Dipeptidyl peptidase-4 inhibitor treatment induces a greater increase in plasma levels of bioactive GIP than GLP-1 in non-diabetic subjects

Abstract

ObjectiveGlucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) possess multiple bioactive isoforms that are rendered non-insulinotropic by the enzyme dipeptidyl peptidase-4 (DPP-4). Recently, some ELISA kits have been developed to specifically measure “active” GIP and GLP-1, but it is unclear if these kits can accurately quantify all bioactive forms. Therefore, it remains uncertain to what extent treatment with a DPP-4 inhibitor boosts levels of biologically active GIP and GLP-1. Thus, we evaluated our novel receptor-mediated incretin bioassays in comparison to commercially available ELISA kits using plasma samples from healthy subjects before and after DPP-4 inhibitor administration.MethodsWe utilized cell lines stably co-transfected with human GIP or GLP-1 receptors and a cAMP-inducible luciferase expression construct for the bioassays and commercially available ELISA kits. Assays were tested with synthetic GIP and GLP-1 receptor agonists and plasma samples collected from subjects during a 75 g oral glucose tolerance test (OGTT) performed before or following 3-day administration of a DPP-4 inhibitor.ResultsA GIP isoform GIP(1–30)NH2 increased luciferase activity similarly to GIP(1–42) in the GIP bioassay but was not detectable by either a total or active GIP ELISA kit. During an OGTT, total GIP levels measured by ELISA rapidly increased from 0 min to 15 min, subsequently reaching a peak of 59.2 ± 8.3 pmol/l at 120 min. In contrast, active GIP levels measured by the bioassay peaked at 15 min (43.4 ± 6.4 pmol/l) and then progressively diminished at all subsequent time points. Strikingly, at 15 min, active GIP levels as determined by the bioassay reached levels approximately 20-fold higher after the DPP-4 inhibitor treatment, while total and active GIP levels determined by ELISA were increased just 1.5 and 2.1-fold, respectively. In the absence of DPP-4 inhibition, total GLP-1 levels measured by ELISA gradually increased up to 90 min, reaching 23.5 ± 2.4 pmol/l, and active GLP-1 levels determined by the bioassay did not show any apparent peak. Following administration of a DPP-4 inhibitor there was an observable peak of active GLP-1 levels as determined by the bioassay at 15 min after oral glucose load, reaching 11.0 ± 0.62 pmol/l, 1.4-fold greater than levels obtained without DPP-4 inhibitor treatment. In contrast, total GLP-1 levels determined by ELISA were decreased after DPP-4 inhibitor treatment.ConclusionOur results using bioassays indicate that there is a greater increase in plasma levels of bioactive GIP than GLP-1 in subjects treated with DPP-4 inhibitors, which may be unappreciated using conventional ELISAs.

Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics

“…Identified as a novel adipokine in AT [129], DPP4 is strongly expressed on the apical surfaces of the polarized epithelium of various organs such as lung and liver, and increased DPP4 results in failures to resolve inflammation and chronic subclinical activation of the immune system [128]. Interestingly, DPP4 is upregulated in obesity, especially in the insulin resistance state [129,130]. Inhibition of DPP4 prevented fibrosis in obese white AT [131].…”

Differential Effects of Monounsaturated and Polyunsaturated Fats on Satiety and Gut Hormone Responses in Healthy Subjects

“…Plasma total ghrelin and total GIP concentrations were measured by Elisa kits from Millipore [18]. The intra-assay CV for GIP and ghrelin were 1.8% and 3.6%.…”

Glucose-Dependent Insulinotropic Polypeptide Mitigates 6-OHDA-Induced Behavioral Impairments in Parkinsonian Rats

“…In the present study, in a unilateral 6-OHDA MFB lesion rat model of PD, we demonstrated that GIP treatment stabilized apomorphine-induced rotational behavior and showed positive changes in open field locomotor tests, as well as some anxiety-like behaviors. This was achieved at a plasma active GIP concentration that is achievable in humans by use of a DPP-4 inhibitor [ 24 , 25 ]. To our knowledge, our study is the first to evaluate the action of GIP in a 6-OHDA PD animal model and adds to the growing literature that GIP may be of value as a treatment strategy for PD [ 26 , 27 ].…”

“…A 50% GIP dose reduction resulted in an 80% decline in total, as well as active GIP plasma levels. Importantly, these concentrations are achievable in humans following the use of DPP-4 inhibitors [ 24 , 25 ].…”