scholarly journals A novel neurotensin/xenin fusion peptide enhances beta cell function and exhibits antidiabetic efficacy in high fat fed mice

2021 ◽  
Author(s):  
Rachele Perry ◽  
Sarah L Craig ◽  
Victor A Gault ◽  
Peter Flatt ◽  
Nigel Irwin
Keyword(s):  
Treatment Group ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Combined Treatment ◽  
Fusion Peptide ◽  
Biologically Active ◽  
Oral Glucose ◽  
High Fat

Neurotensin and xenin possess antidiabetic potential, mediated in part through augmentation of incretin hormone, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), action. In this study, fragment peptides of neurotensin and xenin, acetyl-neurotensin (8-13) and xenin-8-Gln, were fused together to create Ac-NT/XN-8-Gln. Following assessment of enzymatic stability, effects of Ac-NT/XN-8-Gln on in vitro beta-cell function were studied. Sub-chronic antidiabetic efficacy of Ac-NT/XN-8-Gln alone, and in combination with the clinically approved GLP-1 receptor agonist exendin-4, was assessed in high fat fed (HFF) mice. Ac-NT/XN-8-Gln was highly resistant to plasma enzyme degradation and induced dose-dependent insulin-releasing actions (p<0.05 to p<0.01) in BRIN-BD11 beta-cells and isolated mouse islets. Ac-NT/XN-8-Gln augmented (p<0.001) the insulinotropic actions of GIP, while possessing independent beta-cell proliferative (p<0.001) and anti-apoptotic (p<0.01) actions. Twice daily treatment of HFF mice with Ac-NT/XN-8-Gln for 32 days improved glycaemic control and circulating insulin, with benefits significantly enhanced by combined exendin-4 treatment. This was reflected by reduced body fat mass (p<0.001), improved circulating lipid profile (p<0.01) and reduced HbA1c concentrations (p<0.01) in the combined treatment group. Following an oral glucose challenge, glucose levels were markedly decreased (p<0.05) only in combination treatment group and superior to exendin-4 alone, with similar observations made in response to glucose plus GIP injection. The combined treatment group also presented with improved insulin sensitivity, decreased pancreatic insulin content as well as increased islet and beta-cell areas. These data reveal that Ac-NT/XN-8-Gln is a biologically active neurotensin/xenin fusion peptide that displays prominent antidiabetic efficacy when administered together with exendin-4.

scholarly journals ZBED6 counteracts high-fat diet-induced glucose intolerance by maintaining beta cell area and reducing excess mitochondrial activation

Diabetologia ◽  
2021 ◽  
Author(s):  
Xuan Wang ◽  
Shady Younis ◽  
Jing Cen ◽  
Yun Wang ◽  
Camilla Krizhanovskii ◽  
...  
Keyword(s):  
Beta Cell ◽  
Glucose Intolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Beta Cell Function ◽  
Cell Function ◽  
Cell Area ◽  
High Fat ◽  
Beta Cell Area

