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Page 1 of 42A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Insulin sensitivity, pancreatic insulin content and triglyceride levels were not changed. These data demonstrate that C-terminal acylation particularly with myristic acid provides a class of stable, longer-acting forms of GIP for further evaluation in diabetes therapy.Keywords: dipeptidylpeptidase-IV (DPP-IV); glucose-dependent insulinotropic polypeptide (GIP); GIP agonist; glucose homeostasis; insulin secretion. Firstly, insensitivity of the beta-cell to the insulin-releasing actions of GIP in type 2 diabetes has been noted [5,6]. However, it has emerged that rather than representing a GIP specific defect, this is a readily reversible phenomenon that can be rectified by improved diabetes control using other glucose-lowering drugs [7,8]. Thus combination therapy or use of modified GIP analogues can be expected to overcome any beta-cell insensitivity. Indeed the insulin-releasing and anti-diabetic potential of several amino-terminally modified GIP analogues have been demonstrated both in animal models and in preliminary studies in patients with type 2 diabetes [9]. Secondly, the pharmacokinetic profile of the native GIP hormone is severely compromised through rapid proteolytic degradation with the enzyme dipeptidylpeptidase-IV (DPP-IV; EC 3.4.14.5) generating the inactive major degradation product GIP(3-42) [10]. Thirdly, GIP and its associated metabolites are quickly eliminated and cleared from the body primarily via the kidney [11]. To date, only the biological efficacy of C-16 fatty acid derivatised GIP analogues have been reported [14][15][16][17][18]. Therefore, in the present study we characterised the effects of a range of fatty acid chain lengths (C-14, C-16 and C-18) with or without N-terminal acetylation on metabolic A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59...