Exendin-4 is a 39-amino acid peptide incretin mimetic. Exendin-4,also known as Exenatide,was originally isolated from the venom of Gila monster lizard called Heloderma suspectum1. This potent GLP-1R agonist is a long-acting analog of the mammalian intestinal hormone glucagon-like peptide I (GLP-1) and therefore exhibits glucoregulatory activities to control plasma glucose levels2. Exendin-4 enhances insulin synthesis and secretion in a glucose-dependent manner,while downregulating inappropriately high glucagon release,slowing gastric emptying and decreasing appetite2. The increase in maximum insulin secretion is due to a greater increase in cAMP production in pancreatic β cells3. Exendin-4 is a potent agonist of the Glucagon-Like Peptide-1 Receptor (GLP-1R ; Kd = 136pM).
It has been reported that exendin-4 is a more potent insulinotropic agent when given intravenously to rats than is glucagon-like peptide-1 (GLP-1) as indicated by the lower ED50 (ED50 0.19 nmol/kg for glucagon-like peptide-1 versus 0.0143 nmol/kg for exendin-4)3. Subcutaneous administration of exendin-4 at doses of 5µg and 10 µg twice daily attenuates glycemia in patients with type 2 diabetes,who are treated with metformin,an antidiabetic drug and not achieving adequate glycemic control4. In these patients,exendin-4 was tolerated and triggered a reduction in glycated hemoglobin (HbA1C ≤ 7%),with no weight gain and no increased incidence of hypoglycemia4. Long-term treatment with exendin-4 has a beneficial effect on the pancreatic β-cell function by stimulating both the neogeneration and the proliferation of β-cells when administered to rats2. Furthermore,exendin-4 has shown anti-atherosclerogenetic properties5 as well as the ability to reduce hepatic steatosis in obese ob/ob mice by improving insulin sensitivity6.
The recent identification in Heloderma horridum venom of exendin-3,a new member of the glucagon superfamily that acts as a pancreatic secretagogue,prompted a search for a similar peptide in Heloderma suspectum venom. An amino acid sequencing assay for peptides containing an amino-terminal histidine residue (His1) was used to isolate a 39-amino acid peptide,exendin-4,from H. suspectum venom. Exendin-4 differs from exendin-3 by two amino acid substitutions,Gly2-Glu3 in place of Ser2-Asp3,but is otherwise identical. The structural differences make exendin-4 distinct from exendin-3 in its bioactivity. In dispersed acini from guinea pig pancreas,natural and synthetic exendin-4 stimulate a monophasic increase in cAMP beginning at 100 pM that plateaus at 10 nM. The exendin-4-induced increase in cAMP is inhibited progressively by increasing concentrations of the exendin receptor antagonist,exendin-(9-39) amide. Unlike exendin-3,exendin-4 does not stimulate a second rise in acinar cAMP at concentrations greater than 100 nM,does not stimulate amylase release,and does not inhibit the binding of radiolabeled vasoactive intestinal peptide to acini. This indicates that in dispersed pancreatic acini,exendin-4 interacts only with the recently described exendin receptor.
Diabetes is a disease of increasing prevalence in the general population and of unknown cause. Diabetes is manifested as hyperglycemia due to a relative deficiency of the production of insulin by the pancreatic beta-cells. One determinant in the development of diabetes is an inadequate mass of beta-cells,either absolute (type 1,juvenile diabetes) or relative (type 2,maturity-onset diabetes). Earlier,we reported that the intestinal hormone glucagon-like peptide I (GLP-I) effectively augments glucose-stimulated insulin secretion. Here we report that exendin-4,a long-acting GLP-I agonist,stimulates both the differentiation of beta-cells from ductal progenitor cells (neogenesis) and proliferation of beta-cells when administered to rats. In a partial pancreatectomy rat model of type 2 diabetes,the daily administration of exendin-4 for 10 days post-pancreatectomy attenuates the development of diabetes. We show that exendin-4 stimulates the regeneration of the pancreas and expansion of beta-cell mass by processes of both neogenesis and proliferation of beta-cells. Thus,GLP-I and analogs thereof hold promise as a novel therapy to stimulate beta-cell growth and differentiation when administered to diabetic individuals with reduced beta-cell mass.
