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

NCT ID: NCT02971202

Last Updated: 2019-08-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 33 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-31
• Study Completion Date: 2019-02-28

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.

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).

Conditions

Type 1 Diabetes Mellitus; Maturity-Onset Diabetes of the Young, Type 2; MODY2; Insulin Resistance

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: OTHER

Hyperinsulinemic, euglycemic clamp

Intervention Type: DRUG

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% dextrose

Intervention Type: DRUG

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.

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.

Group Type: OTHER

Hyperinsulinemic, euglycemic clamp

Intervention Type: DRUG

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% dextrose

Intervention Type: DRUG

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.

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.

Group Type: OTHER

Hyperinsulinemic, euglycemic clamp

Intervention Type: DRUG

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% dextrose

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

glucose clamp; pancreatic clamp

Eligibility Criteria

Inclusion Criteria

• BMI 19-28 kg/m^2

• Age 13-51
• T1DM duration 1-20 years
• HbA1c 5.9-8.0%

• age 13-51
• positive GCK genetic sequencing
• HbA1c 5.9-8.0%

• age 18-5.1
• HbA1c < 5.5%

Exclusion Criteria

• 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

• any diabetes medication except insulin
• fasting c-peptide > 0.7 ng/mL

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 51 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Justin Gregory

Assistant Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Justin M Gregory, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University School of Medicine

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31092478 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

161504

Identifier Type: -

Identifier Source: org_study_id