(Val8)GLP-1-Glu-PAL: a GLP-1 Agonist That Improves Hippocampal Neurogenesis, Glucose Homeostasis, and β-Cell Function in High-Fat-Fed Mice

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.

Download Full-text

Zinc Supplementation Improves Glucose Homeostasis in High Fat-Fed Mice by Enhancing Pancreatic β-Cell Function

Nutrients ◽

10.3390/nu9101150 ◽

2017 ◽

Vol 9 (10) ◽

pp. 1150 ◽

Cited By ~ 11

Author(s):

Vinícius Cooper-Capetini ◽

Diogo de Vasconcelos ◽

Amanda Martins ◽

Sandro Hirabara ◽

José Donato Jr. ◽

...

Keyword(s):

Glucose Homeostasis ◽

Cell Function ◽

Zinc Supplementation ◽

Pancreatic Β Cell ◽

High Fat ◽

Β Cell ◽

Β Cell Function

Download Full-text

Neprilysin Deficiency Is Associated With Expansion of Islet β-Cell Mass in High Fat-Fed Mice

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155418765164 ◽

2018 ◽

Vol 66 (7) ◽

pp. 523-530 ◽

Cited By ~ 5

Author(s):

Jacqueline H. Parilla ◽

Rebecca L. Hull ◽

Sakeneh Zraika

Keyword(s):

Glucose Homeostasis ◽

High Fat Diet ◽

Cell Function ◽

Cell Mass ◽

Regulatory Peptides ◽

Wild Type ◽

High Fat ◽

Β Cell ◽

Beneficial Effects ◽

Β Cell Function

Neprilysin (NEP) is an endopeptidase known to modulate nervous, cardiovascular, and immune systems via inactivation of regulatory peptides. In addition, it may also contribute to impaired glucose homeostasis as observed in type 2 diabetes (T2D). Specifically, we and others have shown that NEP is upregulated under conditions associated with T2D, whereas NEP deficiency and/or inhibition improves glucose homeostasis via enhanced glucose tolerance, insulin sensitivity, and pancreatic β-cell function. Whether increased β-cell mass also occurs with lack of NEP activity is unknown. We sought to determine whether NEP deficiency confers beneficial effects on β- and α-cell mass in a mouse model of impaired glucose homeostasis. Wild-type and NEP−/− mice were fed low- or high-fat diet for 16 weeks, after which pancreatic β- and α-cell mass were assessed by immunostaining for insulin and glucagon, respectively. Following low-fat feeding, NEP−/− mice exhibited lower β- and α-cell mass compared with wild-type controls. A high-fat diet had no effect on these parameters in wild-type mice, but in NEP−/− mice, it resulted in the expansion of β-cell mass. Our findings support a role for NEP in modulating β-cell mass, making it an attractive T2D drug target that acts via multiple mechanisms to affect glucose homeostasis.

Download Full-text

TGS1: a novel regulator of β-cell mass and function

10.1101/2021.09.20.461105 ◽

2021 ◽

Author(s):

Manuel Blandino-Rosano ◽

Pau Romaguera-Llacer ◽

Ashley Lin ◽

Janardan K Reddy ◽

Ernesto Bernal-Mizrachi

Keyword(s):

Cell Cycle ◽

Glucose Homeostasis ◽

High Fat Diet ◽

Cell Function ◽

Cell Mass ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Β Cell Function ◽

And Function

Type 2 diabetes (T2D) is a metabolic disorder associated with abnormal glucose homeostasis and is characterized by intrinsic defects in β-cell function and mass. Trimethylguanosine synthase 1 (TGS1) is an evolutionarily conserved enzyme that methylates small nuclear and nucleolar RNAs (snRNAs and snoRNAs) and is involved in pre-mRNA splicing, transcription, and ribosome production. However, the role of TGS1 in β-cells and glucose homeostasis had not been explored. Here we show that TGS1 is upregulated by insulin and upregulated in islets from mice exposed to a high-fat diet and in human β-cells from T2D donors. Using mice with conditional (βTGS1KO and βTGS1Het) and inducible (MIP-CreERT-TGS1KO) TGS1 deletion, we determine that TGS1 regulates β-cell mass and function. Unbiased approaches allowed us to identify a link between TGS1 and ER stress and cell cycle arrest and how TGS1 regulates β-cell apoptosis. Deletion of TGS1 results in an increase in the unfolded protein response by increasing XBP-1, ATF-4, and the phosphorylation of eIF2α, and several changes in cell cycle inhibitors and activators such as p27 and Cyclin D2. This study establishes TGS1 as a key player regulating β-cell mass and function as well as playing a role in the adaptive β-cell function to a high-fat diet. These observations can be used as a stepping-stone for the design of novel strategies using TGS1 as a therapeutic target for the treatment of diabetes.

Download Full-text

Soy Leaf Extract Containing Kaempferol Glycosides and Pheophorbides Improves Glucose Homeostasis by Enhancing Pancreatic β-Cell Function and Suppressing Hepatic Lipid Accumulation in db/db Mice

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.5b01639 ◽

2015 ◽

Vol 63 (32) ◽

pp. 7198-7210 ◽

Cited By ~ 20

Author(s):

Hua Li ◽

Hyeon-Seon Ji ◽

Ji-Hyun Kang ◽

Dong-Ha Shin ◽

Ho-Yong Park ◽

...

