 1/11 (9.1%) | 1 |
| Surgical and medical procedures | ||||||
| Swelling at biopsy site | 0/12 (0%) | 0 | 0/10 (0%) | 0 | 2/11 (18.2%) | 2 |
| Redness at biopsy site | 0/12 (0%) | 0 | 0/10 (0%) | 0 | 2/11 (18.2%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Justin M. Gregory MD MSCI |
|---|---|
| Organization | Vanderbilt University Medical Center |
| Phone | 615-875-9669 |
| justin.m.gregory.1@vumc.org |
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