Enteroinsular axis of db/db mice and efficacy of dipeptidyl peptidase IV inhibition

doi:10.1053/meta.2003.50014

Metabolism

Volume 52, Issue 1, January 2003, Pages 81-86

https://doi.org/10.1053/meta.2003.50014 Get rights and content

Abstract

In type 2 diabetic patients, the administration of glucagon-like peptide-1 (GLP-1), known as an incretin, exerts antidiabetic effects. However, GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPPIV) after its release. DPPIV inhibition is thought to be a rational strategy to treat type 2 diabetes. In this study, using C57BLKS/J-db/db (db/db) mice as a model of type 2 diabetes, we examined the effect of acute DPPIV inhibition on glucose tolerance at the early and later stages of diabetes, determining plasma active GLP-1 and insulin levels. In addition, we investigated changes of plasma DPPIV activity. Compared with normal C57BL6/J (B6) and db/+ mice, significantly increased plasma DPPIV activities were observed in db/db mice. Expression of the proglucagon gene encoding GLP-1 was significantly upregulated in the colon of db/db mice. The administration of valine-pyrrolidide, a DPPIV inhibitor, resulted in potentiated insulin secretion mediated by increased endogenous GLP-1 action, leading to improved glucose tolerance in db/db mice at 6 weeks of age. However, although acute DPPIV inhibition with valine-pyrrolidide resulted in higher plasma active GLP-1 and insulin levels in db/db mice at 23 weeks of age, it did not improve glucose tolerance. The function of the enteroinsular axis is preserved in both stage of diabetes and the DPPIV inhibitor potentiated it, but the progression of insulin resistance appeared to block the improvement of glucose tolerance through DPPIV inhibition. Our results suggest that DPPIV inhibition is a suitable approach for treatment of impaired glucose tolerance (IGT), and type 2 diabetes in the early stage. Copyright 2003, Elsevier Science (USA). All rights reserved.