Abstract Aims/hypothesis ZBED6 (zinc finger, BED-type containing 6) is known to regulate muscle mass by suppression of Igf2 gene transcription. In insulin-producing cell lines, ZBED6 maintains proliferative capacity at the expense of differentiation and beta cell function. The aim was to study the impact of Zbed6 knockout on beta cell function and glucose tolerance in C57BL/6 mice. Methods Beta cell area and proliferation were determined in Zbed6 knockout mice using immunohistochemical analysis. Muscle and fat distribution were assessed using micro-computed tomography. Islet gene expression was assessed by RNA sequencing. Effects of a high-fat diet were analysed by glucose tolerance and insulin tolerance tests. ZBED6 was overexpressed in EndoC-βH1 cells and human islet cells using an adenoviral vector. Beta cell cell-cycle analysis, insulin release and mitochondrial function were studied in vitro using propidium iodide staining and flow cytometry, ELISA, the Seahorse technique, and the fluorescent probes JC-1 and MitoSox. Results Islets from Zbed6 knockout mice showed lowered expression of the cell cycle gene Pttg1, decreased beta cell proliferation and decreased beta cell area, which occurred independently from ZBED6 effects on Igf2 gene expression. Zbed6 knockout mice, but not wild-type mice, developed glucose intolerance when given a high-fat diet. The high-fat diet Zbed6 knockout islets displayed upregulated expression of oxidative phosphorylation genes and genes associated with beta cell differentiation. In vitro, ZBED6 overexpression resulted in increased EndoC-βH1 cell proliferation and a reduced glucose-stimulated insulin release in human islets. ZBED6 also reduced mitochondrial JC-1 J-aggregate formation, mitochondrial oxygen consumption rates (OCR) and mitochondrial reactive oxygen species (ROS) production, both at basal and palmitate + high glucose-stimulated conditions. ZBED6-induced inhibition of OCR was not rescued by IGF2 addition. ZBED6 reduced levels of the mitochondrial regulator PPAR-γ related coactivator 1 protein (PRC) and bound its promoter/enhancer region. Knockdown of PRC resulted in a lowered OCR. Conclusions/interpretation It is concluded that ZBED6 is required for normal beta cell replication and also limits excessive beta cell mitochondrial activation in response to an increased functional demand. ZBED6 may act, at least in part, by restricting PRC-mediated mitochondrial activation/ROS production, which may lead to protection against beta cell dysfunction and glucose intolerance in vivo. Graphical abstract

Nr4a1 and Nr4a3 Knock Out Mice Have Impaired Glucose Clearance and Beta-Cell Function under High-Fat Feeding

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 2040-P
Author(s):  
COURTNEY J. SMITH ◽  
KYLE B. KENER ◽  
JEFFERY S. TESSEM
Keyword(s):  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
High Fat ◽  
Knock Out ◽  
Glucose Clearance ◽  
Knock Out Mice ◽  
Fat Feeding

[I10W]tigerinin-1R enhances both insulin sensitivity and pancreatic beta cell function and decreases adiposity and plasma triglycerides in high-fat mice

2015 ◽  
Vol 53 (2) ◽  
pp. 303-315 ◽  
Author(s):  
Dinesh K. Srinivasan ◽  
Opeolu O. Ojo ◽  
Bosede O. Owolabi ◽  
J. Michael Conlon ◽  
Peter R. Flatt ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
High Fat ◽  
Plasma Triglycerides ◽  
Pancreatic Beta Cell Function

scholarly journals Dipeptidyl-Peptidase-IV Inhibitors, Imigliptin and Alogliptin, Improve Beta-Cell Function in Type 2 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Xu Liu ◽  
Yang Liu ◽  
Hongzhong Liu ◽  
Haiyan Li ◽  
Jianhong Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Dipeptidyl Peptidase ◽  
Chinese Patients ◽  
Oral Glucose ◽  
Model Assessment

ObjectsImigliptin is a novel dipeptidyl peptidase-4 inhibitor. In the present study, we aimed to evaluate the effects of imigliptin and alogliptin on insulin resistance and beta-cell function in Chinese patients with type-2 diabetes mellitus (T2DM).MethodsA total of 37 Chinese T2DM patients were randomized to receive 25 mg imigliptin, 50 mg imigliptin, placebo, and 25 mg alogliptin (positive drug) for 13 days. Oral glucose tolerance tests were conducted at baseline and on day 13, followed by the oral minimal model (OMM).ResultsImigliptin or alogliptin treatment, compared with their baseline or placebo, was associated with higher beta-cell function parameters (φs and φtot) and lower glucose area under the curve (AUC) and postprandial glucose levels. The changes in the AUC for the glucose appearance rate between 0 and 120 min also showed a decrease in imigliptin or alogliptin groups. However, the insulin resistance parameter, fasting glucose, was not changed. For the homeostatic model assessment (HOMA-β and HOMA-IR) parameters or secretory units of islets in transplantation index (SUIT), no statistically significant changes were found both within treatments and between treatments.ConclusionsAfter 13 days of treatment, imigliptin and alogliptin could decrease glycemic levels by improving beta-cell function. By comparing OMM with HOMA or SUIT results, glucose stimulation might be more sensitive for detecting changes in beta-cell function.

