Circulating dipeptidyl peptidase-4 is independently associated with the presence and severity of NAFLD/NASH in individuals with and without obesity and metabolic disease.

INTRODUCTION: Dipeptidyl peptidase 4 (DPP4) levels are associated to metabolic and cardiovascular diseases in humans; initial evidence reported a relationship between DPP4 and chronic liver diseases. Aim of this study was to investigate hepatic and systemic DPP4 levels/activity in relation to NAFLD/NASH in individuals with and without metabolic disease. METHODS: We recruited fifty-two obese individuals undergoing bariatric surgery and intra-operative liver biopsy at Sapienza University, Rome, Italy. The association between DPP4 levels/activity and NAFLD was also evaluated in 126 non-obese individuals recruited in the same setting. RESULTS: NAFLD patients had significantly higher circulating DPP4 activity than no-NAFLD in both the obese and non-obese cohorts; plasma DPP4 activity and levels linearly correlated with steatosis grade and inflammation at the liver biopsy. Hepatic DPP4 mRNA was not associated to either its circulating levels/activity or NAFLD. In the multivariate logistic regression analysis on all the study participants (n = 178), higher circulating DPP4 activity was associated with NAFLD independently of potential confounders with OR (95% CI): 3.5 (1.2-10.21), p = 0.022. CONCLUSIONS: This study demonstrates the coexistence of increased plasma DPP4 levels and activity in NAFLD. Circulating DPP4 measurement may represent a novel cost-effective strategy for NAFLD/NASH risk stratification and a potential tool for monitoring disease's progression in established NAFLD.

Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human.

At present, more than 200 countries and territories are directly affected by the coronavirus disease-19 (COVID-19) pandemic. Incidence and case fatality rate are significantly higher among elderly individuals (age>60 years), type 2 diabetes and hypertension patients. Cellular receptor ACE2, serine protease TMPRSS2 and exopeptidase CD26 (also known as DPP4) are the three membrane bound proteins potentially implicated in SARS-CoV-2 infection. We hypothesised that common variants from TMPRSS2 and CD26 may play critical role in infection susceptibility of predisposed population or group of individuals. Coding (missense) and regulatory variants from TMPRSS2 and CD26 were studied across 26 global populations. Two missense and five regulatory SNPs were identified to have differential allelic frequency. Significant linkage disequilibrium (LD) signature was observed in different populations. Modelled protein-protein interaction (PPI) predicted strong molecular interaction between these two receptors and SARS-CoV-2 spike protein (S1 domain). However, two missense SNPs, rs12329760 (TMPRSS2) and rs1129599 (CD26), were not found to be involved physically in the said interaction. Four regulatory variants (rs112657409, rs11910678, rs77675406 and rs713400) from TMPRSS2 were found to influence the expression of TMPRSS2 and pathologically relevant MX1. rs13015258 a 50 UTR variant from CD26 have significant role in regulation of expression of key regulatory genes that could be involved in SARS-CoV-2 internalization. Overexpression of CD26 through epigenetic modification at rs13015258-C allele was found critical and could explain the higher SARS-CoV-2 infected fatality rate among type 2 diabetes.

Assessment of the Multifunctional Behavior of Lupin Peptide P7 and Its Metabolite Using an Integrated Strategy.

LTFPGSAED (P7) is a multifunctional hypocholesterolemic and hypoglycemic lupin peptide. While assessing its angiotensin-converting enzyme (ACE) inhibitory activity, it was more effective in intestinal Caco-2 cells (IC50 of 13.7 µM) than in renal HK-2 cells (IC50 of 79.6 µM). This discrepancy was explained by the metabolic transformation mediated by intestinal peptidases, which produced two main detected peptides, TFPGSAED and LTFPG. Indeed LTFPG, dynamically generated by intestinal dipeptidyl peptidase IV as well as its parent peptide P7 were linearly absorbed by mature Caco-2 cells. An in silico study demonstrated that the metabolite was a better ligand of the ACE enzyme than P7. These results are in agreement with an in vivo study, previously performed by Aluko et al., which has shown that LTFPG is an effective hypotensive peptide. Our work highlights the dynamic nature of bioactive food peptides that may be modulated by the metabolic activity of intestinal cells.

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.

Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here, we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent SARS-CoV-2, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells, and confirm that human ACE2 is the receptor for the recently emerging SARS-CoV-2.

Flow Cytometry Assessment of CD26+ Leukemic Stem Cells in Peripheral Blood: A Simple and Rapid New Diagnostic Tool for Chronic Myeloid Leukemia.

BACKGROUND: Recent investigations in chronic myeloid leukemia (CML) have focused on the identification and characterization of leukemic stem cells (LSCs). These cells reside within the CD34+ /CD38─ /Lin─ fraction and score positive for CD26 (dipeptidylpeptidase IV) a marker, expressed in both bone marrow (BM) and peripheral blood (PB) samples, that discriminates CML cells from normal hematopoietic stem cells (HSCs) or from LSCs of other myeloid neoplasms. CD26 evaluation could be a useful tool to improve the identification of CML LCSs by using flow-cytometry assay. METHODS: CD26+ LSCs have been isolated from EDTA PB and BM samples of patients with leucocytosis suspected for CML. Analysis of LSCs CML has been performed by using custom-made lyophilized pre-titrated antibody mixture test and control tube and a CD45+ /CD34+ /CD38- /CD26+ panel as a strict flow cytometric gating strategy. RESULTS: The expression of CD26 on CD34+ /CD38- population was detectable in 211/211 PB and 84/84 BM samples of subsequently confirmed BCR-ABL+ CP-CML patients. None of the 32 samples suspicious for CML but scoring negative for circulating CD26+ LSCs were diagnosed as CML after conventional cytogenetic and molecular testing. To validate our results, we checked for PB CD26+ LSCs in patients affected by other hematological disorders and they all scored negative for CD26 expression. CONCLUSIONS: We propose flow cytometry evaluation of CD26 expression on PB CD34+ /CD38- population as a new rapid, reproducible, and powerful diagnostic tool for the diagnosis of CML. © 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.

Does the treatment of type 2 diabetes mellitus with the DPP-4 inhibitor vildagliptin reduce HbA1c to a greater extent in Japanese patients than in Caucasian patients?

BACKGROUND: Previous work suggests that Japanese patients with type 2 diabetes mellitus (T2DM) may respond more favorably to a DPP-4 (dipeptidyl peptidase-4) inhibitor than Caucasians. We aimed to compare the efficacy of the DPP-4 inhibitor vildagliptin (50 mg twice daily [bid]) between Japanese and Caucasian populations. METHODS: This analysis pooled data from 19 studies of drug-naïve patients with T2DM who were treated for 12 weeks with vildagliptin 50 mg bid as monotherapy. The pool comprised Japanese patients (n=338) who had been treated in Japan and Caucasian patients (n=1,275) who were treated elsewhere. Change from baseline (Δ) in glycated hemoglobin (HbA1c) at 12 weeks (in millimoles per mole) versus baseline HbA1c (both in percentage National Glycohemoglobin Standardization Program units [NGSP%] and millimoles per mole) for each population was reported. Universal HbA1c in millimoles per mole was calculated from either the Japanese Diabetes Society or the NGSP% HbA1c standards. RESULTS: At baseline, mean values for Japanese and Caucasian patients, respectively, were as follows: age, 59 years and 56 years; % male, 69% and 57%. The average HbA1c was reduced from 7.90% to 6.96% (Japanese Diabetes Society) and from 8.57% to 7.50% (United States National Glycohemoglobin Standardization Program), while HbA1c was reduced from 63 mmol/mol to 53 mmol/mol and from 70 mmol/mol to 58 mmol/mol in Japanese and Caucasians, respectively. ΔHbA1c increased with increasing baseline in both populations. The slopes were the same (0.41, r (2)=0.36; and 0.41, r (2)=0.15), and the intercepts were 15.4 mmol/mol and 17.2 mmol/mol, respectively. In Japanese patients, mean ΔHbA1c was greater by 1.7 mmol/mol (0.2% NGSP HbA1c) at any given baseline HbA1c than in Caucasians (P=0.01). CONCLUSION: The present pooled analysis suggests that Japanese patients respond better to vildagliptin treatment compared with Caucasians. However, when glycemic control was corrected by using the same glycemic standard, the difference in HbA1c reduction between these populations was not clinically meaningful.

