Dipeptidyl Peptidase-4 Concentration Research Articles

Association of DPP-4 Concentrations with the Occurrence of Gestational Diabetes Mellitus and Excessive Gestational Weight Gain.

Gestational diabetes mellitus (GDM) is considered one of the most common diseases that occur during pregnancy. In addition to increasing the risk of numerous complications throughout gestation, it is also believed to have a long-term potential to impact the risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease for the mother and her offspring. While there are clear guidelines for healthy weight gain in pregnancy depending on pre-pregnancy BMI, as well as dietary and training recommendations to achieve this, an increasing number of women are experiencing excessive gestational weight gain (EGWG). Such patients have a higher risk of developing GDM and gestational hypertension, as well as requiring caesarian delivery. Dipeptidyl peptidase-4 (DPP-4) is a glycoprotein that seems to play an important role in glucose metabolism, and inhibition of its activity positively affects glucose regulation. The aim of our study was to compare DPP-4 concentrations in patients with GDM and EGWG with healthy women. DPP-4 levels were assessed in serum and urine samples collected on the day of delivery. The bioelectrical impedance analysis (BIA) method was also used to analyze the body composition of patients on the second day of the postpartum period. DPP-4 serum concentrations were significantly higher in patients in the GDM and EGWG groups compared to healthy women. Urinary DPP-4 concentrations were significantly higher in the control and GDM groups than in the EGWG group. Serum DPP-4 levels were positively correlated with BMI measured before pregnancy, on the delivery day, and in the early postpartum period, among other factors. According to our knowledge, this is the first study to determine DPP-4 levels in EGWG patients. DPP-4 may be related to the occurrence of GDM and EGWG; however, this requires further research.

Diabetic individuals with COVID-19 exhibit reduced efficacy of gliptins in inhibiting dipeptidyl peptidase 4 (DPP4). A suggested explanation for increased COVID-19 susceptibility in patients with type 2 diabetes mellitus (T2DM)

AimsDipeptidyl peptidase 4 (DPP4) has been proposed as a coreceptor for SARS-CoV-2 cellular entry. Considering that type 2 diabetes mellitus (T2DM) has been identified as the most important risk factor for SARS-CoV-2, and that gliptins (DPP4 inhibitors) are a prescribed diabetic treatment, this study aims to unravel the impact of DPP4 in the intersection of T2DM/COVID-19. Materials and methodsWe analyzed 189 serum human samples, divided into six clinical groups (controls, T2DM, T2DM + gliptins, COVID-19, COVID-19 + T2DM, and COVID-19 + T2DM + gliptins), measuring DPP4 protein concentration and activity by Western blot, ELISA, and commercial activity kits. The obtained results were verified in Huh-7 cellular models. Key findingsBoth DPP4 concentration and activity were decreased in COVID-19 patients, and as in T2DM patients, compared to controls. Despite these lower levels, the ratio of DPP4 activity/concentration in COVID-19 sera was the highest (0.782 ± 0.289 μU/ng vs. 0.547 ± 0.050 μU/ng in controls, p < 0.0001), suggesting a compensating mechanism in these patients. Supernatants of Huh-7 cells incubated with COVID-19 serum showed a consistent and significantly lower DPP4 concentration and activity. Furthermore, COVID-19 + T2DM + gliptins patients showed a higher serum DPP4 concentration and activity than T2DM + gliptin subjects (p < 0.05), indicating that sera from COVID-19 convalescents interfere with gliptins. SignificanceEither SARS-CoV-2 or some metabolites present in the sera of COVID-19-convalescent patients interact with soluble DPP4 or even gliptins themselves since the inhibitory effect of gliptins on DPP4 activity is being prevented. The interactions between DPP4, gliptins, and SARS-CoV-2 should be further elucidated to reveal the mechanism of action for these interesting observations.

