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

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).

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