[Once-weekly DPP-4 inhibitor].

Trelagliptin is the first once-weekly dipeptidyl peptidase-4(DPP-4) inhibitor in the world. Trelagliptin inhibits DPP-4 activity with lower drug concentration compared with other once- (or twice-) daily DPP-4 inhibitors in in vitro study. More than 70 % of DPP-4 activity is inhibited even 1 week after administration of trelagliptin administration in human study. 24-week trelagliptin monotherapy improved HbA1c(-0.33%) and fasting plasma glucose levels in Japanese patients with type 2 diabetes. Trelagliptin did not affect body weight and frequency of hypoglycemic events in this study. 52-week monotherapy and add-on therapy of trelagliptin also improved HbA1c levels without body weight gain and severe hypoglycemia. Therefore, trelagliptin has high efficacy and safety on glucose control in Japanese patients with type 2 diabetes.

Demographic and Clinical Profiles of Type 2 Diabetes Mellitus Patients Initiating Canagliflozin Versus DPP-4 Inhibitors in a Large U.S. Managed Care Population.

BACKGROUND: Canagliflozin is the first sodium-glucose co-transporter-2 (SGLT-2) inhibitor-a new class of oral antidiabetic (OAD) medication-approved for type 2 diabetes mellitus (T2DM) treatment in the United States. Approved less than 2 years ago, use of canagliflozin is largely uncharacterized. OBJECTIVE: To investigate and compare baseline demographic, clinical, and economic characteristics of patients initiating canagliflozin and dipeptidyl peptidase-4 (DPP-4) inhibitors in the real-world setting. METHODS: Using administrative claims data from a large, geographically diverse U.S. managed care organization, this retrospective study assessed adult T2DM patients (aged ≥ 18 years) initiating treatment with canagli-flozin or DPP-4 agents. Eligible patients had ≥1 medical claim with a T2DM diagnosis and ≥ 1 outpatient pharmacy claim for canagliflozin or a DPP-4 agent between January 1, 2011, and September 30, 2013. Patients with ≥ 1 canagliflozin fill were selected first and assigned to the canagliflozin cohort following a hierarchical approach; the date of the earliest canagliflozin fill was defined as the index date. Remaining patients with DPP-4 fills were then assigned to the DPP-4 cohort, with the index date as the first DPP-4 fill. Only patients with at least 12 months of pre-index (baseline) enrollment were included. Patients with fills for their cohort-defining drug over 3 months before the index date were excluded in order to focus on new initiators. A subset of patients with ≥ 3 months of continuous enrollment following their index dates was used to examine medication patterns after initiation. Patients with hyperglycemia; type 1, gestational, or nonclinical diabetes; or diabetes with hyperosmolar coma were excluded. Demographic, clinical, and economic characteristics were assessed over baseline and compared using two-sample t-tests or chi-square/Fisher's exact tests. Multivariable logistic regression models were built to assess baseline factors associated with initiation of canagliflozin versus DPP-4. RESULTS: Overall, 1,566 patients initiated canagliflozin, and 26,224 patients initiated DPP-4 treatment. Males constituted slightly more than 60% of each treatment group; mean age was approximately 55 years in each cohort. A significantly smaller proportion of canagliflozin patients (41.3%) initiated treatment with endocrinologists compared with DPP-4 patients (69.2%, P less than 0.001), and canagliflozin patients were more likely (29.4%) to initiate treatment with a primary care physician compared with DPP-4 patients (9.9%, P less than 0.001). Comorbidities were present more frequently in canagliflozin initiators: nephropathy (10.6% vs. 7.0%), retinopathy (10.4% vs. 7.5%), dyslipidemia (82.4% vs. 72.2%), and obesity (24.9% vs. 15.6%), respectively (P less than 0.001 for all comparisons). The mean (SD) Quan-Charlson Comorbidity Index score was greater for canagliflozin, 1.05 (1.7), compared with DPP-4 initiators, 0.92 (1.6), P = 0.002. Among the subset of patients with available hemoglobin A1c (A1c) results, a significantly smaller proportion of canagliflozin initiators (16.5%) versus DPP-4 initiators (26.7%) were at the A1c less than 7% treatment goal at baseline (P less than 0.001). Among patients with 3 months follow-up, 89.2% of canagliflozin and 75.1% of DPP-4 initiators had ≥ 1 fill for their index drugs over this time frame. Canagliflozin initiators had significantly greater baseline utilization of office visits, endocrinologist and outpatient services, and more prescription fills. Total diabetes-related medical costs at baseline ($3,025 vs. $3,477 for canagliflozin and DPP-4 initiators) were not significantly different, while mean diabetes-related pharmacy costs were higher in the canagliflozin group ($4,037 vs. $1,411, P less than 0.001). Regression analysis indicated that baseline insulin and glucagon-like peptide-1 use, as well as comorbid dyslipidemia and obesity, were significantly associated with the initiation of canagliflozin versus DPP-4 agents. CONCLUSIONS: In this sample of commercially insured patients within a large managed care plan, canagliflozin was often initiated as second- or third-line therapy, with a relatively high share of patients receiving concomitant antidiabetic injectables, compared with DPP-4 initiators. Canagliflozin initiators had highly elevated A1c levels and were frequently diagnosed with other metabolic conditions. Baseline pharmacy utilization and costs were higher among canagliflozin patients. Future research is needed to assess real-world clinical outcomes after canagliflozin initiation, while taking these baseline differences into account.

