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
Study type: Interventional
Phase: Phase 1

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).
    

Intervention name(s): Hyperinsulinemic, euglycemic clamp; 20% dextrose
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Other intervention name(s): glucose clamp; pancreatic clamp
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: o-glcnacylation; hexosamine