IGF-I Induced Muscle Glucose Uptake and Interstitial IGF-I Concentrations
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      Hormonal disturbances in the GH-IGF-I axis are considered important for the deterioration of
      glycemic control in T1DM particularly in adolescents. In addition it may have direct
      implications on the development of insulin resistance and long-term complications.

      The Investigators hypothesis is that low circulating IGF-I and compensatory hyper-secretion
      of GH, in the presence of peripheral insulin excess, results in increased local IGF-I
      expression explaining both the deterioration in metabolic control and the increased risk for
      microvascular complications. Correction of imbalance in circulating and tissue-specific
      levels of IGF-I could lead to both better early metabolic control and to prevention of early
      diabetic complications in type 1 diabetic (T1DM) patients.

      Aim of the present study is to validate the microdialysis technique as a useable tool to
      predict local biological effects of IGF-1 and to understand the pharmacokinetics of local
      IGF-I actions after sc injection of Increlex in type 1 diabetic patients.
    

Detailed description: 
      Background:

      In healthy subjects, the liver extracts approximately 50 % of insulin. Therefore insulin
      given subcutaneously results in a relative insulin deficiency in the portal circulation of
      the liver, and a relative insulin excess in peripheral tissues. In comparison, normal
      physiological delivery of insulin from the pancreas to the portal circulation, results in
      markedly higher hepatic insulin exposure. The importance of hepatic insulin exposure for GH
      induced IGF-I synthesis comes from studies demonstrating that circulating IGF-I levels can be
      normalized by direct portal insulin infusion (1) or nearly normalized with intra-peritoneal
      insulin delivery (2). Approximately 80 % of circulating IGF-I is liver derived. Whether the
      GH induction of IGF-I production in other tissues such as fat, muscle and the growth plate is
      also insulin dependent has not been studied in humans. While locally produced IGF-I is
      important for linear growth, circulating IGF-I is essential for insulin sensitivity (3).
      Portal insulin deficiency results in uncoupling of GH induced IGF-I synthesis and subnormal
      circulating IGF-I levels in T1DM children with conventional therapy (4).

      In newly diagnosed T1DM subcutaneous insulin treatment increases circulating IGF-I (5). The
      beneficial effects of 12 weeks adjuvant IGF-I treatment on metabolic control was demonstrated
      in conventionally insulin treated T1DM adolescents (6). There is also strong evidence for the
      role of IGF-I in the pathogenesis of diabetic kidney disease, atherosclerosis and
      proliferative retinopathy (7, 8, 9).

      Interestingly, recent reports suggest an important role of IGF-I in stimulating beta cell
      regeneration (10). Thus a role for improvement of IGF-I in prolonging endogenous insulin
      secretion in the early phase of T1DM disease appears promising.

      The Investigators have previously developed a microdialysis approach to measure local IGF-I
      protein levels from the human muscle tissue. The Investigators were in that study able to
      show that exercise increases local IGF-I levels. (11, 12) However, no further analysis
      concerning tissue-specific glucose metabolism was performed.

      The Investigators hypothesis is that low circulating IGF-I and compensatory hyper-secretion
      of GH, in the presence of peripheral insulin excess, results in increased local IGF-I
      expression explaining both the deterioration in metabolic control and the increased risk for
      microvascular complications.

      In conclusion, correction of imbalance in circulating and tissue-specific levels of IGF-I
      could lead to both better early metabolic control and to prevention of early diabetic
      complications in type 1 diabetic (T1DM) patients.

      Study Design:

      This is a placebo controlled crossover study of the effect of sc IGF-1 (Increlex)
      administration on glucose infusion rate (whole body glucose utilization) and interstitial
      muscle IGF-1 concentrations under euglycemic clamp conditions in T1DM adolescents and young
      adults (18-23 y of age). Each subject is studied twice and randomized to receive IGF-1 (120
      μg/ kg, Increlex®, Ipsen) or placebo. Glucose control is optimized by CSII (Continuous
      Subcutaneus Insulin Infusion) for 2 days and subjects are studied after an overnight fast
      using a constant low rate insulin infusion to block hepatic glucose production. After a
      single s.c. bolus of IGF-1, the effects of IGF-1 on the peripheral glucose disposal rate will
      be assessed based on the rate of a variable glucose infusion. Local muscle IGF-1 measured by
      microdialysis will be related to the peripheral glucose disposal rate (mainly determined by
      muscle glucose uptake). Patients with T1DM will be studied for several reasons: 1) They are a
      target group for long term treatment, 2) They are IGF-I deficient and thus more likely to
      have a significant effect of sc IGF-I injections, 3) muscle levels may or may not be low.

      The following assessments will be performed:

        -  Height & Weight

        -  Glucose utilization rate (normoinsulinemic, euglycemic clamp)

        -  Blood parameters: P-glucose, Growth Hormone (GH), IGF-1, Insulin Like Growth Factor
           Binding Proteins 1-3 (IGFBP1-3) and Glucagon

        -  Microdialysis IGF-1
    

Intervention name(s): Increlex; 0.9% Saline
Intervention type(s): Drug; Drug
Intervention description(s): Increlex 120 micrograms/kg body weight single subcutaneous injection; Placebo (0,1 ml of 0.9% Saline) single subcutaneous injection
Intervention MeSH terms: Mecasermin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science