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Gemigliptin suppresses salivary dysfunction in streptozotocin-induced diabetic rats
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Citation Excerpt :
In previous reports, similar inefficacy of DPP-4 inhibitors on blood glucose levels has been observed in diabetic animal models [31–33]. Nagakura et al. have reported that DPP-4 inhibitors were unable to improve hyperglycemia in animal models presenting late-stage diabetes [34]. Several recent studies have revealed that individual DPP4 inhibitors demonstrate protective effects against some diabetic complications via distinct off-target actions.
Patients with diabetes commonly experience hyposalivation, which induces discomfort in eating, swallowing, dryness, smell, and speaking, as well as increases the incidence of periodontal disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently used as antidiabetic drugs that lower glucose levels by utilizing similar mechanisms; however, additional protective functions of each gliptin have been discovered. In this study, the protective roles of gemigliptin, a DPP4 inhibitor, against salivary dysfunction under diabetic conditions were investigated. Streptozotocin-induced diabetic rats received gemigliptin 10 mg/kg or 100 mg/kg via oral gavage for 3 weeks. The weights of salivary gland tissues, saliva secretion, and antioxidant capacity in salivary glands were reduced after diabetes induction, but were significantly preserved following gemigliptin treatment. In salivary gland analysis, expression of apoptotic proteins, as well as amylase and aquaporin-5 (AQP5) protein expression, were increased following gemigliptin treatment. Furthermore, the number of TUNEL-positive cells decreased after gemigliptin treatment. Therefore, gemigliptin has protective roles against salivary dysfunction observed in diabetes, mediated via antioxidant, anti-apoptotic, and salivary secretion mechanisms. These results may help in selecting a suitable drug for patients with diabetes experiencing salivary dysfunction.
Cellular Sites and Mechanisms Linking Reduction of Dipeptidyl Peptidase-4 Activity to Control of Incretin Hormone Action and Glucose Homeostasis
2017, Cell Metabolism
Pharmacological inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme potentiates incretin action and is widely used to treat type 2 diabetes. Nevertheless, the precise cells and tissues critical for incretin degradation and glucose homeostasis remain unknown. Here, we use mouse genetics and pharmacologic DPP4 inhibition to identify DPP4⁺ cell types essential for incretin action. Although enterocyte DPP4 accounted for substantial intestinal DPP4 activity, ablation of enterocyte DPP4 in Dpp4^Gut−/− mice did not produce alterations in plasma DPP4 activity, incretin hormone levels, and glucose tolerance. In contrast, endothelial cell (EC)-derived DPP4 contributed substantially to levels of soluble plasma DPP4 activity, incretin degradation, and glucose control. Surprisingly, DPP4⁺ cells of bone marrow origin mediated the selective degradation of fasting GIP, but not GLP-1. Collectively, these findings identify distinct roles for DPP4 in the EC versus the bone marrow compartment for selective incretin degradation and DPP4i-mediated glucoregulation.
Novel findings of secreted cyclophilin A in diabetic nephropathy and its association with renal protection of dipeptidyl peptidase 4 inhibitor
2016, Clinica Chimica Acta
Our previous clinical indicated that urinary cyclophilin A was a good marker for diabetic nephropathy.
We used animal and cell models of diabetic nephropathy to examine the role of cyclophilin A in disease progression.
Significantly increased urinary cyclophilin A could be detected in db/db at the 8th week. Linagliptin (3 mg/kg/day and 15 mg/kg/day) could suppress urinary 8-hydroxy-2′-deoxyguanosine at the 8th and 16th week but only the high dose Linagliption could suppress cyclophilin A at the 8th week. Compared to 8-hydroxy-2′-deoxyguanosine, cyclophilin A was a stronger, earlier, and more sensitive marker. Immunohistochemical staining for cyclophilin A was also positive for db/db. In cell studies, oxidative stress and hyperglycemia could stimulate MES-13 and HK-2 cells to secrete cyclophilin A. Hyperglycemia stimulated HK-2 cells to secrete TGFβ1, which caused secretion of cyclophilin A. The secreted cyclophilin A further stimulated CD 147 to move outward from cytosol onto cell membrane in confocal microscopy, which was associated with the p38 MAPK pathway in the downstream.
Secreted cyclophilin A may play an important role in diabetic nephropathy in the mouse model and is associated with TGFβ1, CD 147, and the p38 MAPK pathway.
The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin
2016, Metabolism: Clinical and Experimental
Combining different drug classes to improve glycemic control is one treatment strategy for type 2 diabetes. The effects on insulin sensitivity of long-term treatment with the sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin alone or co-administered with the dipeptidyl peptidase-4 inhibitor linagliptin (both approved antidiabetes drugs) were investigated in mice using euglycemic–hyperinsulinemic clamps.
db/db mice (n = 15/group) were treated for 8 weeks with 10 mg/kg/day empagliflozin monotherapy, 10 mg/kg/day empagliflozin plus 3 mg/kg/day linagliptin combination therapy, or 3 mg/kg/day linagliptin monotherapy. At the end of the study, euglycemic–hyperinsulinemic clamp studies were performed 4 days after the last dose of treatment.
