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

NCT02971202 | Completed Phase 1 Results DMC

• 1 other identifier: 161504
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

o-glcnacylation; hexosamine

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (2)

• Hepatic Insulin Sensitivity

  4 1/2 hours into clamp study

• Adipose Tissue Insulin Sensitivity

  4 1/2 hours into clamp study

Study Arms (3)

Hyperinsulinemic, euglycemic clamp: T1DM

OTHER

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; Drug: 20% dextrose

Hyperinsulinemic, euglycemic clamp:MODY2

OTHER

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; Drug: 20% dextrose

Hyperinsulinemic euglycemic clamp:Control

OTHER

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; Drug: 20% dextrose

Interventions

Hyperinsulinemic, euglycemic clamp 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.

Also known as: glucose clamp, pancreatic clamp

Hyperinsulinemic euglycemic clamp:Control; Hyperinsulinemic, euglycemic clamp: T1DM; Hyperinsulinemic, euglycemic clamp:MODY2

20% dextrose 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; Hyperinsulinemic, euglycemic clamp: T1DM; Hyperinsulinemic, euglycemic clamp:MODY2

Eligibility Criteria

• Age: 13 Years - 51 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• \- 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%

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• 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.

  PMID: 31092478 DERIVED

MeSH Terms

Conditions

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

Interventions

Glucose Clamp Technique; Glucose

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Chemistry Techniques, Analytical; Investigative Techniques; Hexoses; Monosaccharides; Sugars; Carbohydrates

Results Point of Contact

• Title: Justin M. Gregory MD MSCI
• Organization: Vanderbilt University Medical Center

justin.m.gregory.1@vumc.org

615-875-9669

Study Officials

• Justin M Gregory, MD

  Vanderbilt University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Pediatrics

Study Record Dates

• First Submitted: October 27, 2016
• First Posted: November 22, 2016
• Study Start: December 1, 2016
• Primary Completion: February 1, 2019
• Study Completion: February 1, 2019
• Last Updated: August 1, 2019
• Results First Posted: August 1, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR

Locations

US (1)