Liraglutide administered peripherally not only improves metabolic parameters but exerts additional beneficial effects on cognitive function and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established.

The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys 37 Myr) (N-acetylGIP with myristic acid conjugated at Lys 37 ), a simple combination of both peptides and a Lira-AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys 37 Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN-BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys 37 Myr), a simple combination of both peptides and the Lira-AcGIP preparation demonstrated improved DPP-IV resistance (P < 0.001), while stimulating cAMP production and insulin secretion (1.4-2-fold; P < 0.001). The Lira-AcGIP preparation was more potent at lowering plasma glucose (20-51 % reduction; P < 0.05-P < 0.001) and stimulating insulin secretion (1.5-1.8-fold; P < 0.05-P < 0.001) compared with Liraglutide and N-AcGIP(Lys 37 Myr) or a simple peptide combination. Daily administration of the Lira-AcGIP preparation to ob/ob mice lowered bodyweight (7-9 %; P < 0.05), food intake (23 %; P < 0.05) and plasma glucose (46 % reduction; P < 0.001), while increasing plasma insulin (1.5-1.6-fold; P < 0.001). The Lira-AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P < 0.05-P < 0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys 37 Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.

Oxyntomodulin (Oxm) is a hormone which has been shown to exhibit a range of potentially beneficial actions for alleviation of obesity-diabetes. However, exploitation of Oxm-based therapies has been severely restricted due to degradation by the enzyme dipeptidylpeptidase-IV (DPP-IV). Thus, the aim of this study was to assess the glucose-lowering, insulin-releasing and anorexigenic actions of chemically modified, enzyme-resistant analogues of Oxm. Oxm, (d-Ser(2))Oxm and (d-Ser(2))Oxm[mPEG-PAL], were incubated with DPP-IV to assess enzyme stability and pancreatic beta-cells to evaluate insulin secretion. cAMP production was assessed using glucagon-like peptide-1 (GLP-1) and glucagon receptor transfected cells. In vivo effects of Oxm analogues on glucose homeostasis, insulin secretion, food intake and bodyweight were examined in obese diabetic (ob/ob) mice. (d-Ser(2))Oxm[mPEG-PAL] displayed enhanced DPP-IV resistance compared to (d-Ser(2))Oxm and Oxm. All peptides demonstrated similar in vitro cAMP and insulin-releasing actions, which was associated with dual action at GLP-1 and glucagon receptors. Acute administration of (d-Ser(2))Oxm[mPEG-PAL] and (d-Ser(2))Oxm reduced plasma glucose and food intake, whilst plasma insulin levels were elevated. Once-daily administration of (d-Ser(2))Oxm[mPEG-PAL] for 14 days to ob/ob mice decreased food intake, bodyweight, plasma glucose and increased plasma insulin. Furthermore, daily (d-Ser(2))Oxm[mPEG-PAL] improved glucose tolerance, increased glucose-mediated insulin secretion, pancreatic insulin content, adiponectin and decreased both visfatin and triglyceride levels. The ability of enzyme-resistant (d-Ser(2))Oxm[mPEG-PAL] to improve glucose homeostasis, insulin secretion, satiety, bodyweight and markers of fat metabolism suggests significant promise for Oxm-based therapies for obesity-diabetes.

No abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 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...