The Effects of Dipeptidyl-Peptidase-IV Inhibitor, Vildagliptin, on the Exocrine Pancreas in Spontaneously Diabetic Goto-Kakizaki Rats

Mizukami, Hiroki; Inaba, Wataru; Takahashi, Kazunori; Kamata, Kosuke; Tsuboi, Kentaro; Yagihashi, Soroku

doi:10.1097/mpa.0b013e318287c9b5

Cited by 7 publications

(10 citation statements)

References 40 publications

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“…Our findings rationalize the elevated levels of serum lipase found in patients undergoing DPP4 inhibitor based therapies 28, 29 , keeping in mind that other studies contradict these reports 30, 31 . While several studies have reported that the GLP-1 mimetics do not induce pancreatitis in rats, mouse and/or monkey 47– 49 , these studies did not include DPP4 inhibitors, which are the compounds that might be responsible for interactions with pancreatic proteins according to our study.…”

Section: Discussionsupporting

confidence: 89%

“…From the set of proteins with significant congruent matches with these two motifs, we identified a pancreatic lipase 26 and a gastric lipase 27 , keeping the context of lipases, acute pancreatitis and GLP-1 based therapies in mind. Our findings rationalize the elevated levels of serum lipase found in patients undergoing DPP4 inhibitor based therapies 28, 29 , although these reports are in disagreement with other findings 30, 31 . While it is logical and expected to find scaffolds that are congruent to trypsin and DPP4 active sites in lipases based on the current results and our previous findings 22 , we also show the presence of the serine catalytic triad in close proximity to the active site residues of proteins which have a completely different enzymatic mechanism (for example, in glutaminyl cyclase which is a transferase 32 ).…”

Section: Introductionsupporting

confidence: 60%

“…While some researchers feel that it is not acceptable to assume that ‘absence of evidence is evidence of absence’ 41, 42 , others believe that current data are not conclusive and the ‘benefits by far outweigh the potential risks’ 16 . Adding to the uncertainties are conflicting reports presented by different groups 28– 31 . Notwithstanding the antagonistic views on the subject, it is unanimously accepted that current data are insufficient to establish a causal pathogenic effect of these drugs on such side effects 43 .…”

Section: Discussionmentioning

confidence: 99%

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Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

Chakraborty¹,

Rendón-Ramírez²,

Ásgeirsson³

et al. 2015

F1000Res

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The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

Chakraborty¹,

Rendón-Ramírez²,

Ásgeirsson³

et al. 2015

F1000Res

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“…A trend towards a slightly elevated risk of pancreatitis, only with GLP-1R agonists, was also shown in a recent pooled analysis of phase Ⅲ trials, although the number of cases was very small and the statistical power was limited [101] . However larger preclinical studies did not established an association of incretin-based therapies with pancreatitis [102][103][104][105][106][107][108][109] . Interestingly in three of these studies, GLP-1R activation or DPP-4 inhibition had a beneficial effect on exocrine pancreatic function and structure [103,104] .…”

Section: Safety Of Incretin-based Therapiesmentioning

confidence: 99%

“…However larger preclinical studies did not established an association of incretin-based therapies with pancreatitis [102][103][104][105][106][107][108][109] . Interestingly in three of these studies, GLP-1R activation or DPP-4 inhibition had a beneficial effect on exocrine pancreatic function and structure [103,104] . A recent study also suggested that pancreatic findings attributed to incretin-based therapies in rodents are commonly observed background findings, without any drug treatment and independent of diet or glycemic status [110] .…”

Section: Safety Of Incretin-based Therapiesmentioning

confidence: 99%

Incretin-based therapies in prediabetes: Current evidence and future perspectives

Papaetis¹

2014

WJD

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The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.© 2014 Baishideng Publishing Group Inc. All rights reserved. Key words:Type 2 diabetes; Prediabetes; Impaired fasting glucose; Impaired glucose tolerance; Glucagonlike peptide-1; Dipeptidyl peptidase-4 inhibitors; Glucagon-like peptide-1 receptor agonists Core tip: The beneficial effects of incretin-based therapies on β-cell function in patients with type 2 diabetes (T2D) suggested their possible use in individuals with prediabetes, when greater β-cell mass and function are preserved. Both dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have demonstrated improvements on β-cell function both in preclinical studies and short-term clinical studies. Until future date for their safety are available, large, long term, prevention trials will be required in order to determine whether they can stabilize or reverse β-cell loss and promote a sustained reduction in the development of T2D in this population.Papaetis GS. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J Diabetes 2014; 5(6): 817-834 Available from:

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The dipeptidyl peptidase IV inhibitor vildagliptin suppresses development of neuropathy in diabetic rodents: effects on peripheral sensory nerve function, structure and molecular changes

Tsuboi

Mizukami

Inaba

et al. 2016

Journal of Neurochemistry

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Incretin-related therapy was found to be beneficial for experimental diabetic neuropathy, but its mechanism is obscure. The purpose of this study is to explore the mechanism through which dipeptidyl peptidase IV inhibitor, vildagliptin (VG), influences neuropathy in diabetic rodents. To this end, nonobese type 2 diabetic Goto-Kakizaki rats (GK) and streptozotocin (STZ)-induced diabetic mice were treated with VG orally. Neuropathy was evaluated by nerve conduction velocity (NCV) in both GK and STZ-diabetic mice, whereas calcitonin-gene-related peptide expressions, neuronal cell size of dorsal root ganglion (DRG) and intraepidermal nerve fiber density were examined in GK. DRG from GK and STZ-diabetic mice served for the analyses of GLP-1 and insulin signaling. As results, VG treatment improved glucose intolerance and increased serum insulin and GLP-1 in GK accompanied by the amelioration of delayed NCV and neuronal atrophy, reduced calcitonin-gene-related peptide expressions and intraepidermal nerve fiber density. Diet restriction alone did not significantly influence these measures. Impaired GLP-1 signals such as cAMP response element binding protein, protein kinase B/ Akt (PKB/Akt) and S6RP in DRG of GK were restored in VGtreated group, but the effect was equivocal in diet-treated GK. Concurrently, decreased phosphorylation of insulin receptor substrate 2 in GK was corrected by VG treatment. Consistent with the effect on GK, VG treatment improved NCV in diabetic mice without influence on hyperglycemia. DRG of VG-treated diabetic mice were characterized by correction of GLP-1 signals and insulin receptor substrate 2 phosphorylation without effects on insulin receptor b expression. The results suggest close association of neuropathy development with impaired signaling of insulin and GLP-1 in diabetic rodents.

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The Effects of Dipeptidyl-Peptidase-IV Inhibitor, Vildagliptin, on the Exocrine Pancreas in Spontaneously Diabetic Goto-Kakizaki Rats

Abstract: Perturbations of exocrine pancreatic function and structure in GK rats are ameliorated by long-term VG treatment.

Cited by 7 publications

References 40 publications

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

Incretin-based therapies in prediabetes: Current evidence and future perspectives

The dipeptidyl peptidase IV inhibitor vildagliptin suppresses development of neuropathy in diabetic rodents: effects on peripheral sensory nerve function, structure and molecular changes

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