scholarly journals Hypoglycemic effect of gastric bypass operation in type 2 diabetes rats: Influence on dipeptidyl peptidase-IV and glucagon-like peptide-1

2014 ◽  
Vol 22 (22) ◽  
pp. 3281
Author(s):  
Shou-Kun Chen ◽  
Yan Kong ◽  
Peng-Bo Zhang ◽  
Hua Wei ◽  
Xiu-Zhong Zhang ◽  
...  
2003 ◽  
Vol 31 (3) ◽  
pp. 529-540 ◽  
Author(s):  
BD Green ◽  
VA Gault ◽  
MH Mooney ◽  
N Irwin ◽  
CJ Bailey ◽  
...  

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.


2004 ◽  
Vol 180 (3) ◽  
pp. 379-388 ◽  
Author(s):  
BD Green ◽  
MH Mooney ◽  
VA Gault ◽  
N Irwin ◽  
CJ Bailey ◽  
...  

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.


2019 ◽  
Vol 229 (4) ◽  
pp. e2
Author(s):  
Bernardo M. Pessoa ◽  
Matthew G. Browning ◽  
Jad Khoraki ◽  
Guilherme Mazzini ◽  
Luke Wolfe ◽  
...  

2009 ◽  
Vol 161 (1) ◽  
pp. 201-206 ◽  
Author(s):  
Bernd Schultes ◽  
Barbara Ernst ◽  
Florian Schmid ◽  
Martin Thurnheer

ContextObesity resulting from damage to the hypothalamus, i.e. hypothalamic obesity, is a severe condition that currently lacks any effective evidence-based therapy.ObjectiveOur goal was to describe the course of hypothalamic obesity in a craniopharyngioma patient treated with distal gastric bypass surgery and to outline distinct aspects of multidisciplinary case management.Patient and methodsA 29-year-old man, who had undergone craniopharyngioma resection at the age of 8, was referred to our Interdisciplinary Obesity Centre with a body mass index (BMI) of 52.0 kg/m2, type 2 diabetes and obstructive sleep apnoea syndrome (OSAS). After careful preoperative preparation, including the adjustment of hormone substitution therapy for panhypopituitarism, nutritional counselling and a supervised exercise program, he underwent a distal gastric bypass operation.ResultsEighteen months after the operation the patient's BMI had decreased to 31.9 kg/m2, type 2 diabetes was in complete remission, and OSAS appeared to be improved. Also, feelings of hunger were markedly reduced after the operation. A standard regimen of supplements successfully prevented any severe nutritional deficiencies. After weight loss, the dose of hydrocortisone could be distinctly reduced without any signs of adrenal insufficiency while GH substitution had to be markedly increased to achieve normal IGF1 levels.ConclusionsOur case demonstrates that within a multidisciplinary team approach, a distal gastric bypass operation can be a safe and highly effective therapy for patients with hypothalamic obesity. Also, our findings hint at an effect of gastric bypass surgery on hunger and eating behaviour that may not essentially rely on hypothalamic mechanisms.


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