Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)
Condition: Type 1 Diabetes Mellitus; Maturity-Onset Diabetes of the Young, Type 2; MODY2; Insulin Resistance
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Resistance; Hyperglycemia; Hyperinsulinism; Diabetes Mellitus, Type 2
Intervention: Hyperinsulinemic, euglycemic clamp; 20% dextrose
Intervention 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 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.
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 33.0
Sex: All
Minimum age: 13 Years
Maximum age: 51 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: o-glcnacylation; hexosamine

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.
    

Eligibility 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