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

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

Timeline

Start

2014-05

Primary completion

2015-09

Completion

2015-09

Publications

• Background Bezaire V, Mairal A, Ribet C, Lefort C, Girousse A, Jocken J, Laurencikiene J, Anesia R, Rodriguez AM, Ryden M, Stenson BM, Dani C, Ailhaud G, Arner P, Langin D. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J Biol Chem. 2009 Jul 3;284(27):18282-91. doi: 10.1074/jbc.M109.008631. Epub 2009 May 11.
• Background Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006 May 5;312(5774):734-7. doi: 10.1126/science.1123965.
• Background Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Ryden M, Arner E, Sicard A, Jenkins CM, Viguerie N, van Harmelen V, Gross RW, Holm C, Arner P. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005 Nov;54(11):3190-7. doi: 10.2337/diabetes.54.11.3190.
• Background Schweiger M, Schreiber R, Haemmerle G, Lass A, Fledelius C, Jacobsen P, Tornqvist H, Zechner R, Zimmermann R. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem. 2006 Dec 29;281(52):40236-41. doi: 10.1074/jbc.M608048200. Epub 2006 Oct 30.
• Background Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004 Nov 19;306(5700):1383-6. doi: 10.1126/science.1100747.
• Background Yang X, Lu X, Lombes M, Rha GB, Chi YI, Guerin TM, Smart EJ, Liu J. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 2010 Mar 3;11(3):194-205. doi: 10.1016/j.cmet.2010.02.003.
• Background Nielsen TS, Vendelbo MH, Jessen N, Pedersen SB, Jorgensen JO, Lund S, Moller N. Fasting, but not exercise, increases adipose triglyceride lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein and mRNA content in human adipose tissue. J Clin Endocrinol Metab. 2011 Aug;96(8):E1293-7. doi: 10.1210/jc.2011-0149. Epub 2011 May 25.
• Background Teunissen BE, Smeets PJ, Willemsen PH, De Windt LJ, Van der Vusse GJ, Van Bilsen M. Activation of PPARdelta inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts. Cardiovasc Res. 2007 Aug 1;75(3):519-29. doi: 10.1016/j.cardiores.2007.04.026. Epub 2007 May 3.
• Background Birzniece V, Sata A, Ho KK. Growth hormone receptor modulators. Rev Endocr Metab Disord. 2009 Jun;10(2):145-56. doi: 10.1007/s11154-008-9089-x.
• Background Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24.
• Background Silva CM, Kloth MT, Whatmore AJ, Freeth JS, Anderson N, Laughlin KK, Huynh T, Woodall AJ, Clayton PE. GH and epidermal growth factor signaling in normal and Laron syndrome fibroblasts. Endocrinology. 2002 Jul;143(7):2610-7. doi: 10.1210/endo.143.7.8909.
• Background Beauville M, Harant I, Crampes F, Riviere D, Tauber MT, Tauber JP, Garrigues M. Effect of long-term rhGH administration in GH-deficient adults on fat cell epinephrine response. Am J Physiol. 1992 Sep;263(3 Pt 1):E467-72. doi: 10.1152/ajpendo.1992.263.3.E467.
• Fisker FA, Voss TS, Svart MV, Kampmann U, Vendelbo MH, Bengtsen MB, Lauritzen ES, Moller N, Jessen N. Insulin Signaling Is Preserved in Skeletal Muscle During Early Diabetic Ketoacidosis. J Clin Endocrinol Metab. 2023 Dec 21;109(1):e155-e162. doi: 10.1210/clinem/dgad464.
• Lauritzen ES, Svart MV, Voss T, Moller N, Bjerre M. Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans. Endocr Res. 2021 Feb;46(1):20-27. doi: 10.1080/07435800.2020.1831015. Epub 2020 Oct 19.
• Voss TS, Vendelbo MH, Kampmann U, Pedersen SB, Nielsen TS, Johannsen M, Svart MV, Jessen N, Moller N. Substrate metabolism, hormone and cytokine levels and adipose tissue signalling in individuals with type 1 diabetes after insulin withdrawal and subsequent insulin therapy to model the initiating steps of ketoacidosis. Diabetologia. 2019 Mar;62(3):494-503. doi: 10.1007/s00125-018-4785-x. Epub 2018 Dec 1.

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