Improvement of glycemic control in streptozotocin-induced diabetic rats by Atlantic salmon skin gelatin hydrolysate as the dipeptidyl-peptidase IV inhibitor.

In our previous study, Atlantic salmon skin gelatin hydrolysed with flavourzyme possessed 42.5% dipeptidyl-peptidase (DPP)-IV inhibitory activity at a concentration of 5 mg mL(-1). The oral administration of the hydrolysate (FSGH) at a single dose of 300 mg per day in streptozotocin (STZ)-induced diabetic rats for 5 weeks was evaluated for its antidiabetic effect. During the 5-week experiment, body weight increased, and the food and water intake was reduced by FSGH in diabetic rats. The daily administration of FSGH for 5 weeks was effective for lowering the blood glucose levels of diabetic rats during an oral glucose tolerance test (OGTT). After the 5-week treatment, plasma DPP-IV activity was inhibited; the plasma activity of glucagon-like peptide-1 (GLP-1), insulin, and the insulin-to-glucagon ratio were increased by FSGH in diabetic rats. The results indicate that FSGH has the function of inhibiting GLP-1 degradation by DPP-IV, resulting in the enhancement of insulin secretion and improvement of glycemic control in STZ-induced diabetic rats.

Review of models used in economic analyses of new oral treatments for type 2 diabetes mellitus.

