The methionine aminopeptidase 2 inhibitor, TNP-470, enhances the antidiabetic properties of sitagliptin in mice by upregulating xenin

Craig, Sarah; Gault, Victor; Flatt, Peter; Irwin, Nigel

doi:10.1016/j.bcp.2020.114355

Cited by 8 publications

(7 citation statements)

References 61 publications

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“…Although informative, these antagonist studies are unable to provide a complete picture of the undoubted importance of synergy between GLP-1 and CCK1 receptor pathways for [Lys 12 Pal]Ex-4/CCK mediated benefits (26,27). Encouraged by these observations, we embarked on a longerterm in vivo study in mice that were administered low dose injections of STZ daily over 14 days to compromise beta-cell function in association with ad libitum access to high fat diet to induce insulin resistance and beta-cell stress (33). The resulting phenotype was characterised by failure of classical islet hypertrophy and beta-cell compensation in HFF-STZ mice, culminating in severe hyperglycaemia with blood glucose >12 mmol/l.…”

Section: Discussionmentioning

confidence: 99%

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Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes

et al. 2021

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Combined activation of GLP-1 and CCK1 receptors has potential to synergistically augment the appetite-suppressive and glucose homeostatic actions of the individual parent peptides. In the current study, pancreatic beta-cell benefits of combined GLP-1 and CCK1 receptor upregulation were established, before characterising bioactivity and antidiabetic efficacy of an acylated dual-acting GLP-1/CCK hybrid peptide, namely [Lys12Pal]Ex-4/CCK. Both exendin-4 and CCK exhibited (p<0.001) proliferative and anti-apoptotic effects in BRIN BD11 beta-cells. Proliferative benefits were significantly (p<0.01) augmented by combined peptide treatment when compared to either parent peptide alone. These effects were linked to increases (p<0.001) in GLUT2 and glucokinase beta-cell gene expression, with decreased (p<0.05-p<0.001) expression of NFκB and BAX. [Lys12Pal]Ex-4/CCK exhibited prominent insulinotropic actions in vitro, coupled with beneficial (p<0.001) satiety and glucose homeostatic effects in the mice, with bioactivity evident 24 h after administration. Following twice daily injection of [Lys12Pal]Ex-4/CCK for 28 days in diabetic high fat fed (HFF) mice with streptozotocin (STZ)-induced compromised beta-cells, there were clear reductions (p<0.05-p<0.001) in energy intake and body weight. Circulating glucose was returned to lean control concentrations, with associated increases (p<0.001) in plasma and pancreatic insulin levels. Glucose tolerance and insulin secretory responsiveness were significantly (p<0.05-p<0.001) improved by hybrid peptide therapy. In keeping with this, evaluation of pancreatic histology revealed restoration of normal islet alpha- to beta-cell ratios and reduction (p<0.01) in centralised islet glucagon staining. Improvements in pancreatic islet morphology were associated with increased (p<0.05) proliferation and reduced (p<0.001) apoptosis of beta-cells. Together, these data highlight the effectiveness of sustained dual GLP-1 and CCK1 receptor activation by [Lys12Pal]Ex-4/CCK for the treatment of obesity-related diabetes.

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Section: Discussionmentioning

confidence: 99%

“…; non-fasted) tests were conducted. Terminal analyses involved dissection of pancreatic tissue, which was processed for quantification of hormone content or pancreatic islet morphology, following acid ethanol protein extraction or fixation in 4% PFA, respectively(33).…”

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confidence: 99%

Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes

et al. 2021

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“…Future studies are required to confirm the hypothesis. Furthermore, the glucose-lowering effect of TNP-470 in combination with sitagliptin therapy is superior to these drugs alone [ 83 ]. However, the clinical potential of TNP-470 remains to be confirmed.…”

Section: Adecs: the Gatekeeper Of Adipocyte Metabolismmentioning

confidence: 99%

Adipose endothelial cells mastering adipose tissues metabolic fate

Liao

Ran

et al. 2022

Adipocyte

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Dynamic communication within adipose tissue depends on highly vascularized structural characteristics to maintain systemic metabolic homoeostasis. Recently, it has been noted that adipose endothelial cells (AdECs) act as essential bridges for biological information transmission between adipose-resident cells. Hence, paracrine regulators that mediate crosstalk between AdECs and adipose stromal cells were summarized. We also highlight the importance of AdECs to maintain adipocytes metabolic homoeostasis by regulating insulin sensitivity, lipid turnover and plasticity. The differential regulation of AdECs in adipose plasticity often depends on vascular density and metabolic states. Although choosing pro-angiogenic or anti-angiogenic therapies for obesity is still a matter of debate in clinical settings, the growing numbers of drugs have been confirmed to play an anti-obesity effect by affecting vascularization. Pharmacologic angiogenesis intervention has great potential as therapeutic strategies for obesity.

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“… 86 , 87 However, further dose-response studies are still required in human volunteers to uncover the complete adverse side effect profile of xenin. Ultimately, xenin-based therapies need to be further assessed in the human setting to confirm translatability of the many positive findings from preclinical trials, 21 , 26 , 59 , 76 , 78 , 79 , 82 , 83 and progress benefits towards the clinic.…”

Section: Discussionmentioning

confidence: 99%

“… 59 Additional related studies have demonstrated how specifically elevating xenin concentrations through use of the methionine aminopeptidase inhibitor 2, TNP-470, can also augment the antidiabetic efficacy of sitagliptin. 82 Moreover, as well as increasing xenin secretion, TNP-470 is a putative anti-obesity agent, 83 - 85 highlighting obvious benefits of this treatment modality in obesity-driven forms of diabetes. Given xenin has confirmed GIP-potentiating actions, the combination of therapies that increase xenin bioactivity alongside established DPP-4 inhibitor drugs clearly warrants further consideration as a novel therapeutic option in the management of type 2 diabetes mellitus in humans.…”

Section: Dual and Triple Acting Therapeutic Approaches That Incorporate Xenin Elementsmentioning

confidence: 99%

Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders

Craig

Irwin

Gault

2021

Clin Med Insights Endocrinol Diabetes

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Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes.

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The methionine aminopeptidase 2 inhibitor, TNP-470, enhances the antidiabetic properties of sitagliptin in mice by upregulating xenin

Cited by 8 publications

References 61 publications

Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes

Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes

Adipose endothelial cells mastering adipose tissues metabolic fate

Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders

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