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Type 1 Diabetes MellitusPhase 1NCT02971202

Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)

A Phase 1 study testing Hyperinsulinemic, euglycemic clamp and 20% dextrose in people with Type 1 Diabetes Mellitus and Maturity-Onset Diabetes of the Young, Type 2, run by Vanderbilt University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 13 to 51 yearsHealthy volunteers can take part
What is being tested?
Hyperinsulinemic, euglycemic clamp and 20% dextrose
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
33 participants
Where
1 siteUnited States
Study dates
Dec 2016to Feb 2019
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 13 to 51 years
  • All sexes
  • Healthy volunteers accepted
  • Child, Adult

Who may be able to join

  • 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:
Show all 12Show fewer
  • 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%

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

Other trials in United States

About this study

Official title: A Novel Cross-sectional Analysis of Insulin Sensitivity Among Adolescents and Young Adults With Type 1 Diabetes, MODY2, and Normal Controls: the Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance

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.

Read the 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:

  1. non-diabetic control subjects,
  2. patients with well controlled T1DM, and
  3. 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).

Being tested
Hyperinsulinemic, euglycemic clamp, 20% dextrose
Keywords
o-glcnacylation, hexosamine
Medical subject headings
Diabetes Mellitus, Type 1, Maturity-Onset Diabetes of the Young, Type 2, Insulin Resistance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Hyperinsulinemic, euglycemic clampDrug

    Also called glucose clamp, pancreatic 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.
  • 20% dextroseDrug

    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.

Study groups in NCT02971202
Study groupRoleWhat they receive
Hyperinsulinemic, euglycemic clamp: T1DMOtherParticipants 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.
Receives: Drug: Hyperinsulinemic, euglycemic clamp; Drug: 20% dextrose
Hyperinsulinemic, euglycemic clamp:MODY2OtherParticipants 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.
Receives: Drug: Hyperinsulinemic, euglycemic clamp; Drug: 20% dextrose
Hyperinsulinemic euglycemic clamp:ControlOtherParticipants 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.
Receives: Drug: Hyperinsulinemic, euglycemic clamp; Drug: 20% dextrose

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Whole-body Glucose Utilization (Rd)

    The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts.

    Measured: End of clamp study (the study will last 8 hours)

Secondary outcomes (2)
  1. Hepatic Insulin Sensitivity

    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.

    Measured: 4 1/2 hours into clamp study

  2. Adipose Tissue Insulin Sensitivity

    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.

    Measured: 4 1/2 hours into clamp study

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Nov 2016 (estimated)
  2. Study startDec 2016
  3. Primary completionFeb 2019
  4. Study completionFeb 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
33 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02971202
Sponsor's protocol ID
161504
Status last verified
Jul 2019
First submitted
27 Oct 2016
Last updated
1 Aug 2019
Data monitoring committee
Yes
Individual data sharing
Yes: The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. No applicable resources were generated or analyzed during the current study.

Publications

  • Gregory JM, Smith TJ, Slaughter JC, Mason HR, Hughey CC, Smith MS, Kandasamy B, Greeley SAW, Philipson LH, Naylor RN, Letourneau LR, Abumrad NN, Cherrington AD, Moore DJ. Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2). Diabetes. 2019 Aug;68(8):1565-1576. doi: 10.2337/db19-0324. Epub 2019 May 15.

    PubMed 31092478

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Hyperinsulinemic, euglycemic clamp and 20% dextrose in people with Type 1 Diabetes Mellitus and Maturity-Onset Diabetes of the Young, Type 2, run by Vanderbilt University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Whole-body Glucose Utilization (Rd) (time frame: End of clamp study (the study will last 8 hours)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02971202, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2019.

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