BACKGROUND: Economic models are considered to be important, as they help evaluate the long-term impact of diabetes treatment. To date, it appears that no article has reviewed and critically appraised the cost-effectiveness models developed to evaluate new oral treatments [glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] for type 2 diabetes mellitus (T2DM). OBJECTIVES: This study aimed to provide insight into the utilization of cost-effectiveness modelling methods. The focus of our study was aimed at the applicability of these models, particularly around the major assumptions related to the clinical parameters (glycated haemoglobin [A1c], systolic blood pressure [SBP], lipids and weight) used in the models, and subsequent clinical outcomes. METHODS: MEDLINE and EMBASE were searched from 1 January 2004 to 14 February 2013 in order to identify published cost-effectiveness evaluations for the treatment of T2DM by new oral treatments (GLP-1 receptor agonists and DPP-4 inhibitors). Once identified, the articles were reviewed and grouped together according to the type of model. The following data were captured for each study: comparators; country; evaluation and key cost drivers; time horizon; perspective; discounting rates; currency/year; cost-effectiveness threshold, sensitivity analysis; and cost-effectiveness analysis curves. RESULTS: A total of 15 studies were identified in our review. Nearly all of the models utilized a health care payer perspective and provided a lifetime horizon. The CORE Diabetes Model, UK Prospective Diabetes Study (UKPDS) Outcomes Model, Cardiff Diabetes Model, Centers for Disease Control and Prevention (CDC) Diabetes Cost-Effectiveness Group Model and Diabetes Mellitus Model were cited. With the exception of two studies, all of the studies made significant assumptions surrounding the impact of GLP-1 receptor agonists or DPP-4 inhibitors on clinical parameters and subsequent short- and long-term outcomes. Moreover, often the differences in the clinical parameters were relatively small (e.g. 1 or 2 mmHg in blood pressure) and would not be considered by many as clinically important. Yet, the impact of these small clinical changes often resulted in large lifetime changes in health outcomes in the models. In particular, many studies assumed that changes in weight associated with the therapies would equate to improved outcomes, despite limited evidence for this assumption. Although the new oral treatments were regarded as cost effective in most studies based upon the studies reviewed, the validity of these projections, particularly for the longer time frames, is questionable. Indeed, although most of these studies have been conducted in the last 5 years, recent trial evidence has already questioned the validity of most of these studies. CONCLUSION: It is clear that a number of changes are required in the evaluation of diabetes therapies. First and foremost, the basic models need to be updated to include contemporary important clinical trial data assessing hard clinical outcomes in patients with diabetes. Second, there should be less emphasis on 40-year or lifetime costs and consequences of the therapies and a greater focus on short-term (5-year) and intermediate-term (10-year) outcomes. Practice is continually evolving, and the probability that these models would provide any valid predictions beyond 10 years is remote. Third, all modellers should immediately remove the basic assumption that small clinically inconsequential changes in A1c, SBP, lipids and weight result in major clinical improvements in patients. Future models should aim to include all relevant treatment outcomes, whether these relate to effects on underlying diabetes and its complications or to short- or long-term side effects of treatment. We need to explore why cost-saving interventions could benefit further from adding patient characteristics, which may be able to better predict the use of lower-cost alternatives. Moreover, the vast array of different clinical, cost and utility data used in the different models reviewed makes it apparent that a uniform methodology should be developed for diabetes economic models. In this manner, future models could be run using the same data, which would allow for more acceptable comparability between studies.

Growth ability and repopulation efficiency of transplanted hepatic stem cells, progenitor cells, and mature hepatocytes in retrorsine-treated rat livers.

Cell-based therapies as an alternative to liver transplantation have been anticipated for the treatment of potentially fatal liver diseases. Not only mature hepatocytes (MHs) but also hepatic stem/progenitor cells are considered as candidate cell sources. However, whether the stem/progenitor cells have an advantage to engraft and repopulate the recipient liver compared with MHs has not been comprehensively assessed. Therefore, we used Thy1(+) (oval) and CD44(+) (small hepatocytes) cells isolated from GalN-treated rat livers as hepatic stem and progenitor cells, respectively. Cells from dipeptidylpeptidase IV (DPPIV)(+) rat livers were transplanted into DPPIV(-) livers treated with retrorsine following partial hepatectomy. Both stem and progenitor cells could differentiate into hepatocytes in host livers. In addition, the growth of the progenitor cells was faster than that of MHs until days 14. However, their repopulation efficiency in the long term was very low, since the survival period of the progenitor cells was much shorter than that of MHs. Most foci derived from Thy1(+) cells disappeared within 2 months. Many cells expressed senescence-associated ß-galactosidase in 33% of CD44-derived foci at day 60, whereas the expression was observed in 13% of MH-derived ones. The short life of the cells may be due to their cellular senescence. On the other hand, the incorporation of sinusoidal endothelial cells into foci and sinusoid formation, which might be correlated to hepatic maturation, was completed faster in MH-derived foci than in CD44-derived ones. The survival of donor cells may have a close relation to not only early integration into hepatic plates but also the differentiated state of the cells at the time of transplantation.

Expression and prognostic assessment of dipeptidyl peptidase IV and related enzymes in B-cell chronic lymphocytic leukemia.

Recent observations of the deregulated expression of several dipeptidyl peptidase (DP) IV-like enzymes in human cancers have led to presumptions of their pathogenic role in cancer. To further explore this concept we have characterized the expression of all DPIV-like enzymes in chronic lymphocytic leukemia (CLL). We have demonstrated the constitutive expression of DPIV, DP8, DP9, DPII and PEP mRNA and DPIV, DP8 and DP9 protein in CLL. FAP mRNA was not detected in CLL or normal B-lymphocytes. This correlated with an absence of FAP protein on the cell surface. This study also shows that DP8 mRNA expression is significantly upregulated in CLL compared to normal tonsil B-lymphocytes (p < 0.05) which may suggest biological importance in this disease. DP expression could not be correlated with any molecular or clinical prognostic markers for CLL in this cohort including IgVH mutational status, CD38, ZAP-70 or CD49d expression (n = 58). However, the constitutive expression of the DPIV-like enzymes in CLL and their emergence as potent immune regulators makes them candidate therapeutic targets in this disease.

