Exendin-4

Exendin-4, a 39 amino acid peptide, activates GLP-1 (glucagon-like peptide-1) receptors to increase intracellular cAMP in pancreatic acinar cells and has no effect on VIP receptors. Exendin-4 stimulates proliferation of HCAECs through PKA-PI3K/Akt-eNOS activation pathways via a GLP-1(glucagon-like peptide-1) receptor-dependent mechanism. Exendin-4, the long-acting GLP-1 receptor agonist, is an incretin mimetic approved for type 2 diabetes mellitus treatment. Studies also demonstrated its neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer's and Parkinson's diseases.

Combined therapy with melatonin and exendin-4 effectively attenuated the deterioration of renal function in rat cardiorenal syndrome.[Pubmed:28337255]

Am J Transl Res. 2017 Feb 15;9(2):214-229. eCollection 2017.

This study tested the hypothesis that combined therapy with melatonin (Mel) and Exendin-4 (Ex4) would be superior to either therapy alone for preventing the deterioration of renal function in cardiorenal syndrome (CRS). Male adult Sprague Dawley rats (n = 48) were randomly and equally divided into sham-control (SC), chronic kidney disease (CKD; induced by 5/6 nephrectomy), CRS (CKD + dilated cardiomyopathy, DCM; induced by doxorubicin 7 mg/kg i.p. every 5 days, 4 doses), CRS-Mel (20 mg/kg/day), CRS-Ex4 (10 microg/kg/day) and CRS-Mel-Ex4. They were euthanized by day 60 after CRS induction. By day 60, plasma creatinine level, urine protein/creatinine ratio and kidney injury histopathology score were highest in CRS, lowest in SC, and progressively decreased from CKD, CRS-Mel, CRS-Ex4 to CRS-Mel-Ex4 (all P<0.0001). The kidney protein expressions of inflammation (TNF-alpha/NF-kappaB/MMP-9/iNOS/RANTES), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), apoptosis (cleaved caspase-3/cleaved PARP/Bax), DNA-damaged marker (gamma-H2AX) and fibrosis (p-mad3/TFG-beta) showed identical patterns of creatinine level, whereas kidney protein expressions of GLP-1R showed a progressive increase from SC to CRS-Mel-Ex4 (all P<0.0001). Cellular expressions of inflammatory (CD14/CD68), DNA/kidney-damaged (gamma-H2AX/KIM-1) and podocyte/renal tubule dysfunction signaling (beta-catenin/Wnt1/Wnt4) biomarkers in kidney tissue exhibited an identical pattern of creatinine level (all P<0.0001). Podocyte components (podocin/dystroglycan/p-cadherin/synatopodin) were highest in SC, lowest in CRS, and significantly progressively increased from CKD to CRS-Mel-Ex4 (all P<0.0001). In conclusion, combined Mel-Ex4 therapy was superior to either one alone in preserving renal-function and kidney architectural integrity in the setting of CRS.

Exendin-4 does not modify growth or apoptosis of human colon cancer cells.[Pubmed:28318339]

Endocr Res. 2017 Aug;42(3):209-218.

AIM: Glucagon-like peptide-1 (GLP-1) receptor agonists are a kind of very popular antidiabetes drugs. They promote cell proliferation and survival through activation of signaling pathways in human islet cells involving phosphate idylinositol 3 kinase (PI3K) and extracellular regulated kinases 1 and 2 (ERK1/2), which are frequently activated in human colon cancer cells. Then, it is possible that taking GLP-1 receptor (GLP-1R) agonists persistently would induce proliferation of beta cells as well as colon cancer cells. So, clarifying the effects and mechanisms of GLP-1R agonists on colon cancer cells has important clinical implications. MATERIALS AND METHODS: We investigated GLP-1R expression in human colon cancer tissue samples with immunohistochemisty analysis and explored the effects of Exendin-4, a GLP-1 receptor agonist, on colon cancer cells in vitro and in vivo. RESULTS: The results showed lack of GLP-1R expression in both human colon cancer tissues and colon cancer cell lines. Exendin-4 did not enhance the proliferation and migration of colon cancer cell lines in vitro, and nor did it inhibit apoptosis induced by cytotoxic agents such as 5-fluorouracil (5-FU) or irinotecan. In addition, Exendin-4 did not promote the propagation of colon cancer cells in vivo. CONCLUSION: Our study suggests that GLP-1R agonists do not modify the growth or survival of human colon cancer cells and may be safe for diabetic patients with colon cancer.

Pancreas and liver uptake of new radiolabeled incretins (GLP-1 and Exendin-4) in models of diet-induced and diet-restricted obesity.[Pubmed:28365524]

Nucl Med Biol. 2017 Jun;49:57-64.