HbA1c and 2-hour fasting glucose concentrations were improved with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. During the clamp, glucose disposal rates increased and hepatic glucose production decreased with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. Glucose uptake in liver and kidney was higher with empagliflozin monotherapy and combination therapy compared with vehicle; glucose uptake into both muscle and adipose tissue was only affected by linagliptin treatment. Empagliflozin and combination therapy altered the expression of genes involved in the inflammatory response, fatty acid synthesis and oxidation.
These findings suggest that the insulin-sensitizing effects of SGLT2 inhibition contribute to improvements in glycemic control in insulin-resistant states.
Important species differences regarding lymph contribution to gut hormone responses
2015, Peptides
Citation Excerpt :
Intact GLP-1 levels were measured using an in-house 2-site sandwich ELISA for GLP-1 as described previously [18]. DPP-4 activity was assessed kinetically by standard procedures, using H-Gly-Pro-p-nitroaniline as substrate [16], with minor modifications. Total GLP-1 and intact GLP-1 responses were evaluated by AUC (total AUC: whole experiment, incremental AUC: stimulation period with NC) calculated using the trapezoidal rule, tested by paired t-test, and two-way ANOVA for repeated measurement followed by Bonferroni post hoc analysis as appropriate.
GLP-1 is secreted from the gut upon nutrient intake and stimulates insulin secretion. The lymph draining the intestine may transport high levels of GLP-1 to the systemic circulation before it is metabolized by DPP-4. The aims of this study were to investigate to what extent the lymphatic system might contribute to the final level(s) of systemic circulating intact GLP-1 and, in addition, whether secretory profiles in intestinal lymph might reflect lamina propria levels of GLP-1 i.e. before capillary uptake and degradation by endothelial dipeptidyl peptidase-4 (DPP-4).
7 pigs of the YDL-strain were catheterized in the portal vein, carotid artery and cisterna chyli (lymph). Neuromedin C (NC) was infused through an ear vein catheter, before and after injection of a selective DPP-4 inhibitor (vildagliptin). Total and intact GLP-1 levels were measured throughout the 150 min experiments using specific sandwich ELISAs. DPP-4 activity was measured spectrophotometrically.
Concentrations of both total and intact GLP-1 were markedly lower in lymph compared to plasma samples, and did not increase significantly in response to stimulation with NC in the absence/presence of vildagliptin. In contrast, total and intact GLP-1 levels increased significantly in the portal vein and carotid artery. DPP-4 activity was lower in lymph than plasma, and was reduced further by vildagliptin.
Our observations indicate that the lymphatic system does not transport high levels of intact GLP-1 to the systemic circulation, and that GLP-1 levels in cisternal lymph do not reflect the hormone levels in the intestinal lamina propria.
Gemigliptin improves renal function and attenuates podocyte injury in mice with diabetic nephropathy
2015, European Journal of Pharmacology
Podocytes participate in the formation and regulation of the glomerular filtration barrier. Loss of podocytes occurs during the early stages of diabetic nephropathy and impairs glomerular filtration. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as anti-diabetic agents in clinical practice. In this study, we showed that gemigliptin, a novel DPP-4 inhibitor, reduced podocyte apoptosis in type 2 diabetic db/db mice without reducing hyperglycemia. Gemigliptin (100 mg/kg/day) was administered orally for 12 weeks in db/db mice. Blood glucose levels and albuminuria were measured. The renal cortex was collected for histological examination, and molecular assays were used to detect 8-hydroxydeoxyguanosine, advanced oxidation protein products (AOPP), the receptor for advanced glycation end products (RAGE), and integrin-linked kinase (ILK). Type 2 diabetic db/db mice exhibited albuminuria, renal histopathological changes, and podocyte loss. Administration of gemigliptin to db/db mice suppressed albuminuria, enzyme activity and expression of DPP-4, and podocyte apoptosis. The effect of gemigliptin on diabetes-induced podocyte loss was associated with the suppression of oxidative damage, AOPP accumulation, RAGE expression, and ILK expression. These results indicate the possible benefits of using gemigliptin in diabetes patients to treat renal impairment without affecting glycemic control.

View all citing articles on Scopus

^*: Address reprint requests to Kazuto Yamazaki, PhD, Tsukuba Research Laboratories, Eisai Co, Ltd, 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan.

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Enteroinsular axis of db/db mice and efficacy of dipeptidyl peptidase IV inhibition*

Abstract

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Eur J Pharmacol

Metabolism

Metabolism

Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7-36) amide on the rat pancreas

Res Exp Med

Enteroglucagon

Annu Rev Physiol

Glucagon-like peptides

Diabetes

The entero-insular axis in type 2 diabetes—Incretins as therapeutic agents

Exp Clin Endocrinol Diabetes

Effect of aging and diabetes on the enteroinsular axis

J Gerontol

Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes

Curr Pharm Des

Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells

Endocrinology

Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats

Endocrinology

Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus

N Engl J Med

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients

Diabetologia

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus

J Clin Invest

Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM

Diabetes Care