Efficient simulation of ligand-receptor binding processes using the conformation dynamics approach.

The understanding of biological ligand-receptor binding processes is relevant for a variety of research topics and assists the rational design of novel drug molecules. Computer simulation can help to advance this understanding, but, due to the high dimensionality of according systems, suffers from the severe computational cost. Based on the framework provided by conformation dynamics and transition state theory, a novel heuristic approach of simulating ligand-receptor binding processes is introduced, which is not dependent on calculating lengthy molecular dynamics trajectories. First, the relevant portion of conformational space is partitioned with meshless methods. Then, each region is sampled separately, using hybrid Monte Carlo. Finally, the dynamical binding process is reconstructed from the static overlaps between the partial densities obtained in the sampling step. The method characterizes the metastable steps of the binding process and can yield the corresponding transition probabilities.

Pituitary adenylate cyclase-activating peptide (PACAP): assessment of dipeptidyl peptidase IV degradation, insulin-releasing activity and antidiabetic potential.

Pituitary adenylate cyclase-activating peptide (PACAP) is a member of the glucagon family of peptides. Like other members, most notably glucagon-like peptide-1 (GLP-1), PACAP is rapidly degraded by dipeptidylpeptidase IV (DPP IV). This study investigated how degradation by DPP IV affected the insulinotropic activity of PACAP, and whether PACAP exerted acute antihyperglycemic properties in normal or ob/ob mice. DPP IV degradation of PACAP(1-27) over 18 h led to the formation of PACAP(3-27), PACAP(5-27) and ultimately PACAP(6-27). In contrast to 1.4-1.8-fold concentration-dependent stimulation of insulin secretion by PACAP(1-27), these peptide fragments lacked insulinotropic activity. While PACAP(1-27) and PACAP(1-38) generated significant insulin responses when given alone or together with glucose in ob/ob and normal mice, they also elevated plasma glucose. These actions were eliminated following degradation of the peptide by incubation with DPP IV. The hyperglycemic effects may be explained at least partly by a potent glucagon-releasing action in ob/ob and normal mice. In conclusion, PACAP is inactivated by DPP IV and despite insulin-releasing effects, its actions on glucagon secretion and glucose homeostasis do not make it a good therapeutic tool for the treatment of type 2 diabetes.

Therapeutic assessment of glucagon-like peptide-1 agonists compared with dipeptidyl peptidase IV inhibitors as potential antidiabetic drugs.

The most prevalent form of diabetes is non-insulin-dependent or Type 2 diabetes. Innovative strategies to enhance insulin secretion and thereby improve glucose tolerance in patients with this type of diabetes are currently under preclinical and clinical investigation. These therapies include the applications of incretin hormones; gut hormones released postprandially that stimulate insulin secretion in pancreatic beta-cells. Because incretin actions are rapidly terminated by N-terminal cleavage of these peptide hormones by the amino-peptidase dipeptidyl peptidase IV (DPP IV, CD26), the utility of DPP IV inhibitors for the treatment of Type 2 diabetes is also under investigation. This review compares the therapeutic potential and possible side effects of metabolically stable analogues/peptide agonists of the incretin glucagon-like peptide-1 (GLP-1) with the application of DPP IV inhibitors that reduce the rate of endogenous degradation of GLP-1 and other incretins. GLP-1 analogues have been shown to be highly efficacious in the treatment of Type 2 diabetes, with minimal side effects. Of particular importance is the fact that they do not induce hypoglycaemia. However, they are currently available only in an injectable form. In contrast, DPP IV inhibitors have the clear advantage of oral application resulting in better patient compliance. Furthermore, they also potentiate the actions of other incretins normally degraded by the action of DPP IV. However, they possess more potential side effects. Taken together, both approaches offer promising new drugs for the treatment of Type 2 diabetes.