Keyword(s):

Glucose Homeostasis ◽

Lipid Accumulation ◽

Leaf Extract ◽

Cell Function ◽

Pancreatic Β Cell ◽

Β Cell ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Β Cell Function ◽

Kaempferol Glycosides

Download Full-text

VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake

Scientific Reports ◽

10.1038/s41598-020-57599-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Frank Chenfei Ning ◽

Nina Jensen ◽

Jiarui Mi ◽

William Lindström ◽

Mirela Balan ◽

...

Keyword(s):

Pancreatic Islet ◽

Glucose Homeostasis ◽

Lipid Accumulation ◽

Cell Function ◽

Lipid Uptake ◽

Β Cells ◽

Β Cell ◽

Peripheral Tissues ◽

Β Cell Function ◽

Triglyceride Content

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.

Download Full-text

MafB Is Important for Pancreatic β-Cell Maintenance under a MafA-Deficient Condition

Molecular and Cellular Biology ◽

10.1128/mcb.00080-19 ◽

2019 ◽

Vol 39 (17) ◽

Cited By ~ 4

Author(s):

Gulibaikelamu Xiafukaiti ◽

Shayida Maimaiti ◽

Kiyohito Ogata ◽

Akihiro Kuno ◽

Takashi Kudo ◽

...

Keyword(s):

High Fat Diet ◽

Cell Function ◽

Expression Patterns ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Double Knockout ◽

Adult Mice ◽

Pathological Conditions ◽

Β Cell Function

ABSTRACT The pancreatic-islet-enriched transcription factors MafA and MafB have unique expression patterns in β cells in rodents. MafA is specifically expressed in β cells and is a key regulatory factor for maintaining adult β-cell function, whereas MafB plays an essential role in β-cell development during embryogenesis, and its expression in β cells gradually decreases and is restricted to α cells after birth in rodents. However, it was previously observed that MafB started to be reexpressed in insulin-positive (insulin+) β cells in MafA-deficient adult mice. To elucidate how MafB functions in the adult β cell under MafA-deficient conditions, we generated MafA and MafB double-knockout (A0B0) mice in which MafB was specifically deleted from β cells. As a result, the A0B0 mice became more vulnerable to diabetes under a high-fat diet (HFD) treatment, with impaired islet formation and a decreased number of insulin+ β cells because of increased β-cell apoptosis, indicating MafB can take part in the maintenance of adult β cells under certain pathological conditions.

Download Full-text

Effect of a mitochondrial-targeted coenzyme Q analog on pancreatic β-cell function and energetics in high fat fed obese mice

Pharmacology Research & Perspectives ◽

10.1002/prp2.393 ◽

2018 ◽

Vol 6 (3) ◽

pp. e00393 ◽

Cited By ~ 16

Author(s):

Yumi Imai ◽

Brian D. Fink ◽

Joseph A. Promes ◽

Chaitanya A. Kulkarni ◽

Robert J. Kerns ◽

...

Keyword(s):

Cell Function ◽

Coenzyme Q ◽

Pancreatic Β Cell ◽

Obese Mice ◽

High Fat ◽

Β Cell ◽

Β Cell Function

Download Full-text

Herring Milt and Herring Milt Protein Hydrolysate Are Equally Effective in Improving Insulin Sensitivity and Pancreatic Beta-Cell Function in Diet-Induced Obese- and Insulin-Resistant Mice

Marine Drugs ◽

10.3390/md18120635 ◽

2020 ◽

Vol 18 (12) ◽

pp. 635

Author(s):

Yanwen Wang ◽

Sandhya Nair ◽

Jacques Gagnon

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Cell Function ◽

Protein Hydrolysate ◽

High Fat ◽

Β Cell ◽

Insulin Resistant ◽

Β Cell Function ◽

Casein Protein ◽

Dietary Casein

Although genetic predisposition influences the onset and progression of insulin resistance and diabetes, dietary nutrients are critical. In general, protein is beneficial relative to carbohydrate and fat but dependent on protein source. Our recent study demonstrated that 70% replacement of dietary casein protein with the equivalent quantity of protein derived from herring milt protein hydrolysate (HMPH; herring milt with proteins being enzymatically hydrolyzed) significantly improved insulin resistance and glucose homeostasis in high-fat diet-induced obese mice. As production of protein hydrolysate increases the cost of the product, it is important to determine whether a simply dried and ground herring milt product possesses similar benefits. Therefore, the current study was conducted to investigate the effect of herring milt dry powder (HMDP) on glucose control and the associated metabolic phenotypes and further to compare its efficacy with HMPH. Male C57BL/6J mice on a high-fat diet for 7 weeks were randomized based on body weight and blood glucose into three groups. One group continued on the high-fat diet and was used as the insulin-resistant/diabetic control and the other two groups were given the high-fat diet modified to have 70% of casein protein being replaced with the same amount of protein from HMDP or HMPH. A group of mice on a low-fat diet all the time was used as the normal control. The results demonstrated that mice on the high-fat diet increased weight gain and showed higher blood concentrations of glucose, insulin, and leptin, as well as impaired glucose tolerance and pancreatic β-cell function relative to those on the normal control diet. In comparison with the high-fat diet, the replacement of 70% dietary casein protein with the same amount of HMDP or HMPH protein decreased weight gain and significantly improved the aforementioned biomarkers, insulin sensitivity or resistance, and β-cell function. The HMDP and HMPH showed similar effects on every parameter except blood lipids where HMDP decreased total cholesterol and non-HDL-cholesterol levels while the effect of HMPH was not significant. The results demonstrate that substituting 70% of dietary casein protein with the equivalent amount of HMDP or HMPH protein protects against obesity and diabetes, and HMDP is also beneficial to cholesterol homeostasis.

Download Full-text