Correlation of CD40 and DPP-4 Concentration With Corrected TIMI Frame Count in Patients With Coronary Slow Flow

Introduction: Microvascular and endothelial disorders play a significant role in the pathophysiology of coronary slow flow phenomenon (CSFP). However, according to previous studies, the etiology of CSFP is not completely understood. As CD40 and dipeptidyl peptidase-4 (DPP-4) are reported to play an important role in atherosclerosis process as well as microvascular and the endothelial dysfunction, this study evaluated the role of these two biomarkers in the pathophysiology of CSFP. Methods: One-hundred twenty-nine volunteers who were candidates for angiography and fulfilled the inclusion criteria were selected, including 29 patients with coronary artery diseases (CADs) which had less than 50% stenosis (CAD+,&lt;50%) and without CSF, 22 CAD+patients which had 50-90% stenosis (CAD+, 50%-90%) without CSF, 16 CAD+patients with CSF, 22 patients with CSF without stenosis in their arteries, and 40 healthy individuals as controls. The serum levels of CD40 and DPP-4 were measured by an enzyme-linked immunosorbent assay kit. Results: There was no significant correlation between the serum concentration of CD40 and the thrombosis in myocardial infarction (TIMI) frame count (P=0.571). However, the serum concentration of CD40 in CAD+patients with CSF was significantly higher than the values in patients without CSF (P=0.022). Moreover, the concentration of DPP-4 in different coronary vessels did not exhibit any significant relation with TIMI score (P=0.763). Conclusion: In the present study, no significant correlation was found between the serum concentrations of CD40 and DPP-4 and the mean corrected TIMI frame count (CTFC). Accordingly, further studies with larger population sizes are needed to investigate the correlation between CD40 and DPP-4 serum levels and CSFP.

Urinary dipeptidyl peptidase-4 is a useful marker for tubulitis, and it is released from the tubular cells of kidney transplant recipients

BackgroundBiomarkers are needed to diagnose kidney rejection in transplant recipients. We evaluated whether dipeptidyl peptidase-4 (DPP-4) could serve as a biomarker of rejection.MethodsWe determined DPP-4 concentrations and enzymatic activities in serum and urine, as well as DPP-4 expression in 49 kidney biopsy samples from 28 kidney transplant recipients. This study was approved by the ethical standards of the institutional research committee and comply with Helsinki declaration. All patients provided their informed consent. Donors were not from prisoners and were not paid or coerced.ResultsSerum and urinary DPP-4 activities closely correlated with DPP-4 concentrations, but were suppressed by DPP-4 inhibitors. Urinary DPP-4 concentrations increased with acute T cell-mediated rejection (ATCMR; p = 0.030) and higher Banff t and i scores (p < 0.001), and correlated with urinary protein/creatinine ratios (r = 0.450), and inversely with estimated glomerular filtration rate (r = − 0.604). The area under the receiver operator characteristics curves for urinary DPP-4 concentrations with either Banff t3 or i3 scores were 0.811 (95% confidence interval: 0.687–0.934). The expression of DPP-4 in renal tubular cells was decreased in patients with ATCMR and higher in those with Banff t, i, ct, ci, ah, and ti scores, but was not associated with interstitial fibrosis/tubular atrophy.ConclusionsWe speculated that ATCMR leads to DPP-4 release from tubular cells into urine, resulting in a decrease in tubular cell expression. If so, then ATCMR would induce the elevation of urinary DPP-4 and could therefore serve as a biomarker of tubulitis.