Glucagon-like peptide-1 is the main hormonal mediator of the enteroinsular axis. Recently,it has additionally received considerable attention as a possible new treatment for Type II (non-insulin-dependent) diabetes mellitus. Its major disadvantage is that its duration of action is too short to achieve good 24-h metabolic control. Exendin-4,which is produced in the salivary glands of Gila monster lizards,is structurally similar to glucagon-like peptide-1 and shares several useful biological properties with glucagon-like peptide-1. It binds the glucagon-like peptide-1 receptor,stimulates insulin release and increases the cAMP production in beta cells. We report that exendin-4 is a more potent insulinotropic agent when given intravenously to rats than is glucagon-like peptide-1 (ED50 0.19 nmol/kg for glucagon-like peptide-1 vs 0.0143 nmol/kg for exendin-4) and causes a greater elevation in cAMP concentrations in isolated islets. Of even greater interest we found that when given intraperitoneally only once daily to diabetic mice it had a prolonged effect of lowering blood glucose. After 1 week of treatment blood glucoses were 5.0+/-2.6 mmol/l compared to diabetic concentrations of 13.2+/-2.8 mmol/l. After 13 weeks of daily treatment HbA1c was 8.8+/-0.4% in non-treated diabetic animals compared with 4.7+/-0.25% in treated diabetic animals. Blood glucoses also were lower (p < 0.005) and insulin concentrations higher (p < 0.02) in the treated animals. Exendin-4 could therefore be preferable to glucagon-like peptide-1 as a long-term treatment of Type II diabetes.
4-DeFronzo,R. A. et al.,Diabetes Care 28,1092–1100 (2005)
OBJECTIVE : This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses.
RESEARCH DESIGN AND METHODS : A triple-blind,placebo-controlled,30-week study at 82 U.S. sites was performed with 336 randomized patients. In all,272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m(2) and HbA(1c) of 8.2 +/- 1.1%. After 4 weeks of placebo,subjects self-administered 5 microg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 microg exenatide,or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.
RESULTS : At week 30,HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg),-0.40 +/- 0.11% (5 microg),and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects,46% (10 microg),32% (5 microg),and 13% (placebo) achieved HbA(1c) < or =7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg],-1.6 +/- 0.4 kg [5 microg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms,with no severe hypoglycemia.
CONCLUSIONS : Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.
OBJECTIVE: Exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However,their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall,one of the earliest steps in atherosclerogenesis.
RESEARCH DESIGN AND METHODS: After continuous infusion of low (300 pmol . kg(-1) . day(-1)) or high (24 nmol . kg(-1) . day(-1)) dose of exendin-4 in C57BL/6 or apolipoprotein E-deficient mice (apoE(-/-)),we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes.
RESULTS: Treatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE(-/-) mice,the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1,and suppressed nuclear translocation of p65,a component of nuclear factor-kappaB. This effect was reversed by either MDL-12330A,a cAMP inhibitor or PKI(14-22),a protein kinase A-specific inhibitor. In human monocytes,exendin-4 reduced the expression of CD11b.
CONCLUSIONS: Our data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages,and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.
6-Ding,X. et al.,Hepatol. Baltim. Md 43,173–181 (2006)
Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology,and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice,or their lean littermates,were treated with Exendin-4 [10 microg/kg or 20 microg/kg] for 60 days. Serum was collected for measurement of insulin,adiponectin,fasting glucose,lipids,and aminotransferase concentrations. Liver tissue was procured for histological examination,real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice,as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally,GLP-1-treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion,Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism.
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