INTRODUCTION: Radiolabeled GLP-1 and its analog Exendin-4, have been employed in diabetes and insulinoma. No protocol in conventional Diet-Induced Obesity (DIO), and Diet-Restricted Obesity (DRO), has been identified. Aiming to assess pancreatic beta cell uptake in DIO and DRO, a protocol was designed. METHODS: GLP-1-betaAla-HYNIC and HYNIC-betaAla-Exendin-4 were labeled with technetium-99m. Four Swiss mouse models were adopted: Controls (C), Alloxan Diabetes Controls (ADC), DIO and DRO. Biodistribution and ex-vivo planar imaging were documented. RESULTS: Radiolabeling yield was in the range of 97% and both agents were hydrophilic. Fasting Blood Glucose (FBG) was 79.2+/-8.2mg/dl in C, 590.4+/-23.3mg/dl in ADC, 234.3+/-66.7mg/dl in DIO, and 96.6+/-9.3 in DRO (p=0.010). Biodistribution confirmed predominantly urinary excretion. DIO mice exhibited depressed uptake in liver and pancreas, for both radiomarkers, in the range of ADC. DRO only partially restored such values. (99m)Tc-HYNIC-betaAla-Exendin-4 demonstrated better results than GLP-1-betaAla-HYNIC-(99m)Tc. CONCLUSIONS: 1) Diet-induced obesity remarkably depressed beta cell uptake; 2) Restriction of obesity failed to normalize uptake, despite robust improvement of FBG; 3) HYNIC-betaAla-Exendin-4 was the most useful marker; 4) Further studies are recommended in obesity and dieting, including bariatric surgery.

Insulin resistance and exendin-4 treatment for multiple system atrophy.[Pubmed:28334990]

Brain. 2017 May 1;140(5):1420-1436.

See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of alpha-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between alpha-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue Exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric alpha-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with Exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist Exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.

Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4.[Pubmed:12183643]

J Pharmacol Exp Ther. 2002 Sep;302(3):881-8.

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the L cells of the gastrointestinal tract in response to food. It has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation. In type 2 diabetes, GLP-1, by continuous infusion, can normalize blood glucose and is presently being tested in clinical trials as a therapy for this disease. More recently, GLP-1 has been found to have central nervous system (CNS) effects and to stimulate neurite outgrowth in cultured cells. We now report that GLP-1, and its longer-acting analog Exendin-4, can completely protect cultured rat hippocampal neurons against glutamate-induced apoptosis. Extrapolating these effects to a well defined rodent model of neurodegeneration, GLP-1 and Exendin-4 greatly reduced ibotenic acid-induced depletion of choline acetyltransferase immunoreactivity in basal forebrain cholinergic neurons. These findings identify a novel neuroprotective/neurotrophic function of GLP-1 and suggest that such peptides may have potential for halting or reversing neurodegenerative processes in CNS disorders, such as Alzheimer's disease, and in neuropathies associated with type 2 diabetes mellitus.

Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells.[Pubmed:8396143]

J Biol Chem. 1993 Sep 15;268(26):19650-5.

Exendin-4 purified from Heloderma suspectum venom shows structural relationship to the important incretin hormone glucagon-like peptide 1-(7-36)-amide (GLP-1). We demonstrate that Exendin-4 and truncated exendin-(9-39)-amide specifically interact with the GLP-1 receptor on insulinoma-derived cells and on lung membranes. Exendin-4 displaced 125I-GLP-1, and unlabeled GLP-1 displaced 125I-Exendin-4 from the binding site at rat insulinoma-derived RINm5F cells. Exendin-4 had, like GLP-1, a pronounced effect on intracellular cAMP generation, which was reduced by exendin-(9-39)-amide. When combined, GLP-1 and Exendin-4 showed additive action on cAMP. They each competed with the radio-labeled version of the other peptide in cross-linking experiments. The apparent molecular mass of the respective ligand-binding protein complex was 63,000 Da. Exendin-(9-39)-amide abolished the cross-linking of both peptides. Exendin-4, like GLP-1, stimulated dose dependently the glucose-induced insulin secretion in isolated rat islets, and, in mouse insulinoma beta TC-1 cells, both peptides stimulated the proinsulin gene expression at the level of transcription. Exendin-(9-39)-amide reduced these effects. In conclusion, Exendin-4 is an agonist and exendin-(9-39)-amide is a specific GLP-1 receptor antagonist.

Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.[Pubmed:8405712]

Diabetes. 1993 Nov;42(11):1678-82.

A complementary DNA for a glucagon-like peptide-1 receptor was isolated from a human pancreatic islet cDNA library. The isolated clone encoded a protein with 90% identity to the rat receptor. In stably transfected fibroblasts, the receptor bound [125I]GLP-1 with high affinity (Kd = 0.5 nM) and was coupled to adenylate cyclase as detected by a GLP-1-dependent increase in cAMP production (EC50 = 93 pM). Two peptides from the venom of the lizard Heloderma suspectum, Exendin-4 and exendin-(9-39), displayed similar ligand binding affinities to the human GLP-1 receptor. Whereas Exendin-4 acted as an agonist of the receptor, inducing cAMP formation, exendin-(9-39) was an antagonist of the receptor, inhibiting GLP-1-induced cAMP production. Because GLP-1 has been proposed as a potential agent for treatment of NIDDM, our present data will contribute to the characterization of the receptor binding site and the development of new agonists of this receptor.

Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas.[Pubmed:1313797]

J Biol Chem. 1992 Apr 15;267(11):7402-5.

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.

Exendin-4 (Exenatide), a 39 amino acid peptide, is a long-acting glucagon-like peptide-1 receptor agonist with an IC50 of 3.22 nM.

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