In vitro Inhibition of Dipeptidyl Peptidase-4 (DPP-4) and Arginase by a Dietary Supplement and Its Potential for Improving Quality of Life Factors in Adults

Aim: Somatopause is the progressive and age-related decline of growth hormone (GH) production due to changes in hypothalamic-pituitary axis signaling and results in typical physiological changes associated with the aging process. The purpose of our study was to investigate the anti-aging potential of several botanical ingredients, including noni fruit juice, as well as a dietary supplement formulation.&#x0D; Methodology: Dipeptidyl peptidase-4 (DPP-4) influences hypothalamic-pituitary axis signaling and reduces GH production and secretion. Since DPP-4 concentrations increase with age, we evaluated the ability of several botanical ingredients to inhibit DPP-4 activity in vitro. We subsequently formulated an anti-aging dietary supplement with this blend of botanical ingredients by adding amino acids (L-arginine, L-Lysine, citrulline and beta-alanine), gamma-aminobutyric acid (GABA), flax seed oil and several nutrients. The supplement was evaluated for anti-arginase activity in vitro, as the expression of this enzyme also increases with age. The dietary supplement was also consumed by three men and one woman, ages 56 to 62, with relevant but disparate medical histories. Following short-term ingestion of the supplement, these volunteers were interviewed to ascertain any changes in health status.&#x0D; Results: We discovered that a blend of the botanical ingredients synergistically inhibited DPP-4 in vitro by up to approximately 99%. A concentration-dependent reduction in arginase activity was also observed for the anti-aging dietary supplement. Further, all volunteers reported positive improvements in at least one quality of life factor, which included more restful sleep, reduced musculoskeletal discomfort, increased energy, improved physical stamina and better skin quality.&#x0D; Conclusion: These initial findings suggest that the anti-aging dietary supplement can mitigate declines in quality of life associated with aging by reducing DPP-4 and arginase activities, thereby supporting healthy GH production and endothelial nitric oxide production.

Effects of Sambiloto (Andrographis paniculata) on GLP-1 and DPP-4 Concentrations between Normal and Prediabetic Subjects: A Crossover Study.

Background The extract of Andrographis paniculata (Burm. F.) Wall. Ex. Nees. (sambiloto) (穿心蓮 chuān xīn lián) has been reported to have an antidiabetic effect on mice models and has been used traditionally in the community. The exact mechanism of sambiloto extract in decreasing plasma glucose is unclear, so we investigated the role of sambiloto extract in the incretin pathway in healthy and prediabetic subjects. Methods This study was a randomized, placebo-controlled, crossover, double-blind trial. It included 38 people who were healthy and 35 people who had prediabetes. All subjects were randomly assigned to receive either the intervention sambiloto extract or a placebo. All subjects were randomly assigned to receive the first intervention for 14 days. There was a washout period between subsequent interventions. The primary outcome was glucagon-like peptide 1 (GLP-1) concentration, and secondary outcomes were fasting insulin, 2-hour postprandial insulin, homeostasis model assessment of insulin resistance (HOMA-IR), fasting blood glucose, 2-hour postprandial blood glucose, dipeptidyl peptidase-4 (DPP-4), and glycated albumin before and after the intervention. Result After the intervention, GLP-1 concentration significantly increased in prediabetes by 19.6% compared to the placebo (p=0.043). There were no significant differences in the changes of fasting insulin, 2-hour postprandial insulin, HOMA-IR, fasting blood glucose, 2-hour postprandial blood glucose, DPP-4, and glycated albumin levels after the intervention. Sambiloto extract did not inhibit the DPP-4 enzyme in healthy and prediabetic subjects. Conclusion Sambiloto extract increased GLP-1 concentration without inhibiting the DPP-4 enzyme in prediabetic subjects. This trial is registered with ClinicalTrials.gov (ID: NCT03455049), registered on 6 March 2018—retrospectively registered (https://clinicaltrials.gov/ct2/show/NCT03455049).

