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Holst JJ, Physiol Rev 87:1409-39, 2007 Drucker FJ, Cell Metab 135-165, 2006 INSULIN SECRETION PKA IC Ca++ MOLECULAR ACTIONS OF GLP-1 ON BETA CELL Insulin Secretion cAMP Epac2 PI-3K INSULIN GENE TRANSCRIPTION Pdx-1 replenishes beta cell insulin stores prevents beta cell exhaustion BETA CELL GLUCOSE SENSITIVITY increased GLUT2 and Glucokinase restores glucose responsitivity to resistant beta cells INSULIN RESPONSES TO PHYSIOLOGICALAND PHARMACOLOGICAL LEVELS OF GLP-1 Pharmacological GLP-1 levels2(15 mM hyperglycemic clamp) Physiological GLP-1 levels1(15 mM hyperglycemic clamp) 6000 6000 GLP-1 infusion-0.5 pmol/kg/min GLP-1 infusion-1.0 pmol/kg/min Plasma GLP-1: 46 pM Healthy controls 4000 4000 Insulin (pmol/L) Insulin (pmol/L) Plasma GLP-1:126 pmol/L Type 2 diabetes 2000 2000 Plasma GLP-1:41 pM Type 2 diabetes 0 0 0 60 120 0 60 120 Time (min) Time (min) 1

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This signalling divergence IGF-1R-independent ERK activation vs IGF-1R-dependent Akt/mTOR activation is one of the central research questions in the MGF field and is the mechanistic basis for the functionally distinct roles of MGF (proliferation, satellite cell activation, anti-differentiation) and mature IGF-1 (differentiation, protein synthesis, hypertrophy) in the sequential muscle regeneration programme

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