Metabolic Signalling in Muscle- and Adipose-tissue Following Insulin Withdrawal and Growth Hormone Injection.
Condition: Diabetes Mellitus Type I; Ketoacidosis
MeSH terms: Diabetes Mellitus; Ketosis; Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      Diabetes mellitus type I (DM I) is characterized by lack of endogenous insulin and these
      patients are 100% dependent on insulin substitution to survive.

      Insulin is a potent anabolic hormone with its primary targets in the liver, the skeletal
      muscle-tissue and - adipose-tissue.

      Severe lack of insulin leads to elevated blood glucose levels, dehydration, electrolyte
      derangement, ketosis and thus eventually ketoacidosis.

      Insulin signalling pathways are well-known.

      Growth hormone (GH) is also a potent anabolic hormone, responsible for human growth and
      preservation of protein during fasting. GH (in concert with lack of insulin) induces
      lipolysis during fasting. It is not known how GH exerts its lipolytic actions.

      The aim is to define insulin and growth hormone (GH) signalling pathways in 3 different
      states in patients with DM I.

      And to test whether ATGL-related lipolysis in adipose tissue contributes to the development
      of ketosis.

        1. Good glycemic control

        2. Lack of insulin (ketosis/ketoacidosis)

        3. Good glycemic control and GH injection
    

Detailed description: 
      Diabetes mellitus type I (DMI ) is characterized by lack of endogenous insulin and these
      patients are 100% dependent on insulin substitution to survive.

      Insulin is a potent anabolic hormone with its primary targets in- the liver, -the skeletal
      muscle-tissue and - fat-tissue.

      In the liver it enhances glycogenesis and inhibits glycogenolysis and gluconeogenesis.

      In skeletal muscle-tissue, it enhances glucose transport into the cell, glycogenesis,
      glycolysis, glucose oxidation and protein synthesis.

      In fat-tissue, it inhibits lipolysis and enhances lipogenesis.

      This indicates that a fall in serum insulin levels lead to increased blood glucose and
      increased levels of FFA's (free fatty acids) in the blood - eventually leading to ketone
      production.

      If this condition is not corrected, it will lead to ketoacidosis, which is a potentially
      life-threatening condition, that is to be corrected under hospital admission with
      fluid-therapy, electrolyte- and insulin-substitution.

      Insulin has been studied thoroughly and signalling pathways are well known.

      An interesting pathway is suppression of lipolysis. The most important and rate-limiting
      lipase in triglyceride hydrolysis is adipose triglyceride lipase (ATGL)(1-5). A connection
      between ATGL and G0/G1 switch gene (G0S2) has been shown (6,7). During lipolysis ATGL is
      up-regulated and G0S2 is down-regulated and the promoter region for G0S2 has binding-sites
      for glucose, insulin dependent transcription factors and peroxisome proliferator-activated
      receptors y (PPAR-y)(8).

      One former study has shown that fasting reduces G0S2 and increases ATGL in humane
      adipose-tissue(7).

      The anti-lipolytic effects of insulin, could be thought, to be mediated through increased
      transcription of G0S2 which then in turn inhibits ATGL. Conversely, increased lipolysis
      during lack of insulin.

      Growth hormone and growth hormone dependent synthesis og IGF-1 (Insulin-like growth factor -
      1) is crucial for human growth before and during adolescence. As an adult GH and IGF-1 are
      still potent growth factors and also they exert essential regulatory properties on human
      metabolism(9,10)

      GH- signalling pathways go through the GH-receptor, which phosphorylates and thus activates
      the receptor associated Janus Kinase 2 (JAK2). The signals from this point have been examined
      in numerous studies.

      In rodents, the signal has been shown to run three ways (9,10) Studies on human fibroblast
      cells have been able to support two of these pathways (MAPK - mitogen-activated protein
      kinase and STAT - signal transducer and activator of transcription), but not through the
      insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3-K) pathway.

      In human (in vivo) studies, GH stimulation and phosphorylation of STAT5 has been evident,
      however an association between GH stimulation and activation of MAPK and PI3-K has not been
      shown (11).

      The latter is interesting and remarkable, considering the insulin-agonistic and antagonistic
      effects of GH.

      GH stimulates lipolysis, but exactly how the lipolytic properties of GH are mediated is not
      fully understood. However, it is shown that GH has an effect on hormone-sensitive lipase (12)
      (HSL).

      Other options could be, as found in rodents, interaction via PI3-K signaling pathway or via
      G0S2/ATGL interaction, either directly or perhaps mediated through IGF-1.

      Humane intracellular signaling-pathways during development of ketosis/ketoacidosis are not
      well-known. The investigators believe that understanding these pathways and the exact
      mechanisms behind the development of ketoacidosis, is of great importance.
    

Intervention name(s): Insulin withdrawal; Norditropin
Intervention type(s): Drug; Drug
Intervention description(s): Withdrawal of usual (evening) insulin, replaced by Insuman Rapid (10% of the amount of usual evening insulin) as a continuous IV- administration overnight until 8 o'clock on the study day.; 0,4 mg of GH administered at 7.05 A.M. on the study day.
Other intervention name(s): Insuman Rapid; Growth Hormone
Intervention MeSH terms: Hormones
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Diabetes Mellitus type I; Ketoacidosis; Insulin withdrawal; Growth hormone injection; Lipolysis and ATGL