Optimization and validation of a fluorogenic dipeptidyl peptidase 4 enzymatic assay in human plasma

During the development of a specific dipeptidyl peptidase 4 (DPP4) inhibitor to treat type 2 diabetes, a fluorogenic kinetic analysis for DPP4 enzymatic activity using Gly-Pro-Aminomethylcoumarin (AMC) as a substrate was optimized and validated for recombinant DPP4 and human plasma samples. The sensitivity, calibration curve, detection range, accuracy, precision, recovery efficiency, Km constant, short/long-term stability, and stability after freezing-thawing cycles were analyzed. DPP4 enzymatic activity (mU/min) was measured as the initial velocity (Vo) of the enzymatic reaction over time. The sensitivity of the Vo value was 14,488 mU/min for recombinant DPP4 and 17,995 mU/min for human plasma samples. The dynamic ranges of the calibration curve were linear and reliable between 1.11 × 104–1.86 × 106 mU/min of the mean Vo value and in the DPP4 concentration range of 23.4–3,000 ng/mL. The assay's accuracy and precision met acceptance criteria for all samples. Plasma DPP4 was stable under various storage temperatures, even after three freeze-thaw cycles. Our optimized, validated bioanalytic method for measuring DPP4 activity in plasma samples was successfully employed to evaluate the effect of evogliptin (DA-1229) tartrate, which irreversibly and dose-dependently inhibits DPP4 enzymatic activity, without the dilution effect of human plasma samples and irrespective of the co-treated metformin.

Decreased shedding dipeptidyl peptidase 4 from membrane in Hashimoto's thyroiditis

AimsThis study aimed to determine the concentration and enzymatic activity of dipeptidyl peptidase 4 (DPP4) in serum and peripheral blood mononuclear cells (PBMCs) from patients with Hashimoto’s thyroiditis (HT) and to explore the potential mechanism of the abnormal DPP4 in HT development. MethodsA total of 33 newly diagnosed HT patients and 31 age- and sex-matched healthy controls were enrolled. Clinical characteristics and thyroid function data were collected for all participants. Serum DPP4 and kallikrein-related peptidase 5 (KLK5) concentrations were measured by sandwich enzyme-linked immunosorbent assay. DPP4 enzymatic activities in serum and PBMCs were determined by enzymatic assay. DPP4, KLK5 and interferon (IFN)-γ mRNA expression levels in PBMCs were evaluated by quantitative real-time polymerase chain reaction. ResultsSerum DPP4 level and activity were significantly lower in the HT group compared with the control group. However, DPP4 mRNA expression was significantly increased and both serum KLK5 concentration and KLK5 mRNA expression in PBMCs were significantly decreased in HT patients. Correlation analyses revealed that DPP4 concentration was positively correlated with DPP4 enzymatic activity in serum. No significant difference in DPP4 activity was found in PBMCs. DPP4 enzymatic activity in PBMCs was negatively correlated with DPP4 enzymatic activity in serum. IFN-γ mRNA expression in PBMCs was significantly increased in HT patients. ConclusionsDPP4 is involved in the development and pathological process of HT. Decreased cleavage of membrane-anchored DPP4 by KLK5 may be responsible for the decreased serum DPP4 levels in HT patients.

DPP4 deletion in adipose tissue improves hepatic insulin sensitivity in diet-induced obesity.

Besides a therapeutic target for type 2 diabetes, dipeptidyl peptidase 4 (DPP4) is an adipokine potentially upregulated in human obesity. We aimed to explore the role of adipocyte-derived DPP4 in diet-induced obesity and insulin resistance with an adipose tissue-specific knockout (AT-DPP4-KO) mouse. Wild-type and AT-DPP4-KO mice were fed for 24 wk with a high fat diet (HFD) and characterized for body weight, glucose tolerance, insulin sensitivity by hyperinsulinemic-euglycemic clamp, and body composition and hepatic fat content. Image and molecular biology analysis of inflammation, as well as adipokine secretion, was performed in AT by immunohistochemistry, Western blot, real-time-PCR, and ELISA. Incretin levels were determined by Luminex kits. Under HFD, AT-DPP4-KO displayed markedly reduced circulating DPP4 concentrations, proving AT as a relevant source. Independently of glucose-stimulated incretin hormones, AT-DPP4-KO had improved glucose tolerance and hepatic insulin sensitivity. AT-DPP4-KO displayed smaller adipocytes and increased anti-inflammatory markers. IGF binding protein 3 (IGFBP3) levels were lower in AT and serum, whereas free IGF1 was increased. The absence of adipose DPP4 triggers beneficial AT remodeling with decreased production of IGFBP3 during HFD, likely contributing to the observed, improved hepatic insulin sensitivity.

