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

scholarly journals Impaired compensatory beta-cell function and growth in response to high-fat diet in LDL receptor knockout mice

2014 ◽  
Vol 95 (4) ◽  
pp. 296-308 ◽  
Author(s):  
Ricardo B. d. Oliveira ◽  
Carolina P. d. F. Carvalho ◽  
Carla C. Polo ◽  
Gabriel d. G. Dorighello ◽  
Antônio C. Boschero ◽  
...  
Keyword(s):  
Beta Cell ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Beta Cell Function ◽  
Cell Function ◽  
Ldl Receptor ◽  
High Fat ◽  
Ldl Receptor Knockout Mice

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.

PS2 - 7. MicroRNA-132 improves beta-cell function in high-fat diet fed mice

2013 ◽  
Vol 11 (4) ◽  
pp. 186-186
Author(s):  
Janine K. Kruit ◽  
Niels L. Mulder ◽  
Rick Havinga ◽  
Albert K. Groen
Keyword(s):  
Beta Cell ◽  
High Fat Diet ◽  
Beta Cell Function ◽  
Cell Function ◽  
High Fat

scholarly journals BLUEBERRY JUICE AND ANTHOCYANINS MODULATE OBESITY, LEPTIN AND BETA CELL FUNCTION IN MICE FED A HIGH FAT DIET

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Ronald L. Prior ◽  
S. Wilkes ◽  
T. Rogers ◽  
R. C. Khanal ◽  
X. Wu ◽  
...  
Keyword(s):  
Beta Cell ◽  
High Fat Diet ◽  
Beta Cell Function ◽  
Cell Function ◽  
High Fat ◽  
Blueberry Juice

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 Influence of a high-fat diet during chronic hyperglycemia on beta-cell function in pancreatic islet transplants to streptozotocin-diabetic rats

2001 ◽  
pp. 521-527 ◽  
Author(s):  
S Hiramatsu ◽  
V Grill
Keyword(s):  
Fatty Acids ◽  
Beta Cell ◽  
High Fat Diet ◽  
Beta Cell Function ◽  
Cell Function ◽  
High Fat ◽  
Negative Effects ◽  
Low Fat ◽  
Low Fat Diet ◽  
Chronic Hyperglycemia

Chronically elevated non-esterified fatty acids (NEFAs) can exert negative effects on beta-cell function both in vitro and in vivo. Negative effects of fatty acids have been difficult to evaluate in overt diabetes because of the attendant hyperglycemia that gives rise to the confounding influence of 'glucotoxicity'. In this work, we tested for the effects of NEFAs in diabetes by (i) taking into account potential effects of prevailing levels of hyperglycemia, and (ii) focusing on lingering (and therefore possibly more serious) effects. A diabetic transplantation model was used in which two islet grafts with 200 and 20 rat islets respectively were transplanted under the kidney capsule of syngeneic recipients previously made diabetic by streptozotocin injection. Rats were then fed either a high-fat or a low-fat diet for 7 weeks, followed by 1 week of normal laboratory chow. During dietary intervention, food was consumed ad libitum in one protocol, but was restricted in the low-fat group in a second protocol (in order to match blood-glucose levels). A high-fat diet did not affect body weight. At the end of the protocols, graft-bearing kidneys were isolated and perfused. Insulin responses to 27.8 mM glucose in perfusion were uniformly absent, in keeping with previously documented effects of chronic hyperglycemia. In contrast, 10 mM arginine induced a marked increase in insulin secretion after a low-fat diet, an effect that was significantly reduced after a high-fat diet (109 +/- 39 vs 13 +/- 15 fmol/min (P < 0.05) and 95 +/- 18 vs 32 +/- 5 fmol/min (P < 0.05) in the 2 protocols respectively). Regardless of protocol, no effect of diet could be detected on graft contents of insulin or preproinsulin mRNA. Thus, under conditions in which influences of chronic hyperglycemia could be accounted for, a previous high-fat diet with elevated NEFAs inhibited arginine-induced insulin secretion; however, the results indicate that insulin biosynthesis and/or beta-cell mass were not affected.

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

scholarly journals Investigation of the progress in the women with gestational diabetes mellitus postpartum

2021 ◽  
pp. 45-51
Author(s):  
Thi To Nhu Phan ◽  
Trung Vinh Hoang
Keyword(s):  
Diabetes Mellitus ◽  
Logistic Regression ◽  
Glucose Tolerance ◽  
Beta Cell ◽  
Glucose Intolerance ◽  
Beta Cell Function ◽  
Cell Function ◽  
Postpartum Women ◽  
Matsuda Index ◽  
History Of

Aims: Our aim was to evaluate the uptake of postpartum screening, the prevalence and the risk factors for glucose intolerance in women with a recent history of gestational diabetes mellitus (GDM). Methods: All women with a history of GDM are advised to undergo a 75g oral glucose tolerance test (OGTT) around 6 - 12 weeks postpartum. Indices of insulin sensitivity (the Matsuda index and the reciprocal of the homeostasis model assessment of insulin resistance, HOMA-IR) and an index of beta-cell function, the Insulin Secretion-Sensitivity Index-2 (ISSI-2) were calculated based on the OGTT postpartum. Multivariable logistic regression was used to some factors. Results: Of all women (135) who received an OGTT postpartum, 42.2% (57) had glucose intolerance (11.8% impaired fasting glucose, 24.4% impaired glucose tolerance and 6.0% both impaired fasting and impaired glucose tolerance) and 1.5% (2) had overt diabetes. Compared to women with a normal OGTT postpartum, women with glucose intolerance and diabetes were older (32.5 ± 4.3 vs. 30.8 ± 4.8 years, p = 0.049), were more often obese (34.5% vs. 17.3%, p = 0.023). In the multivariable logistic regression, an EM background [OR = 2.76 (1.15 - 6.62), p = 0.023] and the HbA1c level at the time of the OGTT in pregnancy [OR = 4.78 (1.19 - 19.20), p = 0.028] remained significant predictors for glucose intolerance postpartum. Women with glucose intolerance and diabetes postpartum had a similar insulin sensitivity [Matsuda index 0.656 (0.386 - 1.224) vs. 0.778 (0.532 - 1.067), p = 0.709; HOMA-IR 0.004 (0.002 - 0.009) vs. 0.064 (0.003 - 0.007), p = 0.384] but a lower beta-cell function compared to women with a normal OGTT postpartum, remaining significant after adjustment for confounders [ISSI-2 1.6 (1.2 - 2.1) vs. 1.9 (1.7 - 2.4), p = 0.002]. Conclusions: Glucose intolerance is very frequent in early postpartum in women with GDM these women have an impaired beta-cell function. Nearly one third of women did not attend the scheduled OGTT postpartum and these women have an adverse risk profile. More efforts are needed to engage and stimulate women with GDM to attend the postpartum OGTT.

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