Metabolic Signalling in Muscle- and Adipose-tissue Following Insulin Withdrawal and Growth Hormone Injection.
Metabolic Signalling in Muscle- and Adipose-tissue Following Insulin Withdrawal and Growth Hormone Injection.
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
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.
Inclusion Criteria:

 Diagnosis of Diabetes Mellitus Type I, C-peptide negative, 19 < BMI < 26, Written consent -

 Exclusion Criteria:

 Ischemic heart disease, Cardiac arrythmia, Epilepsy, Other medical illness

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