High serum concentration of dipeptidyl peptidase 4 at early stage of obesity – preliminary study

Background: Adipose tissue has been recognized as an endocrine organ of considerable complexity, able to secrete adipose-derived factors named adipokines. The secretion of adipokines depends greatly on the volume of body fat, which in turn significantly changes their activity towards a diabetogenic, proinflammatory, and atherogenic pattern. One of the discovered adipokines is dipeptidyl peptidase 4 (DPP4).&lt;br&gt;Objectives: The aim of this preliminary study was to establish an association between serum concentration of DPP4 and obesity at early stage.&lt;br&gt;Material and methods: A total of 32 obese adult volunteers and 40 lean controls were studied. Total cholesterol, triglycerides, HDL (high-density lipoprotein), LDL (low-density lipoprotein) and glucose concentrations were assessed in serum/plasma samples by using commercial tests. Body mass index (BMI) and waist-hip ratio (WHR) were determined. Serum concentrations of DPP4, leptin, visfatin, CRP (C-reactive protein), and TNF-alpha (tumor necrosis factor alpha) were measured using commercial ELISA immunoassay tests.&lt;br&gt;Results: Serum concentrations of DPP4, leptin and visfatin were significantly higher in obese than in lean subjects. The concentration of DPP4 positively correlated with BMI and body mass. Serum CRP and TNF-alpha were increased in obese compared to non-obese, and had a positive correlation with BMI, WHR and body mass.&lt;br&gt;Conclusions: We showed that there is an association between the DPP4, leptin and visfatin concentration in serum and elevated body weight and BMI even at early stage of obesity (I stage of obesity). It suggest the importance of adipose tissue reduction to prevent rise of adipokines levels and further negative metabolic and inflammatory changes.

Epigenetic regulation of hepatic Dpp4 expression in response to dietary protein

Dipeptidyl peptidase 4 (DPP4) is known to be elevated in metabolic disturbances such as obesity, type 2 diabetes and fatty liver disease. Lowering DPP4 concentration by pharmacological inhibition improves glucose homeostasis and exhibits beneficial effects to reduce hepatic fat content. As factors regulating the endogenous expression of Dpp4 are unknown, the aim of this study was to examine whether the Dpp4 expression is epigenetically regulated in response to dietary components. Primary hepatocytes were treated with different macronutrients, and Dpp4 mRNA levels and DPP4 activity were evaluated. Moreover, dietary low-protein intervention was conducted in New Zealand obese (NZO) mice, and subsequently, effects on Dpp4 expression, methylation as well as plasma concentration and activity were determined. Our results indicate that Dpp4 mRNA expression is mediated by DNA methylation in several tissues. We therefore consider the Dpp4 southern shore as tissue differentially methylated region. Amino acids increased Dpp4 expression in primary hepatocytes, whereas glucose and fatty acids were without effect. Dietary protein restriction in NZO mice increased Dpp4 DNA methylation in liver leading to diminished Dpp4 expression and consequently to lowered plasma DPP4 activity. We conclude that protein restriction in the adolescent and adult states is a sufficient strategy to reduce DPP4 which in turn contributes to improve glucose homeostasis.

Association between Serum Dipeptidyl Peptidase-4 Concentration and Obesity-related Factors in Health Screen Examinees.

