The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function

AbstractType 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.

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The methanolic extract of Thymus praecox subsp. skorpilii var. skorpilii restores glucose homeostasis, ameliorates insulin resistance and improves pancreatic β-cell function on streptozotocin/nicotinamide-induced type 2 diabetic rats

Journal of Ethnopharmacology ◽

10.1016/j.jep.2018.10.028 ◽

2019 ◽

Vol 231 ◽

pp. 29-38 ◽

Cited By ~ 12

Author(s):

Muhammet Emin Cam ◽

Ayse Nur Hazar-Yavuz ◽

Sila Yildiz ◽

Busra Ertas ◽

Betul Ayaz Adakul ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Homeostasis ◽

Cell Function ◽

Methanolic Extract ◽

Diabetic Rats ◽

Pancreatic Β Cell ◽

Β Cell ◽

Β Cell Function ◽

Type 2 Diabetic

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Translational factor eIF4G1 regulates glucose homeostasis and pancreatic β-cell function

10.2337/figshare.13110335.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Seokwon Jo ◽

Amber Lockridge ◽

Ramkumar Mohan ◽

Nicholas Esch ◽

...

Keyword(s):

Glucose Homeostasis ◽

Cell Function ◽

Scaffolding Protein ◽

Insulin Content ◽

Insulin Biosynthesis ◽

Cell Physiology ◽

Β Cells ◽

Β Cell ◽

Initiation Complex ◽

Β Cell Function

Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling, is associated with diabetes in both humans and mice. In the present study, we tested the hypothesis that eIF4G1 is critical for β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells <i>in vivo</i> (βeIF4G1KO). Adult male and female βeIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. β-cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in both proliferation and apoptosis in β-cells of βeIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca<sup>2+</sup> flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5’-cap binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single β-cells or intact islets of βeIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and β-cell function.

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Conjugated Estrogens and Bazedoxifene Improve β Cell Function in Obese Menopausal Women

Journal of the Endocrine Society ◽

10.1210/js.2019-00074 ◽

2019 ◽

Vol 3 (8) ◽

pp. 1583-1594 ◽

Cited By ~ 1

Author(s):

Dragana Lovre ◽

Erin Peacock ◽

Bonnie Katalenich ◽

Cynthia Moreau ◽

Beibei Xu ◽

...

Keyword(s):

Body Composition ◽

Postmenopausal Women ◽

Glucose Homeostasis ◽

Cell Function ◽

Model Assessment ◽

Β Cell ◽

Conjugated Estrogens ◽

Markers Of Inflammation ◽

Menopausal Women ◽

Β Cell Function

Abstract Context Studies suggest that menopausal hormone therapy (MHT) prevents type 2 diabetes (T2D). The combination of conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is an MHT that improves obesity and T2D in preclinical models of menopausal metabolic syndrome. The effect of CE/BZA on adiposity and glucose homeostasis in obese postmenopausal women is unknown. Objective To investigate the effect of CE/BZA on body composition, glucose homeostasis, and markers of inflammation in obese postmenopausal women. Research Design, Intervention, and Participants Randomized, double-blind, placebo-controlled pilot trial of 12 obese menopausal women assigned to 12-week treatment with CE 0.45 mg/BZA 20 mg (n = 7) or placebo (n = 5). At baseline and after 12 weeks, we assessed body composition (dual-energy X-ray absorptiometry), glucose homeostasis (IV glucose tolerance test), and inflammation biomarkers. Results Women treated with CE/BZA exhibited increased β cell function using homeostatic model assessment-B [median (interquartile range) CE/BZA vs placebo: 18.5 (−0.9 to 320.6) μU/mM vs −25.5 (−39.9 to −0.1) μU/mM; P = 0.045], and decreased basal glucose concentrations (Gb) [−5.2 (−9.2 to −1.7) mg/dL vs 2.7 (0.9 to 4.9) mg/dL; P = 0.029]. Insulin sensitivity was higher in the placebo arm [1.35 (1.12 to 1.82) (μU/mL) min−1 vs −0.24 (−1.50 to 0.19) (μU/mL) min−1; P = 0.029]. No changes between treatment groups were observed for the acute insulin response to glucose (AIRg), the disposition index (DI), body composition, and inflammatory biomarkers. Conclusions A 12-week treatment of obese postmenopausal women with CEs/BZA improves fasting β cell function and glucose concentrations without change in AIRg, HOMA-IR, DI, body composition, or markers of inflammation.

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Inactivation of the dual Bmp/Wnt inhibitor Sostdc1 enhances pancreatic islet function

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00531.2011 ◽

2012 ◽

Vol 303 (6) ◽

pp. E752-E761 ◽

Cited By ~ 24

Author(s):

Kathryn D. Henley ◽

Kimberly A. Gooding ◽

Aris N. Economides ◽

Maureen Gannon

Keyword(s):

Insulin Secretion ◽

Glucose Homeostasis ◽

High Fat Diet ◽

Cell Function ◽

Metabolic Stress ◽

Islet Function ◽

High Fat ◽

Β Cell ◽

Β Cell Function ◽

Bmp Pathway

Current endeavors in the type 2 diabetes (T2D) field include gaining a better understanding of extracellular signaling pathways that regulate pancreatic islet function. Recent data suggest that both Bmp and Wnt pathways are operative in pancreatic islets and play a positive role in insulin secretion and glucose homeostasis. Our laboratory found the dual Bmp and Wnt antagonist Sostdc1 to be upregulated in a mouse model of islet dysmorphogenesis and nonimmune-mediated lean diabetes. Because Bmp signaling has been proposed to enhance β-cell function, we evaluated the role of Sostdc1 in adult islet function using animals in which Sostdc1 was globally deleted. While Sostdc1-null animals exhibited no pancreas development phenotype, a subset of mutants exhibited enhanced insulin secretion and improved glucose homeostasis compared with control animals after 12-wk exposure to high-fat diet. Loss of Sostdc1 in the setting of metabolic stress results in altered expression of Bmp-responsive genes in islets but did not affect expression of Wnt target genes, suggesting that Sostdc1 primarily regulates the Bmp pathway in the murine pancreas. Furthermore, our data indicate that removal of Sostdc1 enhances the downregulation of the closely related Bmp inhibitors Ctgf and Gremlin in islets after 8-wk exposure to high-fat diet. These data imply that Sostdc1 regulates expression of these inhibitors and provide a means by which Sostdc1-null animals show enhanced insulin secretion and glucose homeostasis. Our studies provide insights into Bmp pathway regulation in the endocrine pancreas and reveal new avenues for improving β-cell function under metabolic stress.

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