scholarly journals AAV8-mediated gene transfer of microRNA-132 improves beta cell function in mice fed a high-fat diet

2019 ◽  
Vol 240 (2) ◽  
pp. 123-132 ◽  
Author(s):  
Niels L Mulder ◽  
Rick Havinga ◽  
Joost Kluiver ◽  
Albert K Groen ◽  
Janine K Kruit
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Gene Transfer ◽  
Beta Cell ◽  
Beta Cells ◽  
High Fat Diet ◽  
Beta Cell Function ◽  
Cell Function ◽  
Beta Cell Proliferation ◽  
High Fat

MicroRNAs have emerged as essential regulators of beta cell function and beta cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta cell function in vivo. To overexpress miR-132 specifically in beta cells, we employed adeno-associated virus (AAV8)-mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR-132 did not impact glucose homeostasis in chow-fed animals. Overexpression of miR-132 did improve insulin secretion and hence glucose homeostasis in high-fat diet-fed mice. Furthermore, miR-132 overexpression increased beta cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8-mediated gene transfer of miR-132 to beta cells improves beta cell function in mice in response to a high-fat diet. This suggests that increased miR-132 expression is beneficial for beta cell function during hyperglycemia and obesity.

scholarly journals Advancing Dinner Timing Is an Effective Strategy in Improving Glucose Tolerance in Free-Living Adults: A Randomized Cross-Over Trial

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 585-585
Author(s):  
Hassan Dashti ◽  
Jesus Lopez ◽  
Céline Vetter ◽  
Millán Pérez-Ayala ◽  
Juan Carlos Baraza ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Disease Risk ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Effective Strategy ◽  
Free Living

Abstract Objectives Eating at times that conflict with our physiology and coincide with the biological evening has been associated with increased disease risk. In free-living adults from the ONTIME-MT study (#NCT03036592) study, we tested the hypothesis that advancing the timing of dinner relative to bedtime, simulated by advancing an evening oral glucose tolerance test (OGTT), will result in improved glucose control. Methods In a randomized, cross-over study design, following an 8h fast, each participant underwent two evening 2-hour 75-gram oral OGTT: early and late (4h vs. 1h prior to habitual bedtime), simulating early and late dinner timing. Habitual bedtime was determined using one-week of electronic sleep logs via smartphone application. The OGTT order was randomized and separated by 1-week washout period. Light intensity was kept bright (≥450 lux) and dim (0–25 lux) in the early and late conditions, respectively. Melatonin was assessed at the start and end of each OGTT by radioimmunoassay. Postprandial glucose and insulin were determined using incremental area under the curve (AUC). Insulin sensitivity and beta-cell function were evaluated using standard metrices: insulin sensitivity index (ISI), corrected insulin response (CIR), and disposition index (DI). Values were compared using paired t-tests and differences were considered significant at P < 0.05. Results A total of 750 participants (mean age = 37 ± 14; 70% female; mean BMI = 26.12 ± 5.66) underwent OGTTs in two evening timing conditions. As expected, melatonin levels were higher in the late vs. early condition (4.49 ± 4.15-fold lower in the early vs. late meal condition. In the early condition, there was an 8.68% lower AUC for glucose (P = .0001) and 4.4% higher insulin AUC (P = 0.059), relative to the late condition. In addition, the CIR was 16% (P = .0001) higher and the DI was higher by 20% (P = .014) in the early compared to the late condition. The ISI was similar in both conditions (P = 0.66). Conclusions In this large study, glucose tolerance was better during early vs. late evening OGTT. Better glucose tolerance was primarily attributed to improved insulin secretion and beta-cell function. These results indicate that for the general population, advancing dinner relative to bedtime may be a novel and an effective strategy to improve glucose tolerance. Funding Sources ONTIME-MT was funded by the NIH R01 grant R01DK105072.

Sign in / Sign up

Export Citation Format

Share Document