BackgroundDipeptidyl peptidase-4 (DPP-4) is an aminopeptidase that inhibits the enzymatic degradation of glucagon-like peptide-1, glucose-dependent insulinotropic polypeptides, neuropeptides, and various chemokines. Recent studies reported that serum DPP-4 concentration is correlated with clinical parameters of obesity. However, research on these correlations has never been conducted in Korea. Therefore, we investigated the relationship between serum DPP-4 concentration and various clinical parameters of obesity in the Korean population.MethodsPatients who visited the Health Promotion Center at Keimyung University Dongsan Medical Center for a regular medical examination between January 2013 and March 2013 and consented to participate in this study were included. We measured and analyzed parameters of obesity. In addition, serum DPP-4 concentration was determined using an enzyme-linked immunosorbent assay kit.ResultsSerum DPP-4 concentration was positively correlated with lean body mass, total cholesterol level, and creatinine level. Serum DPP-4 concentration was higher in the obese group than in the normal body mass index (BMI) group. No significant difference in serum DPP-4 concentration was found between the metabolically healthy group and metabolically unhealthy group.ConclusionSerum DPP-4 concentration was higher in the obesity group than in the normal BMI group, which was associated with obesity-related factors.

Dipeptidyl peptidase 4 serum activity and concentration are increased in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex disease, the aetiology of which is not well understood. Alterations in potential candidate genes involved in the biosynthesis and metabolism of androgens, folliculogenesis and insulin and glucose metabolism have been suggested as possible aetiologies. Dipeptidyl peptidase-4 (DPP4) plays a key role in glucose homoeostasis and, thus, in the regulation of insulin secretion. The aim of our study was to analyse the DPP4 activity and concentrations in the serum of PCOS and non-PCOS patients and, additionally, study the activation of the DPP4 promoter by androgens in vitro. Serum samples were obtained from 288 female patients treated at the Center for Reproductive Medicine and Andrology (154 non-PCOS and 134 patients with PCOS). DPP4 activity was measured by the conversion of the DPP4 substrate Gly-Pro p-nitroanilide hydrochloride and DPP4 concentration with a commercial ELISA. Luciferase reporter assays, qPCR and Western Blot analyses were performed for the in vitro evaluation of the activation of the DPP4 promoter by androgens. DPP4 serum activity was increased in women with PCOS, regardless of which Rotterdam criteria led to the PCOS diagnosis. Furthermore, DPP4 serum levels were strongly correlated with the anti-Müllerian hormone (AMH) serum level. In vitro, the DPP4 promoter was stimulated by androgens in luciferase reporter assays, and DPP4 mRNA expression was increased in KGN granulosa carcinoma cells after androgen treatment. The results suggested that a deregulation of DPP4 serum levels could be an additional characteristic of the metabolic imbalances associated with PCOS.

Pioglitazone Increases Serum DPP-4 Level in Type 2 Diabetes Mellitus

Objective: The aim of this study is to clarify the effect of pioglitazone on serum Dipeptidyl peptidase-4 (DPP-4) level in type 2 diabetes mellitus. Methods: Chronological changes in serum DPP-4 level were observed in 22 patients treated with pioglitazone and 15 with metformin during 12 months. Serum DPP-4 concentrations were measured by an ELISA kit. Results: In the pioglitazone group, serum DPP-4 levels were significantly increased from baseline (774 ± 198 ng/mL) with mean changes of 53 mg/mL [6.8% increase, 95% confidence interval (CI) 2 to 104, p<0.05] after 3 months and of 74 mg/mL (9.4% increase, 95% CI 21 to 126, p<0.01) after 12 months. On the other hand, serum DPP-4 levels were not changed in the metformin group. Percent change in serum DPP-4 level was significantly and positively correlated with percent change in body mass index (r=0.39, p<0.02). The association was still significant even after adjusting for age, duration of diabetes, serum creatinine, and HbAc1 (β=0.59, p<0.02). Conclusion: The present study showed that pioglitazone, but not metformin, chronologically increased serum DPP-4 levels during 12 months.

Lower dipeptidyl peptidase-4 following exercise training plus weight loss is related to increased insulin sensitivity in adults with metabolic syndrome

Dipeptidyl peptidase-4 (DPP-4) is a circulating glycoprotein that impairs insulin-stimulated glucose uptake and is linked to obesity and metabolic syndrome. However, the effect of exercise on plasma DPP-4 in adults with metabolic syndrome is unknown. Therefore, we determined the effect of exercise on DPP-4 and its role in explaining exercise-induced improvements in insulin sensitivity. Fourteen obese adults (67.9±1.2 years, BMI: 34.2±1.1kg/m2) with metabolic syndrome (ATP III criteria) underwent a 12-week supervised exercise intervention (60min/day for 5 days/week at ∼85% HRmax). Plasma DPP-4 was analyzed using an enzyme-linked immunosorbent assay. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp (40mU/m2/min) and estimated by HOMA-IR. Visceral fat (computerized tomography), 2-h glucose levels (75g oral glucose tolerance), and basal fat oxidation as well as aerobic fitness (indirect calorimetry) were also determined before and after exercise. The intervention reduced visceral fat, lowered blood pressure, glucose and lipids, and increased aerobic fitness (P<0.05). Exercise improved clamp-derived insulin sensitivity by 75% (P<0.001) and decreased HOMA-IR by 15% (P<0.05). Training decreased plasma DPP-4 by 10% (421.8±30.1 vs. 378.3±32.5ng/ml; P<0.04), and the decrease in DPP-4 was associated with clamp-derived insulin sensitivity (r=−0.59; P<0.04), HOMA-IR (r=0.59; P<0.04) and fat oxidation (r=−0.54; P<0.05). Increased fat oxidation also correlated with lower 2-h glucose levels (r=−0.64; P<0.02). Exercise training reduces plasma DPP-4, which may be linked to elevated insulin sensitivity and fat oxidation. Maintaining low plasma DPP-4 concentrations is a potential mechanism whereby exercise plus weight loss prevents/delays the onset of type 2 diabetes in adults with metabolic syndrome.

Chronic Administration of Voglibose, an α-Glucosidase Inhibitor, Increases Active Glucagon-Like Peptide-1 Levels by Increasing Its Secretion and Decreasing Dipeptidyl Peptidase-4 Activity in ob/ob Mice

Administration of an alpha-glucosidase inhibitor, voglibose, increases the secretion of glucagon-like peptide (GLP)-1, a key modulator of pancreatic islet hormone secretion and glucose homeostasis. In the present study, novel mechanisms by which voglibose increases active GLP-1 circulation were evaluated. Voglibose (0.001 and 0.005%) was administered in the diet to ob/ob mice for 1 day or 3 to 4 weeks to determine effects on incretin profiles and plasma activity of dipeptidyl peptidase-4 (DPP-4), an enzyme responsible for GLP-1 degradation. Voglibose showed no direct inhibitory effect against DPP-4 in vitro (DPP-4 inhibitor alogliptin, IC(50) < 10 nM). Likewise, 1-day treatment with voglibose did not change plasma DPP-4 activity; however, it increased plasma active GLP-1 by 1.6- to 3.4-fold. After chronic treatment, voglibose stimulated GLP-1 secretion, as evidenced by the 1.3- to 1.5-fold increase in plasma active plus inactive amidated GLP-1 levels. Plasma DPP-4 activity was decreased unexpectedly by 40 to 51%, resulting from reduced plasma DPP-4 concentrations in voglibose-treated mice. Voglibose increased GLP-1 content by 1.5- to 1.6-fold and 1.4- to 1.6-fold in the lower intestine and colon, respectively. The increased GLP-1 content in the colon was associated with elevated expression of gut glucagon gene. Chronic treatment with voglibose resulted in 1.9- to 4.1-fold increase in active GLP-1 circulation, which was higher than 1-day treatment. A similar treatment with pioglitazone (0.03%), an insulin sensitizer, did not affect plasma DPP-4 activity or GLP-1 levels. These results suggest that increased GLP-1 secretion, decreased DPP-4 activity, and increased gut GLP-1 content may have contributed to increased active GLP-1 circulation after chronic treatment with voglibose in a glucose control-independent manner in ob/ob mice.